Irinotecan Action Pathway,Drug Action

Irinotecan is a topoisomerase I inhibitor used in the treatment of cancer. It is hydrolyzed by esterases in the liver, intestine, and cytoplasm into the active metabolite SN-38, which binds to and inhibits the function of topoisomerase I. Topoisomerase I unwinds DNA by making transient single strand breaks that relieves the torsion of supercoiled DNA. In the unwound form, DNA can serve as a template for DNA replication as well as transcription. In the normal state, this effect is transient and the breaks DNA are quickly religated by topoisomerase I itself. SN-38 binding, however, inhibits religation and stabilizes the DNA-topoisomerase I complex in the cleaved DNA form, ultimately leading to breaks in both DNA chains and cell death.


Paclitaxel Action Pathway,Drug Action

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Paclitaxel is an anticancer agent isolated from the bark of the yew tree. It is classified as a microtubule-stabilizing agent and exerts cell killing effects by disrupting mitosis in dividing cells. Microtubules are made up of α- and β- tubulin heterodimers arranged head to tail and assembled to form a cylinder. Microtubules possess complex polymerization dynamics that are essential for movement of chromosomes and proper segregation of daughter cells during mitosis. Paclitaxel binds directly to the inner surface of β-subunits along the length of microtubules. Binding is thought to induce a conformational change in tubulin that increases its affinity for neighbouring molecules. At sufficiently high concentrations, paclitaxel can bind to β-tubulin in a one to one ratio and stimulate microtubule polymerization. At lower clinically relevant drug concentrations, paclitaxel stabilizes microtubules and prohibits further polymerization and depolymerization. Suppression of microtubule dynamics may prevent chromosomes from moving from the spindle poles to the metaphase plate slowing or preventing progression from metaphase to anaphase. Cells enter a state of mitotic arrest from which they may progress to one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur causing cell death. Paclitaxel is susceptible to cellular drug resistance caused by drug efflux via a number of multidrug resistance-associated proteins.


Docetaxel Action Pathway,Drug Action

Docetaxel, a semisynthetic analogue of paclitaxel, is an anticancer agent classified as a microtubule-stabilizing agent. Similar to paclitaxel, it exerts cell killing effects by disrupting mitosis in dividing cells. Microtubules are made up of α- and β- tubulin heterodimers arranged head to tail and assembled to form a cylinder. Microtubules possess complex polymerization dynamics that are essential for movement of chromosomes and proper segregation of daughter cells during mitosis. Docetaxel binds directly to the inner surface of β-subunits along the length of microtubules. Binding is thought to induce a conformational change in tubulin that increases its affinity for neighbouring molecules. At sufficiently high concentrations, docetaxel can bind to β-tubulin in a one to one ratio and stimulate microtubule polymerization. At lower clinically relevant drug concentrations, docetaxel stabilizes microtubules and prohibits further polymerization and depolymerization. Suppression of microtubule dynamics may prevent chromosomes from moving from the spindle poles to the metaphase plate slowing or preventing progression from metaphase to anaphase. Cells enter a state of mitotic arrest from which they may progress to one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur causing cell death. Docetaxel is susceptible to cellular drug resistance caused by drug efflux via a number of multidrug resistance-associated proteins.


Vinblastine Action Pathway,Drug Action

Vinblastine (also named Velban) is a natural alkaloid isolated from the leaves of the Catharanthus roseus (commonly known as the Madagascar periwinkle). Vinblastine are used as chemotherapy medication such as an antimitotic anticancer agent. The mechanism of vinblastine is the inhibition of microtubule dynamics that would cause mitotic arrest and eventual cell death. As a microtubule destabilizing agent, Vinblastine stimulates mitotic spindle destruction and microtubule depolymerization at high concentrations. At lower clinically relevant concentrations, vinblastine can block mitotic progression. Unlike the taxanes, which bind poorly to soluble tubulin, vinblastine can bind both soluble and microtubule-associated tubulin. To be able stabilizing the kinetics of microtule, vinblastine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tublin by the induction of conformational changes of tubulin. Vinblastine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding between vinblastine and solubale tubulin decreases the rate of microtubule dynamics (lengthening and shortening) and increases the duration of attenuated state of microtubules. Therefore, the proper assembly of the mitotic spindle could be prevented; and the tension at the kinetochores of the chromosomes could be reduced. Subsequently, chromosomes can not progress to the spindle equator at the spindle poles. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.


Vincristine Action Pathway,Drug Action

Vincristine (also named leurocristine) is a natural alkaloid isolated from the leaves of the Catharanthus roseus (commonly known as the Madagascar periwinkle). Vincristine are used as chemotherapy medication such as an antimitotic anticancer agent. The mechanism of vincristine is the inhibition of microtubule dynamics that would cause mitotic arrest and eventual cell death. As a microtubule destabilizing agent, Vincristine stimulates mitotic spindle destruction and microtubule depolymerization at high concentrations. At lower clinically relevant concentrations, vincristine can block mitotic progression. Unlike the taxanes, which bind poorly to soluble tubulin, vincristine can bind both soluble and microtubule-associated tubulin. To be able stabilizing the kinetics of microtule, vincristine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tublin by the induction of conformational changes of tubulin. Vincristine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding between vincristine and solubale tubulin decreases the rate of microtubule dynamics (lengthening and shortening) and increases the duration of attenuated state of microtubules. Therefore, the proper assembly of the mitotic spindle could be prevented; and the tension at the kinetochores of the chromosomes could be reduced. Subsequently, chromosomes can not progress to the spindle equator at the spindle poles. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.


Vindesine Action Pathway,Drug Action

Vindesine (also named Eldesine) is a semisynthetic vinca alkaloid. Vindesine are used as chemotherapy medication such as an antimitotic anticancer agent. The mechanism of vindesine is the inhibition of microtubule dynamics that would cause mitotic arrest and eventual cell death. As a microtubule destabilizing agent, vindesine stimulates mitotic spindle destruction and microtubule depolymerization at high concentrations. At lower clinically relevant concentrations, vindesine can block mitotic progression. Unlike the taxanes, which bind poorly to soluble tubulin, vindesine can bind both soluble and microtubule-associated tubulin. To be able stabilizing the kinetics of microtule, vindesine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tublin by the induction of conformational changes of tubulin. Vindesine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding between vindesine and solubale tubulin decreases the rate of microtubule dynamics (lengthening and shortening) and increases the duration of attenuated state of microtubules. Therefore, the proper assembly of the mitotic spindle could be prevented; and the tension at the kinetochores of the chromosomes could be reduced. Subsequently, chromosomes can not progress to the spindle equator at the spindle poles. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.


Vinorelbine Action Pathway,Drug Action

Vinorelbine (also named Navelbine) is a semisynthetic vinca alkaloid. Vinorelbine are used as chemotherapy medication such as an antimitotic anticancer agent. The mechanism of vinorelbine is the inhibition of microtubule dynamics that would cause mitotic arrest and eventual cell death. As a microtubule destabilizing agent, vinorelbine stimulates mitotic spindle destruction and microtubule depolymerization at high concentrations. At lower clinically relevant concentrations, vinorelbine can block mitotic progression. Unlike the taxanes, which bind poorly to soluble tubulin, vinorelbine can bind both soluble and microtubule-associated tubulin. To be able stabilizing the kinetics of microtule, vinorelbine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tublin by the induction of conformational changes of tubulin. Vinorelbine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding between vinorelbine and solubale tubulin decreases the rate of microtubule dynamics (lengthening and shortening) and increases the duration of attenuated state of microtubules. Therefore, the proper assembly of the mitotic spindle could be prevented; and the tension at the kinetochores of the chromosomes could be reduced. Subsequently, chromosomes can not progress to the spindle equator at the spindle poles. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.


Prednisone Action Pathway,Drug Action

Prednisone is a synthetic glucocorticoid that is used clinically for its anti-inflammatory properties. Prednisone is converted to the active metabolite prednisolone in the liver. Prednisolone can diffuse passively across the cell membrane, where it binds to glucocorticoid receptors in the cytoplasm. Upon binding, the glucocorticoid receptor (GR) dissociates from heat shock protein 90, and translocate into the nucleus. In the nucleus, GR dimers can bind to glucocorticoid response element (GRE) in the promoter region of anti-inflammatory genes, which activates their transcription. GRs also inhibit transcription of inflammatory mediators by binding to negative GRE (nGRE). GRs further interact with the transcription factors cAMP-responsive element binding protein and NF-kappa-B, and inihibit their activation of inflammatory gene transcription. GRs also recruit histone deacetylase 2 to inflammatory genes, which leads to DNA condensation at those loci, thus suppressing expression of those genes.


Prednisolone Action Pathway,Drug Action

Prednisolone is a synthetic glucocorticoid that is used clinically for its anti-inflammatory properties. Prednisolone diffuses passively across the cell membrane, where it binds to glucocorticoid receptors in the cytoplasm. Upon binding, the glucocorticoid receptor (GR) dissociates from heat shock protein 90, and translocate into the nucleus. In the nucleus, GR dimers can bind to glucocorticoid response element (GRE) in the promoter region of anti-inflammatory genes, which activates their transcription. GRs also inhibit transcription of inflammatory mediators by binding to negative GRE (nGRE). GRs further interact with the transcription factors cAMP-responsive element binding protein and NF-kappa-B, and inihibit their activation of inflammatory gene transcription. GRs also recruit histone deacetylase 2 to inflammatory gene loci on DNA, which leads to DNA condensation and suppression of gene expression.


Etoposide Action Pathway,Drug Action

Etoposide is an podophyllotoxin derative that is used in the treatment of certain cancers. It inhibits mitosis and induces cell death by acting as a topoisomerase II poison. Topoisomerase II is an enzyme in the nucleus of cells that unwinds DNA by making transient double-stranded breaks, relieving the torsion of supercoiled DNA. In the unwound form, DNA can serve as a template for DNA replication as well as transcription. In the normal state, this effect is transient and the breaks DNA are quickly religated by topoisomerase II itself. Etoposide, however, inhibits religation and stabilizes the DNA-topoisomerase II complex in the cleaved DNA form, ultimately leading to breaks in both DNA chains and cell death.Etoposide is also converted into catechol and o-quinone derivatives in the liver and in lysosomes respectively. These metabolites are highly oxidative and can directly damage DNA, which may also contribute to the drug’s cytotoxic effects.


Teniposide Action Pathway,Drug Action

Teniposide is an podophyllotoxin derative that is used in the treatment of certain cancers. It inhibits mitosis and induces cell death by acting as a topoisomerase II poison. Topoisomerase II is an enzyme in the nucleus of cells that unwinds DNA by making transient double strand breaks, relieving the torsion of supercoiled DNA. In the unwound form, DNA can serve as a template for DNA replication as well as transcription. In the normal state, this effect is transient and the breaks DNA are quickly religated by topoisomerase II itself. Teniposide, however, inhibits religation and stabilizes the DNA-topoisomerase II complex in the cleaved DNA form, ultimately leading to breaks in both DNA chains and cell death.Teniposide is also converted into catechol and o-quinone derivatives in the liver and in lysosomes respectively. These metabolites are highly oxidative and can directly damage DNA, which may also contribute to the drug’s cytotoxic effects.


Lactose Synthesis,Metabolic

Lactose synthesis occurs only in the mammary glands, producing lactose (4-O-B-D-galactosylpyranosyl-a-D-glucopyranoside), the major sugar in milk. Lactose is created by joining two monosaccarides with a B1,4 glycosidic bond. Glucose is first converted to UDP-galactose via the enzyme galactose-1-phosphate uridylyltransferase. UDP-galactose is then transported into the Golgi by the UDP galactose translocator, an antiporter which uses facilitated transport to move UDP galactose into the Golgi and exports UMP. Once inside the Golgi, the UDP galactose and glucose (which moves into the golgi via the GLUT-1 transporter) become substrates for the lactose synthase enzyme complex, comprised of the enzymatic subunit, galactosyltransferase with its regulatory subunit, Alpha-lactalbumin. Lactose synthase creates lactose through bonding galactose from UDP to glucose through a glycosidic bond. Although GT is found in many tissues in the body, Alpha-lactalbumin is only found on the inner surface of the Golgi in the mammary glands, limiting lactose production to the mammaries.


Spermidine and Spermine Biosynthesis,Metabolic

The Spermidine and Spermine Biosynthesis pathway highlights the creation of these cruicial polyamines. Spermidine and spermine are produced in many tissues, as they are involved in the regulation of genetic processes from DNA synthesis to cell migration, proliferation, differentiation and apoptosis. These positiviely charged amines interact with negatively charged phosphates in nucleic acids to exert their regulatory effects on cellular processes. Spermidine originates from the action of spermidine synthase, which converts the methionine derivative S-adenosylmethionine and the ornithine derivative putrescine into spermidine 5'-methylthioadenosine. Spermidine is subsequently processed into spermine by spermine synthase in the presence of the aminopropyl donor, S-adenosylmethioninamine.


Gemcitabine Action Pathway,Drug Action

Gemcitabine is a cytidine analogue used in the treatment of certain cancers. Gemcitabine enters the cell via sodium nucleoside co-transporters (SLC29A1, SLC28A1, and SLC28A3), where it acts through multiple mechanisms to produce a cytotoxic effect. Gemcitabine is phosphorylated into gemcitabine monophosphate by deoxycytidine kinase, which is then subsequently phosphorylated into the diphosphate and triphosphate nucleotides by UMP-CMP kinase and nucleoside diphosphate kinase respectively. Gemcitabine diphosphate inhibits ribonucleoside-diphosphate reductase, a crucial enzyme in the conversion of ribonucleotides into deoxyribonucleotides for DNA synthesis. Gemcitabine triphosphate on the other hand can be incorporated into DNA, causing chain termination. Furthermore, gemcitabine monophosphate can be deaminated into difluoro-deoxyuridine monophosphate, which inhibits thymidylate synthase, an enzyme involved in the production of dTTP for DNA synthesis.


Cyclophosphamide Action Pathway,Drug Action

Cyclophosphamide is an alkylating agent used in the treatment of certain cancers. Following absorption, cyclophosphamide is converted into 4-hydroxyphosphamide by a variety of cytochrome P450 isozymes in the liver. 4-Hydroxyphosphamide is more soluble than cyclophosphamide and is the primary form of the drug that is transported in blood. 4-Hydroxyphosphamide crosses the plasma membrane of the cancer cell and spontaneuosly forms aldophosphamide. This is a reversible reaction. Aldophosphamide can decompose into acrolein and phosphoramide mustard. Phosphoramide mustard is the active alkylating agent and forms alkyl adducts with DNA through a phosphoramide aziridinium intermediate. Alkylation of DNA causes DNA damage and eventually cell death.


Ifosfamide Action Pathway,Drug Action

Ifosfamide is an alkylating agent used in the treatment of certain cancers. Following absorption, ifosfamide is converted into 4-hydroxyifosfamide by a variety of cytochrome P450 isozymes in the liver. 4-Hydroxyifosfamide crosses the plasma membrane of the cancer cell and spontaneuosly forms aldoifosfamide. This is a reversible reaction. Aldoifosfamide can decompose into acrolein and ifosforamide mustard. Ifosforamide mustard is the active alkylating agent and forms alkyl adducts with DNA through an ifosforamide aziridinium intermediate. Alkylation of DNA causes DNA damage and ultimately cell death.


Ethanol Degradation,Metabolic

Ethanol metabolism in humans occurs mainly in the liver, though degradation has also been shown in gastric, pancreatic, and lung tissue. Ethanol degradation occurs via four pathways, three of which are oxidative pathways and are depicted here. The fourth is a nonoxidative pathway which is less well studied but known to produce fatty acid ethyl esters. Each of the three oxidative pathways is differentiated by the mechanism utilized to oxidize ethanol to acetaldehyde in the first step. In the alcohol dehydrogenase mediated ethanol degradation pathway (I), cytoplasmic alcohol dehydrogenase produces the acetaldehyde from the ethanol. In the MEOS mediated ethanol degradation pathway (II), the ethanol enters the endoplasmic reticulum, where the Microsomal Ethanol Oxidising System (MEOS), also know as also known as cytochrome P-450 2E1, does the oxidizing and returns the acetaldehyde to the cytoplasm. In the catalase mediated ethanol degradation pathway (III), the oxidation occurs in the peroxisome via peroxisomal catalase, with the resulting acetaldehyde being released to the cytoplasm. In each of the three oxidative pathways the cytosolic acetaldehyde then enters the mitochondrial compartment, where it is converted to acetate by mitochondrial aldehyde dehydrogenase. The acetate leaves the mitochondria and moves to extra-hepatic tissues for further metabolism. In extra-hepatic cells the acetate is converted to acetyl-CoA via either cytoplasmic or mitochondrial acetyl-CoA synthetase. The alcohol dehydrogenase mediated ethanol degradation pathway (I) is the predominant mechanism of catabolism under conditions of acute alcohol consumption. However, under conditions of chronic ethanol consumption the MEOS mediated ethanol degradation pathway (II) and nonoxidative pathway are induced to assist with ethanol degradation.


Phytanic Acid Peroxisomal Oxidation,Metabolic

Phytanic acid, a branched chain fatty acid, is an important component of fatty acid intake, occuring in meat, fish and dairy products.  Due to its methylation, it cannot be a substrate for acyl-CoA dehydrogenase and cannot enter the mitochondrial beta oxidation pathway.  Phytanic acid is instead activated to its CoA ester form by a CoA synthetase to phytanoyl-CoA, where it can begin the first cycle of alpha oxidation.  Phytanoyl-CoA is a substrate for a specific alpha-hydroxylase (Phytanoyl-CoA hydroxylase), which adds a hydroxyl group to the α-carbon of phytanic acid, creating the 19-carbon homologue, pristanic acid.  Pristanic acid then undergoes further metabolism through beta oxidation.


Refsum Disease,Disease

Adult Refsum Disease (Classic Refsum Disease; Phytanic Acid Oxidase Deficiency; Heredopathia Atactica Polyneurtiformis; Hereditary Motor and Sensory Neuropathy IV; HSMN4; Adult Refsum Disease I; Adult Refsum Disease II), can be caused by mutations in the PHYH (or PAHX) gene, which encodes Phytanoyl-CoA hydroxylase (, the first enzyme in the Phytanic Acid Peroxisomal Oxidation pathway) on chromosome 10 (adult Refsum disease I), and by mutation of the PEX7 gene. A defect in phytanoyl-CoA hydroxylase results in accumulation of phytanic acid in the plasma, as well as low levels of pristanic acid due to the inability for phytanic acid to undergo alpha and beta oxidation. Symptoms include anosmia, ataxia, nystagmus, neurological deterioration and peripheral neuropathy. Adult Refsum disease is distinctly different from Infantile Refsum disease both genetically and phenotypically. Infantile Refsum disease  involves mutations of the PEX1, PEX2 and PEX26 genes.


Threonine and 2-Oxobutanoate Degradation,Metabolic

2-oxobutanoate, also known as 2-Ketobutyric acid, is a 2-keto acid that is commonly produced in the metabolism of amino acids such as methionine and threonine.  Like other 2-keto acids, degradation of 2-oxobutanoate occurs in the mitochondrial matrix and begins with oxidative decarboxylation to its acyl coenzyme A derivative, propionyl-CoA.  This reaction is mediated by a class of large, multienzyme complexes called 2-oxo acid dehydrogenase complexes.  While no 2-oxo acid dehydrogenase complex is specific to 2-oxobutanoate, numerous complexes can catalyze its reaction.  In this pathway the branched-chain alpha-keto acid dehydrogenase complex is depicted.  All 2-oxo acid dehydrogenase complexes consist of three main components: a 2-oxo acid dehydrogenase (E1) with a thiamine pyrophosphate cofactor, a dihydrolipoamide acyltransferase (E2) with a lipoate cofactor, and a dihydrolipoamide dehydrogenase (E3) with a flavin cofactor.  E1 binds the 2-oxobutanoate to the lipoate on E2, which then transfers the propionyl group to coenzyme A, producing propionyl-CoA and reducing the lipoate.  E3 then transfers protons to NAD in order to restore the lipoate.  Propionyl-CoA carboxylase transforms the propionyl-CoA to S-methylmalonyl-CoA, which is then converted to R-methylmalonyl-CoA via methylmalonyl-CoA epimerase.  In the final step, methylmalonyl-CoA mutase acts on the R-methylmalonyl-CoA to produce succinyl-CoA.


Nateglinide Action Pathway,Drug Action

Nateglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, nateglinide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Nateglinide stimulate insulin secretion in a glucose-sensitive manner by inhibiting ATP-dependent potassium channels. As a result, there tends to be a lesser likelihood of hypoglycemia with nateglinide therapy compared to sulfonylureas.


Repaglinide Action Pathway,Drug Action

Repaglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, repaglinide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Repaglinide stimulate insulin secretion in a glucose-sensitive manner by inhibiting ATP-dependent potassium channels. As a result, there tends to be a lesser likelihood of hypoglycemia with repaglinide therapy compared to sulfonylureas.


Homocysteine Degradation,Metabolic

Homocysteine is an amino acid and homologue of cysteine that appears in the body as a result of the degradation of methionine. In mammals, homocysteine is used to biosynthesize cysteine via the following pathway. First the enzyme cystathionine beta-synthetase irreversibly condenses homocysteine with L-serine, forming L-cystathionine. The L-cystathionine is then cleaved by cystathionine gamma-lyase, producing 2-oxobutanoate, L-cysteine, and ammonia. The 2-oxobutanoate is further broken down via the 2-oxobutanoate degradation pathway, producing citric acid cycle intermediates, while the L-cysteine goes to the cysteine metabolism pathway. The homocysteine degradation pathway composes a part of the larger methionine metabolism pathway.


Fatty Acid Biosynthesis,Metabolic

The biosynthesis of fatty acids primarily occurs in liver and lactating mammary glands. The entire synthesis process which produces palmitic acid occurs on a multifunctional dimeric protein Fatty Acid Synthase (FA) in the cytosol. The production of palmitic acid can be summarized as the successive addition of two carbons to an initial acetyl moiety primer. After 7 cycles palimitic acid is released.  The synthesis starts with the sequential transfer of a primer substrate, acetyl-CoA, to the nucleophilic serine residue of the acyltransferase domain of FA. The acetyl moiety is then transferred to the Acyl Carrier Protein (ACP) domain of FA, then finally to the active site of the beta-ketoacyl synthase domain. A chain extender substrate, molonyl-CoA, is transferred to the nucleophilic serine residue of the acyltransferase domain and subsequently to the ACP domain. The acetyl moiety is extend by a condensation reaction, catalysed by the beta-ketoacyl synthase domain, that produces a new Carbon-Carbon bound, this reaction is coupled to a decarboxylation resulting in the production of carbon dioxide. Subsequently beta-ketoacyl condensation product is reduced to a saturated acyl moiety through the step wise action on the beta-ketoacyl reductase, beta-hydroxyacyl dehydrase and enoyl reductase domains respectively. This saturated acyl moiety is then transfer back to the active site of the beta-ketoacyl synthase domain, another molonyl-CoA is loaded and the process repeats. The addition of molonyl moieties occurs 7 times after which the final product is released by that action of thioesterase domain. The final product is 16 carbon long palmitic acid.


Lactose Degradation,Metabolic

Lactose degradation (Lactose metabolism) shows the breakdown of alpha lactose into its constituent sugars, which are then utilized by the body as an energy source. Alpha-Lactose is the major sugar present in milk and the main source of energy supplied to the newborn mammalian in its mother’s milk. Lactose is also an important osmotic regulator of lactation. It is digested by the intestinal lactase, an enzyme expressed in newborns. Its activity declines following weaning. Lactase hydrolyzes alpha lactose into D-glucose and D-galactose, which are actively transported into the intestinal epithelial cells via the SGLT1 (GLUT1) cotransporter. GLUT1 actively transports glucose and galactose with 2 sodium ions. A sodium/potassium ATPase makes ATP by moving three sodium ions to the blood per two potassium ions that cross into the epithelial cell, giving the GLUT1 transporter energy to work. D-glucose and D-galactose diffuse into the blood, facilitated by the SLC2A2 transporter on the basolateral membrane on the intestinal epithelial cells. The sugars are then transported to liver.


Lactose Intolerance,Disease

Lactose Intolerance (Hypolactasia, Adult type; Adult Lactase Deficiency; Disaccaride Intolerance III; Lactase Persistence, Included) is caused by a deceased expression of intestinal lactase, an enzyme expressed in newborns.  Its activity declines following weaning.  Lactase deficiency is present in up to 80 percent of blacks and Latinos, and up to 100 percent of American Indians and Asians.  Persons with lactose intolerance are unable to digest significant amounts of lactose.  Due to the reduced lactase level, lactose present in dairy products cannot be digested in the small intestine and instead are fermented by intestinal bacteria.  Common symptoms include abdominal pain and bloating, excessive flatus, and watery stool following the ingestion of foods containing lactose.  Excess lactose may be present in the urine.


Pyruvaldehyde Degradation,Metabolic

This Pyruvaldehyde degradation pathway (Methylglyoxal degradation;2-oxopropanal degradation), also known as the glyoxalase system, is probably the most common pathway for the degradation of pyruvaldehyde (methylglyoxal), a potentially toxic metabolite due to its interaction with nucleic acids and other proteins. Pyruvaldehyde is formed in low concentrations by glycolysis, fatty acid metabolism and protein metabolism. Pyruvaldehyde is catalyzed by the glyoxylase system, composed of the enzymes lactoylglutathione lyase (glyoxalase I) and glyoxylase II. Glyoxalase I catalyes the isomerization of the spontaneously formed hemithioacetal adduct between glutathione and pyruvaldehyde into S-lactoylglutathione. S-lactoylglutathione is then catalyzed by glyoxalase II into D-lactic acid and glutathione. D-lactic acid is then catalyzed by an unknown quinol in the membrane to pyruvic acid, which then enters pyruvate metabolism.


Glibenclamide Action Pathway,Drug Action

Glibenclamide is a sulfonylurea drug used in the treatment of type 2 diabetes. Glibenclamide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Glibenclamide stimulates insulin secretion by directly inhibiting ATP-dependent potassium channels.


Gliclazide Action Pathway,Drug Action

Gliclazide is a sulfonylurea drug used in the treatment of type 2 diabetes. Gliclazide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Gliclazide stimulates insulin secretion by directly inhibiting ATP-dependent potassium channels.


Inositol Phosphate Metabolism,Metabolic

Inositol phosphates are a group of molecules that are important for a number of cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation. Inositol phsosphates consist of an inositol (a sixfold alcohol of cyclohexane) phosphorylated at one or more positions. There are a number of different inositol phosphates found in mammals, distinguishable by the number and position of the phosphate groups. Inositol phosphate can be formed either as a product of phosphatidylinositol phosphate metabolism or from glucose 6-phosphate via the enzyme inositol-3-phosphate synthase 1. Conversion between the different types of inositol phosphates then occurs via a number of specific inositol phosphate kinases and phosphatases, which add (kinase) or remove (phosphatase) phosphate groups. The differing roles of the numerous inositol phosphates means that their metabolism must be tightly regulated. This is done via the localization and activation/deactivation of the various kinases and phosphatases, which can be found in the cytoplasm, nucleus or endoplasmic reticulum. The unphosphorylated inositol ring can be used to produce phosphoinositides through phosphatidylinositol phosphate metabolism.


Phosphatidylinositol phosphates, or phosphoinositides, are intracellular signaling lipids. Seven different phosphoinositides have been identified in mammals, each distinguished by the number and/or position of the phosphate groups on the inositol ring. The inositol can be mono-, di-, or triphosphorylated, with the remaining phosphoinositides being isomers of these three forms. Phosphoinositides regulate a variety of signal transduction processes, thus playing a number of important roles in the cell, such as actin cytoskeletal reorganization, membrane transport, and cell proliferation. They may also affect protein localization, aggregation, and activity by acting as secondary messengers. The ability of the cell to recognize the different types of phosphoinositides as different cellular signals means that their synthesis and metabolism must be tightly regulated. Synthesis begins with the attachment of an inositol phosphate head group to diacylglycerol via a phospholipase C enzyme, creating a phosphoinositide. Conversion between the different types of phosphoinositides is then done by a number of specific phosphoinositide kinases and phosphatases, which add (kinase) and remove (phosphatase) phosphates from the inositol ring. The specific localization and regulation of the phosphoinositide kinases and phosphatases thus controls the activity of the phosphoinositides. While the phosphoinositides are always located in the membrane, their particular kinases and phosphatases may be found in the cytoplasm or in the membrane of the cell or cell organelles.


Vitamin K Metabolism,Metabolic

Vitamin K describes a group of lipophilic, hydrophobic vitamins that exist naturally in two forms (and synthetically in three others): vitamin K1, which is found in plants, and vitamin K2, which is synthesized by bacteria. Vitamin K is an important dietary component because it is necessary as a cofacter in the activation of vitamin K dependent proteins. Metabolism of vitamin K occurs mainly in the liver. In the first step, vitamin K is reduced to its quinone form by a quinone reductase such as NAD(P)H dehydrogenase. Reduced vitamin K is the form required to convert vitamin K dependent protein precursors to their active states. It acts as a cofactor to the integral membrane enzyme vitamin K-dependent gamma-carboxylase (along with water and carbon dioxide as co-substrates), which carboxylates glutamyl residues to gamma-carboxy-glutamic acid residues on certain proteins, activating them. Each converted glutamyl residue produces a molecule of vitamin K epoxide, and certain proteins may have more than one residue requiring carboxylation. To complete the cycle, the vitamin K epoxide is returned to vitamin K via the vitamin K epoxide reductase enzyme, also an integral membrane protein. The vitamin K dependent proteins include a number of important coagulation factors, such as prothrombin. Thus, warfarin and other coumarin drugs act as anticoagulants by blocking vitamin K epoxide reductase.


Carnitine Synthesis,Metabolic

Carnitine is an ammonium compound that exists in two stereoisomers, of which only L-carnitine is biologically active. Carnitine can be obtained from dietary sources and also biosynthesized. It is necessary for fatty acid oxidation, transporting fatty acids from the cystosol to the mitochondria, where they are broken down via the citric acid cycle to release energy. Carnitine is synthesized from lysine residues in existing proteins. These residues are methylated using lysine methyltransferase enzymes and methyl groups from S-adenosylmethionine, then removed from the protein via hydrolysis. In the next step, the N6,N6,N6-trimethyl-L-lysine is converted to 3-hydroxy-N6,N6,N6-trimethyl-L-lysine t via the mitochondrial enzyme trimethyllysine dioxygenase. The 3-hydroxy-N6,N6,N6-trimethyl-L-lysine is then cleaved to 4-trimethylammoniobutanal and glycine, likely by an aldose identical to serine hydroxymethyltransferase. Next, 4-trimethylammoniobutanal is oxidized by the 4-trimethylaminobutyraldehyde dehydrogenase protein to 4-trimethylammoniobutanoic acid. Finally, 4-trimethylammoniobutanoic acid is transformed into L-carnitine via the enzyme gamma-butyrobetaine dioxygenase. The reactions in the carnitine synthesis pathway occur ubiquitously in the human body with the exception of the last step, as the gamma-butyrobetaine dioxygenase enzyme is found only in the liver and kidney (and at very low levels in the brain). The produced carnitine is then carried to other tissue via a number of transport systems.


Transfer of Acetyl Groups into Mitochondria,Metabolic

Acetyl-CoA is an important molecule, which is precursor to HMG CoA, which is a vital component in cholesterol and ketone synthesis. Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Acetyl-CoA is made in the mitochondria by metabolizing fatty acids, and the oxidation of pyruvate of acetyl-CoA. When the body has an excess of ATP, the energy in acetyl-Coa can be stored in the form of fatty acids. Acetyl-CoA must cross the mitochondrial membrane to the cytosol, where fatty acid synthesis takes place. Acetyl-CoA is combined with oxalacetic acid by the enzyme citrate synthase, creating citric acid. Citric acid is then transported out of the mitochondria, to the cytosol, where the enzyme citrate lyase converts citric acid back into acetyl-CoA and oxalacetic acid. Malate dehydrogenase reduces oxalacetic acid to malate, which then is either transported back into the mitochondria by the malate-alpha ketoglutarate transporter or oxidized to pyruvate by malic enzyme. Pyruvate can then be transported back into the mitochondria and undergo decarboxylation into oxalacetic acid. Malate can also be used to create NADH by the conversion of malate to oxalacetic acid by malate dehydrogenase.


Trehalose Degradation,Metabolic

Trehalose, also known as mycose or tremalose, is a sugar consisting of two 1-1 alpha bonded glucose molecules. It is produced by some plants, bacteria, fungi and invertebrates, and can be used as a source of energy, such as for flight in insects, and as a survival mechanism to avoid freezing and dehydration.After ingestion in the intestine lumen, trehalose can interact with trehalase, which exists in the brush border of the cells there. In a reaction that also requires a water molecule, it is broken. These are then transported into the epithelial cells along with a sodium ion by a sodium/glucose cotransporter, which can bring glucose up its gradient along with sodium moving down its gradient. Once inside the cell, the glucose can then be transported out of the basolateral membrane by a solute carrier family 2 facilitated glucose transporter. From there, the glucose enters the blood stream, and is transported to liver hepatocytes. Once in the liver, glucokinase can use the energy and phosphate from a molecule of ATP to form glucose-6-phosphate, which then goes on to start the process of glycolysis.


Degradation of Superoxides,Metabolic

Reactive oxygen species (ROS) are formed by the normal metabolic process of oxygen. Examples are superoxide, oxygen ions and peroxides and can be of either organic or inorganic origin. ROS are highly reactive due to unpaired valence shell electrons, and can cause serious damage to cells and cell organelles. The environment also may cause ROS to form, from sources such as drought, air pollutants, UV light, cold temperatures, and external chemicals. An organic example of ROS being formed is during the beta oxidation of fatty acids, or photorespiration in photosynthetic organisms. Aerobic organisms who produce energy through the electron transport chain in mitochondria produce ROS as a byproduct. ROS damage commmonly includes DNA damage, lipid peroxidation, oxidation of amino acids in proteins, and oxidatively inactivating enzymes by oxidation of cofactors. Most aerobic organisms have adapted to this dangerous condition of life, and have a system of enzymes and scavenging free radicals. Enzymes such as are essential for defense against ROS, and include superoxide dismutases (SODs) and hydroperoxidase (CAT). Superoxide dismutases are the primary method of disposal of ROS, and convert superoxide radicals to hydrogen peroxide and water. Catalase attacks the hydrogen peroxide produced by SODs, and converts it into oxygen and water. In skin cells, 5,6 dihydroxyindole-2-carboxylic acid oxidase in the melanosome membranes breaks down hydrogen peroxide into water and oxygen.


Capecitabine Action Pathway,Drug Action

Capecitabine is a fluoropyrimidine anticancer drug. After absorption, it is metabolized in the liver to the intermediate 5’-deoxy-5-fluorouridine, which is subsequently converted into 5-fluorouracil (5-FU) by intracellular thymidine phosphorylase. 5-FU exerts cytotoxic effects on the cell by direct incorporation into DNA and RNA as well as by inhibiting thymidylate synthase. Since thymidine phosphorylase is present at 3-10 fold higher concentration in cancer cells compared normal cells, capecitabine’s cytotoxic effect is selective for cancer cells.


Fluorouracil Action Pathway,Drug Action

Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a fluoropyrimidine anticancer drug. By injection into a vein, it is used to treat colon cancer, esophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer. As a cream, it is used for actinic keratosis, basal cell carcinoma, and skin warts. Fluorouracil is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system (Wikipedia). Fluorouracil exerts cytotoxic effects on the cell by direct incorporation into DNA and RNA as well as by inhibiting thymidylate synthase.


Tamoxifen Action Pathway,Drug Action

Tamoxifen is a selective estrogen modulator (SERM) used in the treatment of estrogen-sensitive breast cancer. Tamoxifen itself only has weak anti-estrogen effects and must be converted into more active metabolites to have therapeutic activity. Metabolism takes place in the liver and is carried out primarily by cytochrome P450 enzymes. Tamoxifen is hydroxylated by CYP2D6 and demethylated by CYP3A4 and CYP3A5, producing the active metabolites 4-hydroxytamoxifen and endoxifen. These metabolites inhibit estrogen binding to estrogen receptors in breast cancer cells, which in turn inhibit tumour growth.


Erlotinib Action Pathway,Drug Action

Erlotinib is an anti-EGFR drug used in the treatment of some cancers. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Erlotinib acts as an anticancer drug by binding to the intracellular tyrosine kinase domain of the EGFR and blocking its activity. This in turn inhibits downstream signalling and prevents tumour growth.


Gefitinib Action Pathway,Drug Action

Gefitinib is an anti-EGFR drug used in the treatment of some cancers. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Gefitinib acts as an anticancer drug by binding to the intracellular tyrosine kinase domain of the EGFR and blocking its activity. This in turn inhibits downstream signalling and prevents tumour growth.


Cetuximab Action Pathway,Drug Action

Cetuximab is an anti-EGFR drug used in the treatment of some cancers. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Cetuximab acts as an anticancer drug by binding to the extracellular domain of the EGFR and preventing its activation by epidermal growth factor. This in turn inhibits downstream signalling and prevents tumour growth.


Panitumumab Action Pathway,Drug Action

Panitumumab is an anti-EGFR drug used in the treatment of some cancers. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Panitumumab acts as an anticancer drug by binding to the extracellular domain of the EGFR and preventing its activation by epidermal growth factor. This in turn inhibits downstream signalling and prevents tumour growth.


Trastuzumab Action Pathway,Drug Action

Trastuzumab is an anti-EGFR drug used in the treatment of HER2-positive breast cancer. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Trastuzumab acts as an anticancer drug by binding to the extracellular domain of the EGFR and preventing its activation by epidermal growth factor. This in turn inhibits downstream signalling and prevents tumour growth.


DNA Replication Fork,Metabolic

DNA is composed of two long and complementary strands, with a backbone on the outside and nucleotides in the middle. During replication the two strands of DNA separate; the resulting structure is called the replication fork. The replication fork forms because enzymes called helicases surround the DNA strands and break the hydrogen bonds which hold them together. The result is that two long branches, almost like fork prongs, each of which is a DNA strand. Replication of DNA has two main different processes. Because DNA is replicated in the 5' to 3' direction, and because both DNA strands in the replication fork are negative mirror images of each other, and because the replication fork is created on only one direction down the length of the DNA, two types of replication strands are formed: the leading and the lagging strand. These strands are so named by the way in which DNA polymerase reads the original DNA strand and attaches the complementary nucleotides as it makes its way along the chain. Because the direction of the movement of the replication fork, and the direction of the addition of nucleotides in the leading strand is the same, the process is continuous.That is, a polymerase is able to read the DNA and add the matching nucleotide bases to it continuously. In prokaryotes DNA polymerase III is responsible for creating the leading strand. The lagging strand is oriented in the opposite direction to the leading strand. Thus, replication of the lagging strand occurs in the opposing direction to that of the leading strand and the replication fork. As a result, replication of the lagging strand is a slower and more complicated process than that of the leading strand. Thus it is seen to lag behind the leading strand (hence the name).


Nucleotide Excision Repair ,Metabolic

In order to pass genetic information from one generation to the next, all organisms must accurately replicate their genomes during each cell division. This includes the nuclear genome and mitochondrial and chloroplast genomes. These are normally replicated with high fidelity that is achieved through the action of accurate DNA repair. Nucleotide Excision Repair is one os several mechanisms of DNA repair.  Nucleotide excision repair (NER) operates on base damage caused by exogenous agents (such as mutagenic and carcinogenic chemicals and photoproducts generated by sunlight exposure) that cause alterations in the chemistry and structure of the DNA duplex . Such damage is recognized by a protein called XPC, which is stably bound to another protein called HHRAD23B (R23). The binding of the XPC–HHRAD23 heterodimeric subcomplex is followed by the binding of several other proteins (XPA, RPA, TFIIH and XPG). Of these, XPA and RPA are believed to facilitate specific recognition of base damage. TFIIH is a subcomplex of the RNA polymerase II transcription initiation machinery which also operates during NER. It consists of six subunits and contains two DNA helicase activities (XPB and XPD) that unwind the DNA duplex in the immediate vicinity of the base damage. This local denaturation generates a bubble in the DNA, the ends of which comprise junctions between duplex and single-stranded DNA. The subsequent binding of the ERCC1–XPF heterodimeric subcomplex generates a completely assembled NER multiprotein complex. XPG is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 3’ to the site of base damage. Conversely, the ERCC1–XPF heterodimeric protein is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 5’ to the site of base damage. This bimodal incision generates an oligonucleotide fragment 27–30 nucleotides in length which includes the damaged base. This fragment is excised from the genome, concomitant with restoring the potential 27–30 nucleotide gap by repair synthesis. Repair synthesis requires DNA polymerases or , as well as the accessory replication proteins PCNA, RPA and RFC. The covalent integrity of the damaged strand is then restored by DNA ligase. Collectively, these biochemical events return the damaged DNA to its native chemistry and configuration. ERCC1, excision repair cross-complementing 1; PCNA, proliferating cell nuclear antigen; POL, polymerase; RFC, replication factor C; RPA, replication protein A; TFIIH, transcription factor IIH; XP, xeroderma pigmentosum.


Plasmalogen Synthesis,Metabolic

Plasmalogens are a class of phospholipids found in animals.  Plasmalogens are thought to influence membrane dynamics and fatty acid levels, while also having roles in intracellular signalling and as antioxidants.  Plasmalogens consist of a glycerol backbone with an vinyl-ether-linked alkyl chain at the sn-1 position, an ester-linked long-chain fatty acid at the sn-2 position, and a head group attached to the sn-3 position through a phosphodiester linkage.  It is the vinyl-ether-linkage that separates plasmalogens from other phospholipids.   Plasmalogen biosynthesis begins in the peroxisomes, where the integral membrane protein dihydroxyacetone phosphate acyltransferase (DHAPAT) catalyzes the esterification of the free hydroxyl group of dihydroxyacetone phosphate (DHAP) with a molecule any of long chain acyl CoA.  Next, alkyl-DHAP synthase, a peroxisomal enzyme associated with DHAPAT, replaces the fatty acid on the DHAP with a long chain fatty alcohol.  The third step of plasmalogen biosynthesis is catalyzed by the enzyme acyl/alkyl-DHAP reductase, which is found in the membrane of both the peroxisome and endoplasmic reticulum (ER).  Acyl/alkyl-DHAP reductase uses NADPH as a cofactor to reduce the ketone of the 1-alkyl-DHAP using a classical hydride transfer mechanism.  The remainder of plasmalogen synthesis occurs using enzymes in the ER.  Lysophosphatidate acyltransferases (LPA-ATs) transfer the acyl component of a polyunsaturated acyl-CoA to the the 1-alkyl-DHAP, creating a 1-alkyl-2-acylglycerol 3-phosphate.  The phosphate is then removed by lipid phosphate phosphohydrolase I (PAP-I), and the head group is attached by a choline/ethanolaminephosphotransferase.  The majority of plasmalogens have either ethanolamine or choline as a headgroup, although a small amount of serine and inositol-linked ether-phospholipids can also be found.  In the final step, the vinyl-ether linkage is created by plasmanylethanolamine desaturase, which catalyzes the formation of a double bond in the alkyl chain of the plasmalogen.


Mitochondrial Beta-Oxidation of Short Chain Saturated Fatty Acids,Metabolic

Beta-oxidation is the major degradative pathway for fatty acid esters in humans. Fatty acids and their CoA esters are found throughout the body, playing roles such as components of cellular lipids, regulators of enzymes and membrane channels, ligands for nuclear receptors, precursor molecules for hormones, and signalling molecules. Beta-oxidation occurs in the peroxisomes and mitochondria, the latter of which is depicted here. Whether beta-oxidation starts in the mitochondria or the peroxisome depends on the length of the fatty acid. Medium to long chain fatty acids go directly to the mitochondria, whereas very long chain fatty acids (>22 carbons) may be first metabolized down to octanyl-CoA in the peroxisomes and then transported to the mitochondria for the remainder of the oxidation. Beta-oxidation begins with fatty acids first being activated by an acyl-coenzyme A synthetase. This process uses ATP to produce a reactive fatty acyl adenylate which then reacts with coenzyme A to produce a fatty acyl-CoA. Short and medium chain fatty acids can enter the mitochondria directly via diffusion where they are activated in the mitochondrial matrix by acyl-coenzyme A synthetases. Long chain fatty acids must be activated in the outer mitochondrial membrane then transported as a carnatine complex into the mitochondria. A double bond is formed between C-2 and C-3 to produce trans-Δ2-enoyl-CoA which is catalyzed by acyl-CoA-dehydrogenases in the mitochondria. Enoyl CoA hydratase then hydrates the double bond between C-2 and C-3 to produce a L-beta-hydroxyacyl CoA which then has its hydroxyl group converted to a keto group to produce beta-ketoacyl CoA. Finally, the beta-ketoacyl CoA is cleaved by beta-ketothiolase and a thiol group is inserted between C-2 and C-3 to reduce the acyl-CoA and produce acetyl-CoA. Acetyl-CoA can then enter the citric acid cycle.


Mitochondrial Beta-Oxidation of Medium Chain Saturated Fatty Acids,Metabolic

Beta-oxidation is the major degradative pathway for fatty acid esters in humans. Fatty acids and their CoA esters are found throughout the body, playing roles such as components of cellular lipids, regulators of enzymes and membrane channels, ligands for nuclear receptors, precursor molecules for hormones, and signalling molecules. Beta-oxidation occurs in the peroxisomes and mitochondria, the latter of which is depicted here. Whether beta-oxidation starts in the mitochondria or the peroxisome depends on the length of the fatty acid. Medium to long chain fatty acids go directly to the mitochondria, whereas very long chain fatty acids (>22 carbons) may be first metabolized down to octanyl-CoA in the peroxisomes and then transported to the mitochondria for the remainder of the oxidation.  Beta-oxidation begins with activation of fatty acids by an acyl-coenzyme A synthetase. ATP is used to produce reactive fatty acyl adenylate that can then react with coenzyme A to produce a fatty acyl-CoA. Short and medium chain fatty acids can enter the mitochondria directly via diffusion where they are activated in the mitochondrial matrix by acyl-coenzyme A synthetases. In the first step of the beta-oxidation cycle, a double bond between C-2 and C-3 is formed, producing a trans-Δ2-enoyl-CoA. This is catalyzed by acyl-CoA-dehydrogenases in the mitochondria, which have forms specific to the different lengths of fatty acids. In the second step, enoyl CoA hydratase hydrates the newly formed double bond between C-2 and C-3, producing an L-beta-hydroxyacyl CoA. Next, L-beta-hydroxyacyl CoA dehydrogenase converts the hydroxyl group into a keto group, producing a beta-ketoacyl CoA. In the fourth and final step, the enzyme beta-ketothiolase cleaves the β-ketoacyl CoA and inserts the thiol group of another CoA between C-2 and C-3, reducing the acyl-CoA by 2 carbons and generating acetyl-CoA. The final two steps also have enzymatic forms specific to short chain fatty acids. Additionally, there is a trifunctional protein complex with enzymatic activity capable of performing all of the final 3 steps (hydratase, dehydrogenase, thiolase) in medium to very long chain fatty acids. This four step cycle repeats, removing 2 carbons from the fatty acid each time until it becomes acetyl-CoA. Acetyl-CoA is necessary for the citric acid cycle, among other cellular processes.


Mitochondrial Beta-Oxidation of Long Chain Saturated Fatty Acids,Metabolic

Fatty acids and their CoA esters are found throughout the body, playing roles such as components of cellular lipids, regulators of enzymes and membrane channels, ligands for nuclear receptors, precursor molecules for hormones, and signalling molecules.  Beta-oxidation occurs in the peroxisomes and mitochondria, the latter of which is depicted here.  Whether beta-oxidation starts in the mitochondria or the peroxisome depends on the length of the fatty acid.  Medium to long chain fatty acids go directly to the mitochondria, whereas very long chain fatty acids (>22 carbons) may be first metabolized down to octanyl-CoA in the peroxisomes and then transported to the mitochondria for the remainder of the oxidation.   Beta-oxidation begins with activation of fatty acids by an acyl-coenzyme A synthetase.  ATP is used to produce reactive fatty acyl adenylate that can then react with coenzyme A to produce a fatty acyl-CoA.  Short and medium chain fatty acids can enter the mitochondria directly via diffusion where they are activated in the mitochondrial matrix by acyl-coenzyme A synthetases.  In the first step of the beta-oxidation cycle, a double bond between C-2 and C-3 is formed, producing a trans-Δ2-enoyl-CoA.  This is catalyzed by acyl-CoA-dehydrogenases in the mitochondria, which have forms specific to the different lengths of fatty acids.  In the second step, enoyl CoA hydratase hydrates the newly formed double bond between C-2 and C-3, producing an L-beta-hydroxyacyl CoA.  Next, L-beta-hydroxyacyl CoA dehydrogenase converts the hydroxyl group into a keto group, producing a beta-ketoacyl CoA.  In the fourth and final step, the enzyme beta-ketothiolase cleaves the β-ketoacyl CoA and inserts the thiol group of another CoA between C-2 and C-3, reducing the acyl-CoA by 2 carbons and generating acetyl-CoA.  The final two steps also have enzymatic forms specific to short chain fatty acids.  Additionally, there is a trifunctional protein complex with enzymatic activity capable of performing all of the final 3 steps (hydratase, dehydrogenase, thiolase) in medium to very long chain fatty acids.  This four step cycle repeats, removing 2 carbons from the fatty acid each time until it becomes acetyl-CoA.  Acetyl-CoA is necessary for the citric acid cycle, among other cellular processes.


Dimethylglycine Dehydrogenase Deficiency (DMGDH deficiency; Dimethylglycinuria) phenotype in the catabolism of choline, catalyzing the oxidative demethylation of dimethylglycine (DMG) to form sarcosine. A defect in DMGDH results in the accumulation of N,N-dimethylglycine and creatinine kinase in serum, and N,N-dimethylglycine in urine. Symptoms of this disease include an unusual odor and muscle weakness.


DOPA-Responsive Dystonia,Disease

Dopa-responsive dystonia is a disorder that involves involuntary muscle contractions, tremors, and other uncontrolled movements (dystonia). The features of this condition range from mild to severe. This form of dystonia is called dopa-responsive dystonia because the signs and symptoms typically improve with sustained use of a medication known as L-Dopa. Over time, affected individuals often develop a group of movement abnormalities called parkinsonism. These abnormalities include unusually slow movement (bradykinesia), muscle rigidity, tremors, and an inability to hold the body upright and balanced (postural instability). Mutations in the GCH1 gene are the most common cause of dopa-responsive dystonia. Less often, mutations in the TH or SPR gene cause this condition.


Hyperphenylalaninemia Due to Guanosine Triphosphate Cyclohydrolase Deficiency,Disease

Hyperphenylalaninemia is the high presence of phenylalanine in the system/blood caused by a genetic mutation. In this case a missense error in the gene which encodes GTP cyclohydrolase. Consequently, this form of hyperphenylalaninemia is also called GTP cyclohydrolase I deficiency and/or dopa-responsive dystonia. It is an autosomal recessive mutation.The mutation results in a reduction in the production of BH4 which is a necessary component in the reaction which transforms phenylalanine to other products in the body.Common symptoms include: abnormality of eye mpvement, choreoathetosis, dysphagia, dystonia, excessive salivation, hypekinesis, lethargy, limb hyptertonia, seizures, tremor, among others.


Hyperphenylalaninemia Due to 6-Pyruvoyltetrahydropterin Synthase Deficiency (ptps),Disease

BH4-deficient hyperphenylalaninemia has several causes. One such cause is a PTS deficiency resultant from a genetic mutation. (In particular, a mutation in the gene encoding 6-pyruvoyl-tetrahydropterin synthase.)  The mutation is autosomal recessive. Common symptoms include: muscular hypotonia, ataxia, bradykinesia, choreoathetosis, depressivity, dysphagia, hyperkinesis, hypsarrhythmia, myoclonus, and others. BH4 is a cofactor involved in many things and associated with neurotransmitter synthesis. In short, the reduction of levels of BH4 creates issues in the metabolism of phenylalanine. This cascade of reactions produces the aforementioned symptoms.


Hyperphenylalaninemia Due to DHPR-Deficiency,Disease

Hyperphenylalaninemia due to dihydropteridine reductase deficiency (DHPR) is the high presence of phenylalanine in the system/blood caused by a genetic mutation. More specificially, mutations in the QDPR gene are the root cause of the condition. One observes that such a mutation results in an error encoding a reductase enzyme, and from there a chain reaction of effects lead to the observed effects of the disease. The mutation is autosomal recessive. When tetrahydrobiopterin levels drop, the breakdown of many several amino acids, such as phenylalanine, is reduced and as a result their levels in the blood augment. Symptoms of hyperphenylalaninemia due to dihydropteridine reductase deficiency include: dysphagia, global development delay, microcephaly, and intellectual disability (among others). Treatment consists of BH4 supplements as well as other medical treatments.


Segawa Syndrome,Disease

Dopa-responsive dystonia (autosomal dominant Segawa syndrome) is caused by heterozygous mutation in the gene encoding GTP cyclohydrolase I. GTP cyclohydrolase I is rate-limiting in the conversion of GTP to tetrahydrobiopterin (BH4), the cofactor for tyrosine hydroxylase, which in turn is the rate-limiting enzyme for dopamine synthesis. Patients are characterized by childhood onset dystonia of the legs, progressing to parkinsonism and pseudo-pyramidal deficits, or in adult life with parkinsonism and pseudo-pyramidal signs.  Treatment with levodopa typically resolves the symptoms.


Sepiapterin reductase deficiency results from a metabolic disorder; namely, the underproduction of Sepiapterin. The cause of this underproduction is an autosomal recessive genetic mutation in the SPR gene. This gene is responsible for Sepiapterin production, and naturally, when the gene malfunctions the production of this metabolite is altered leading to a range of effects on the body. In this case, some symptoms of Sepiapterin Deficiency are: motor and speech delay, axial hypotonia, dystonia, weakenss microcephaly, dysarthria, autonomic dysfunction, oculogyric crises, drowsiness, among others.


Galactosemia II (GALK),Disease,Galactokinase deficiency or Galactosemia type II is caused by mutation in the GALK1 gene on chromosome 17q24. Galactokinase deficiency is an autosomal recessive disorder which causes cataract formation in children not maintained on a lactose-free diet. Cataract formation is the result of osmotic phenomena caused by the accumulation of galactitol in the lens.


Galactosemia III,Disease

Galactosemia III (GALE deficiency or UDP-Galactose-4-Epimerase deficiency) is caused by homozygous or compound heterozygous mutation in the UDP-galactose-4-epimerase gene (GALE).  Patients with GALE deficiency may be at increased risk for cataracts. Patients also exhibit symptoms similar to classic galactosemia, including jaundice, vomiting, hypotonia, failure to thrive, hepatomegaly, moderate generalized amino aciduria and marked galactosuria. Although a galactose-free diet is recommended in galactokinase deficiency and in classic galactosemia patients with galactose epimerase deficiency cannot utilize the endogenous pathway for synthesis of UDP-galactose, making them dependent on exogenous galactose; thus, a galactose-restricted rather than a galactose-free diet is recommended in the management of this disorder.


Tyrosine Hydroxylase Deficiency,Disease

Mutations in the Tyrosine hydroxylase (TH) gene cause TH deficiency. The TH gene provides instructions for making the enzyme tyrosine hydroxylase, which takes part in the pathway that produces a group of chemical messengers called catecholamines, namely dopamine, norepinephrine and epinephrine. Dopamine transmits signals to help the brain control physical movement and emotional behavior. Norepinephrine and epinephrine are involved in the autonomic nervous system. Mutations in the TH gene result in reduced activity of the tyrosine hydroxylase enzyme. As a result, the body produces less dopamine, norepinephrine and epinephrine. These catecholamines are necessary for normal nervous system function, and changes in their levels contribute to the abnormal movements, autonomic dysfunction, and other neurological problems seen in people with TH deficiency.


Dopamine beta-hydroxylase deficiency (or norepinephrine deficiency) is caused by mutation in the gene encoding dopamine beta-hydroxylase. Clinical features include orthostatic hypotension, ptosis, nasal stuffiness, and a neonatal history of delayed eye opening. Noradrenaline and adrenaline are generally not detectable in plasma, urine, and cerebrospinal fluid, but dopamine is increased 7- to 12-fold in plasma, 4-fold in urine, and 20-fold in CSF. Treatment with dihydroxyphenylserine has been shown to reduce symptoms and signs of postural hypotension and increase plasma levels of noradrenaline.


Metcaptolactate-cysteine disulfiduria (MCDU) is an autosomal disorder that leads to the loss of function of the enzyme mercaptopyruvate sulfurtransferase. The condition is characterized by the urinary excretion of large amounts of a sulfur-containing amino acid, which is beta-mercaptolactate-cysteine disulfide. Patients exhibit a low IQ, grand mal seizures, flattened nasal bridge, and an excessively arched palate.


5-Oxoprolinase Deficiency,Disease,5-oxoprolinase deficiency can be caused by heterozygous or homozygous mutation in the OPLAH gene (5-Oxoprolinase).  Patients are relatively asymptomatic but they do exhibit high levels of urinary excretion of 5-oxoproline. Patients also exhibit plasma 5-oxoproline levels of about 0.18 mM or higher.  Patients tend to exhibit transient hypoglycemia.


Gamma-glutamyltranspeptidase deficiency is characterized by glutathionemia and glutathionuria. Gamma-glutamyltranspeptidase acts as a glutathionase and catalyzes the transfer of the glutamyl moiety of glutathione to a variety of amino acids and dipeptide acceptors. Patients with this disorder may exhibit mild mental retardation, asthma and easy bruising.


Malonyl CoA decarboxylase deficiency is an autosomal disorder is caused by mutation in the malonyl-CoA decarboxylase gene. The characteristic phenotype of this condition is quite variable, but may include developmental delay in early childhood, seizures, hypotonia, diarrhea, vomiting, metabolic acidosis, hypoglycemia, ketosis, abnormal urinary compounds, lactic acidemia, and hypertrophic cardiomyopathy.


Hypophosphatasia,Disease

Infantile hypophosphatasia is caused by homozygous or compound heterozygosity mutation in the gene encoding tissue-nonspecific alkaline phosphatase. It is an inborn error of metabolism characterized clinically by defective bone mineralization that can be fatal early in infancy.  Three more or less distinct types can be identified: (1) type 1 with onset in utero or in early postnatal life, craniostenosis, severe skeletal abnormalities, hypercalcemia, and death in the first year or so of life; (2) type 2 with later, more gradual development of symptoms, moderately severe 'rachitic' skeletal changes and premature loss of teeth; (3) type 3 with no symptoms, the condition being determined on routine studies. Heterozygotes excrete phosphoethanolamine in the urine and suffer early loss of teeth. Serum and urinary phosphoethanolamine are typically elevated and serum pyridoxal-PO4 concentrations are often markedly elevated.


Hyperornithinemia with Gyrate Atrophy (HOGA),Disease

Gyrate atrophy of the choroid and retina (also called Gyrate atrophy, OAT deficiency, ornithine aminotransferase deficiency, ornithine keto acid aminotransferase deficiency) is an autosomal recessive disorder caused by homozygous or compound heterozygous mutation in the OAT gene (Ornithine aminotransferase).  It is clinically characterized by progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy.  Ornithine levels are typically 10 to 20 times higher than normal in plasma, urine, spinal fluid, and aqueous humor.  Some cases of OAT deficiency are vitamin B6 (pyridoxine) -responsive.


Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder caused by a mutation in the SLC25A15 gene, which encodes the mitochondrial ornithine transporter. It is clinically characterized by mental retardation, spastic paraparesis and myoclonic seizures associated with hyperornithinemia, hyperammonemia, and homocitrullinemia. Ornithine supplementation and restricted protein intake appears to be useful in the treatment of HHH syndrome.


Arginine:glycine amidinotransferase deficiency is an inherited disorder that primarily affects the brain. People with this disorder have mild to moderate intellectual disability and delayed speech development. Some affected individuals develop autistic behaviors that affect communication and social interaction. They may experience seizures, especially when they have a fever. Children with arginine:glycine amidinotransferase deficiency may not gain weight and grow at the expected rate (failure to thrive), and have delayed development of motor skills such as sitting and walking. Affected individuals may also have weak muscle tone and tend to tire easily.


Cholesteryl Ester Storage Disease,Disease

Lysosomal acid lipase deficiency (also known as LIPA deficiency or cholesteryl ester storage disease [CESD] or Wolman disease) is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the LIPA gene (lysosomal acid lipase) on chromosome 10q24-q25.  Wolman disease is an early-onset fulminant disorder of infancy with massive infiltration of the liver, spleen, and other organs by macrophages filled with cholesteryl esters and triglycerides.  Death occurs early in life.  CESD is a milder, later-onset disorder with primary hepatic involvement by macrophages engorged with cholesteryl esters.  This slowly progressive visceral disease has a very wide spectrum of involvement ranging from early onset with severe cirrhosis to later onset of more slowly progressive hepatic disease with survival into adulthood.


Hyper-IgD Syndrome,Disease

Hyperimmunoglobulinemia D with recurrent fever (commonly abbreviated as HIDS) is a periodic fever syndrome originally described in 1984 by the internist Prof. Jos van der Meer, then at Leiden University Medical Centre. No more than 300 cases have been described worldwide. HIDS is one of a number of periodic fever syndromes. It is characterised by attacks of fever, arthralgia, skin lesions including cyclical mouth ulcers, and diarrhea. Laboratory features include an acute phase response (elevated CRP and ESR) and markedly elevated IgD (and often IgA), although cases with normal IgD have been described. (Wikipedia)


Mevalonic Aciduria,Disease

Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often. Mevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).


Wolman Disease,Disease

In Wolman's disease excessive amounts of cholesterol ester in the liver are present mainly in the macrophages of the reticuloendo- thelial system. The livler in Wiolman's disease contains triglyceride at 10 to 20 times the normal concentratlon, most of whilch is present in hepatocytes. The first case of Wolman's disease was published in 1956 by M. Wolman, M.D., reporting a case of a 2 month old girl who had been admitted to the Hadassah University Hospital. Lysosomal   acid   lipase/acid   cholesteryl   ester   hydrolase (LAL/ACEH) plays an important role in cellular processing of plasma lipoproteins and thus contributes to both the homeostatic control of plasma lipoprotein levels and the prevention of cellular lipid overload. Wolman's Disease results from severely reduced levels of the enzyme lysosomal   acid   lipase/acid   cholesteryl   ester   hydrolase.


Xanthinuria Type I,Disease

Xanthinuria Type I is a condition caused by an autosomal recessive mutation. The condition was discovered (though not diagnosed) in 1817, when stones formed of almost pure xanthine were first identified by Marcet. The symptoms arise because of a malfunction in the production of xanthine oxidase. It is a rare . It is characterized by a loss of oxidase  such as in serum and the uric acid found in peepee. As a result, the opposite is true for the presence of xanthine and hypoxanthine. They will be found in the latter and former in increased quantities. Although the condition can cause a wide range of symptoms including renal xanthine stones, what occurs most of the time is that xanthinuria is asymptomatic and diagnosis is product of chance.


Xanthinuria Type II,Disease

Xanthinuria, also known as xanthine oxidase deficiency, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase. Classic xanthinuria is a rare metabolic defect concerning the final reactions of purine catabolism. There are two types of the disorder: type I results from xanthine dehydrogenase (XDH) deficiency, while type II is characterized by lack of both XDH and aldehyde oxidase activity. Both types are clinically similar and are characterized by elevated xanthine concentration in body fluids that can lead to xanthine crystallisation. The most common manifestation of the disease is urolithiasis, but in most cases xanthinuria remains asymptomatic and the diagnosis is accidental.


Cystathioninuria, also called cystathionase deficiency, is an autosomal recessive metabolic disorder that results in an excess of cystathionine in the urine. It is associated with a congenital dysfunction of the enzyme cystathionase, or acquired deficiency of vitamin B6 which is essential for the function of this enzyme. The latter is usually related to an overall deficiency of all the B-complex vitamins.


Carnitine-acylcarnitine translocase (CACT) deficiency is a condition that prevents the body from using certain fats for energy, particularly during periods without food (fasting). Signs and symptoms of this disorder usually begin soon after birth and may include breathing problems, seizures, and an irregular heartbeat (arrhythmia). Affected individuals typically have low blood sugar (hypoglycemia) and a low level of ketones, which are produced during the breakdown of fats and used for energy. Together these signs are called hypoketotic hypoglycemia. People with CACT deficiency also usually have excess ammonia in the blood (hyperammonemia), an enlarged liver (hepatomegaly), and a weakened heart muscle (cardiomyopathy). Many infants with CACT deficiency do not survive the newborn period. Some affected individuals have a less severe form of the condition and do not develop signs and symptoms until early childhood. These individuals are at risk for liver failure, nervous system damage, coma, and sudden death.


Glucose-6-phosphate dehydrogenase deficiency is a genetic disorder that occurs most often in males. This condition mainly affects red blood cells, which carry oxygen from the lungs to tissues throughout the body. In affected individuals, a defect in an enzyme called glucose-6-phosphate dehydrogenase causes red blood cells to break down prematurely. This destruction of red blood cells is called hemolysis. The most common medical problem associated with glucose-6-phosphate dehydrogenase deficiency is hemolytic anemia, which occurs when red blood cells are destroyed faster than the body can replace them. This type of anemia leads to paleness, yellowing of the skin and whites of the eyes (jaundice), dark urine, fatigue, shortness of breath, and a rapid heart rate. In people with glucose-6-dehydrogenase deficiency, hemolytic anemia is most often triggered by bacterial or viral infections or by certain drugs (such as some antibiotics and medications used to treat malaria). Hemolytic anemia can also occur after eating fava beans or inhaling pollen from fava plants (a reaction called favism). Glucose-6-dehydrogenase deficiency is also a significant cause of mild to severe jaundice in newborns. Many people with this disorder, however, never experience any signs or symptoms.


Ribose-5-phosphate isomerase (RPI) deficiency, is a genetic disorder caused by mutations in the RPIA gene that codes for RPI. RPI is an enzyme that is involved in the pentose phosphate pathway as part of carbohydrate degradation. It reversibly converts D-ribulose 5-phosphate into D-ribose 5-phosphate. In the case of this disorder, RPI functions partially in tissues, because if the gene was simply non-functional, it would likely be lethal. This means that a specific type of mutation needs to occur for this disorder to occur, leading to it being the rarest disease in the world, with only three confirmed cases. In the first known case, the patient had one allele containing a frameshift mutation, which led to a truncated protein, while the other allele contained a missense mutation. This combination meant that activity of RPI was found to vary across tissues and cell types.Characteristics of the RPI deficiency include higher ribitol and arabitol levels in a metabolic profile, as well as differences in polyol profiles. There are other symptoms, including leukoencephalopathy and neuropathy, which may be caused by a toxic accumulation of ribitol and arabitol, or a potential lack of ribose-5-phosphate in RNA synthesis.


Transaldolase Deficiency,Disease

Transaldolase deficiency, also known as Eyaid syndrome or TALDO deficiency, is a desease caused by homozygous or compound heterozygous mutations in the TALDO1 gene that encodes for transaldolase. The mutation found in one study was a base pair deletion leading to a premature truncation of the protein, preventing its activity in the cell. Other mutations reported in other studies include other deletions or homozygous base pair substitutions that cause a misfolded and non-functional protein.Transaldolase is an enzyme that reversibly converts D-erythrose 4-phosphate and fructose 6-phosphate to D-sedoheptulose 7-phosphate and D-glyceraldehyde 3-phosphate, as a part of the pentose phosphate pathway. Almost all affected patients show hepatosplenomegaly, liver dysfunction, low counts for all blood cell types, cardiac defects, and come from consanguinous families. They also show dysmorphic features, including a triangular face, low set ears, and a wide mouth with thin lips. Other signs include abnormal concentrations of polyols in urine and plasma, as well as ribose-, xylulose-, and ribulose-5-phosphate being elevated in urine.


3-Hydroxyisobutyric Acid Dehydrogenase Deficiency,Disease,3-Hydroxyisobutyric aciduria  (3-hydroxyisobutyric acid dehydrogenase deficiency) is a rare entity and affected individuals display a range of clinical manifestations including dysmorphic features and neurodevelopmental problems in the majority of patients.


3-Hydroxyisobutyric Aciduria,Disease

3-Hydroxyisobutyric aciduria, a disorder of valine metabolism, has been found in a boy in whom the clinical picture was that of a typical organic acidemia with repeated episodes of ketoacidosis requiring admission to hospital and parenteral fluid therapy, along with impressive failure to thrive and chronic lactic acidemia. The excretion of 3-hydroxyisobutyric acid ranged from 170 to 390 mmol/mol of creatinine. The administration of valine increased this to 18,700 mmol/mol of creatinine and reproduced the clinical picture of ketoacidosis. Concentrations of free carnitine were low, and esterified carnitine was elevated. Treatment with carnitine and a diet restricted in protein appeared to be beneficial.


Isobutyryl-CoA dehydrogenase (IBD) deficiency is a condition that disrupts the breakdown of certain proteins. Normally, proteins from food are broken down into parts called amino acids. Amino acids can be further processed to provide energy for growth and development. People with IBD deficiency have inadequate levels of an enzyme that helps break down a particular amino acid called valine. Most people with IBD deficiency are asymptomatic, which means they do not have any signs or symptoms of the condition. A few children with IBD deficiency have developed features such as a weakened and enlarged heart (dilated cardiomyopathy), weak muscle tone (hypotonia), and developmental delay. This condition may also cause low numbers of red blood cells (anemia) and very low blood levels of carnitine, which is a natural substance that helps convert certain foods into energy. The range of signs and symptoms associated with IBD deficiency remains unclear because very few affected individuals have been reported.


Isovaleric Acidemia,Disease

Isovaleric acidemia is a rare disorder in which the body is unable to process certain proteins properly. It is classified as an organic acid disorder, which is a condition that leads to an abnormal buildup of particular acids known as organic acids. Abnormal levels of organic acids in the blood (organic acidemia), urine (organic aciduria), and tissues can be toxic and can cause serious health problems. Mutations in the IVD gene cause isovaleric acidemia.


Fabry Disease,Disease

Fabry disease is an inherited disorder that results from the buildup of a particular type of fat, called globotriaosylceramide, in the body's cells. Beginning in childhood, this buildup causes signs and symptoms that affect many parts of the body. Characteristic features of Fabry disease include episodes of pain, particularly in the hands and feet (acroparesthesias); clusters of small, dark red spots on the skin called angiokeratomas; a decreased ability to sweat (hypohidrosis); cloudiness of the front part of the eye (corneal opacity); problems with the gastrointestinal system; ringing in the ears (tinnitus); and hearing loss. Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Some affected individuals have milder forms of the disorder that appear later in life and affect only the heart or kidneys. Fabry disease is caused by mutations in the GLA gene.


Krabbe Disease,Disease

Krabbe disease (also called globoid cell leukodystrophy) is a degenerative disorder that affects the nervous system. It is caused by the shortage (deficiency) of an enzyme called galactosylceramidase. This enzyme deficiency impairs the growth and maintenance of myelin, the protective covering around certain nerve cells that ensures the rapid transmission of nerve impulses. Krabbe disease is part of a group of disorders known as leukodystrophies, which result from the loss of myelin (demyelination). This disorder is also characterized by the abnormal presence of globoid cells, which are globe-shaped cells that usually have more than one nucleus. The symptoms of Krabbe disease usually begin before the age of 1 year (the infantile form). Initial signs and symptoms typically include irritability, muscle weakness, feeding difficulties, episodes of fever without any sign of infection, stiff posture, and slowed mental and physical development. As the disease progresses, muscles continue to weaken, affecting the infant's ability to move, chew, swallow, and breathe. Affected infants also experience vision loss and seizures.


Hyperlysinemia II or Saccharopinuria,Disease

Saccharopinuria (also known as: saccharopinemia, saccharopine dehydrogenase deficiency, and alpha-aminoadipic semialdehyde synthase deficiency, hyperlysinemia type II) is an autosomal recessive disease characterized by high concentrations of saccharopine in the plasma and urine.It is caused by the deficiency of the enzyme alpha-aminoadipic semialdehyde synthase (AASS). AASS contains a lysine ketoglutarate reductase (LKR) domain which catalyzes the conversion of lysine to saccharopine, and a saccharapine dehydrogenase (SDH) domain which catalyzes the conversion of saccharopine to alpha-aminoadipic semialdehyde. Hyperlysinemia type II is categorized by the loss in SDH activity but the preservation of significant amounts of LKR activity. This leads to the accumulation of saccharopine. The loss of both enyzmatic functions is categorized as hyperlysinemia type I.


D-Glyceric Acidura,Disease

D-glyceric aciduria is a rare inborn error of serine and fructose metabolism that was first described in 1974. Most affected individuals have presented with neurological symptoms. The molecular basis of D-glyceric aciduria is largely unknown; possible causes that have been discussed are deficiencies of D-glycerate dehydrogenase, triokinase, and D-glycerate kinase. In 1989, van Schaftingen has reported decreased D-glycerate kinase activity in the liver of a single patient with D-glyceric aciduria. Mutations in the GLYCTK gene are reported to be the cause of D-glycerate kinase deficiency.


Familial Lipoprotein Lipase Deficiency,Disease

Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia (British English) involves abnormally elevated levels of any or all lipids and/or lipoproteins in the blood. It is the most common form of dyslipidemia (which also includes any decreased lipid levels). Hyperlipidemias are divided in primary and secondary subtypes. Primary hyperlipidemia is usually due to genetic causes (such as a mutation in a receptor protein), while secondary hyperlipidemia arises due to other underlying causes such as diabetes. Lipid and lipoprotein abnormalities are common in the general population, and are regarded as a modifiable risk factor for cardiovascular disease due to their influence on atherosclerosis. In addition, some forms may predispose to acute pancreatitis.


Sulfite Oxidase Deficiency,Disease

Sulfite oxidase deficiency (SOD) is a disorder, an autosomal recessive disease. In classic SOD, it is usually identified a few days after the birth of an affected individual, and is recognizable through characteristic dysmorphic features, seizures, and other signs of progressive encephalopathy. Patients also have ocular lenses that are dislocated, and usually die within a few months of being born. In late- onset SOD, the disorder is identified only in the later months, usually 6-18 months, of the child’s life by a delay or regression of neurological progress. This disorder is very rare, but the actual prevalence is not known. It can be diagnosed through a sulfite test strip in urine or by a skin fibroblast culture, which will indicate an absence of sulfite oxidase.


Monoamine Oxidase-A Deficiency (MAO-A),Disease

Momoamine oxidase A (MAO-A) deficiency, or Brunner syndrome, is an X-linked recessive genetic disorder caused by a mutation in the MAOA gene that encodes for monoamine oxidase A. As such it is almost exclusively found in men.MAO-A is an enzyme that catalyzes the deamination of amines such as epinephrine, dopamine and tyramine, as part of the tyrosine metabolism pathway. In this disorder, some neurotransmitters such as serotonin and dopamine build up in the brain due to their inability to be properly metabolized. Since serotonin helps to regulate emotions and mood, with epinephrine and norepinephrine regulating stress, the unnecessary presence of the chemicals in the brain can lead to poor impulse control, aggression and other effects. The buildup of chemicals may also damage the brain, leading to a lower IQ in individuals with this disorder. In addition, foods containing the compounds that cannot be broken down, such as tyramine, can cause episodes of increased symptoms in the patients.In the subpathway that converts dopamine to homovanillic acid, there are two instances of MAO-A that are inactivated in this disorder, both in different branches. The first reaction converts dopamine to 3,4-dihydroxyphenylacetaldehyde, while the second converts 3-methoxytyramine to homovanillin. With the inactivation of MAO-A, 3-methoxytyramine builds up as there are no reactions that use it, and both of these paths lead to a decrease in the concentration of homovanillic acid, as there are no other reactions present that produce it. Another reaction, this time converting tyramine to homovanillin, is also prevented by the lack of MAO-A, which leads to an accumulation of tyramine in the body.In another branch of tyrosine metabolism, the absence of MAO-A prevents the oxidation of norepinephrine and epinephrine into 3,4-dihydroxymandelaldehyde. Its absence also prevents the oxidative deamination of metanephrine and normetanephrine into 3-methoxy-4-hydroxyphenylglycolaldehyde. As this is no longer produced, it leads to a decrease in the concentration of vanillylmandelic acid, which is produced from 3-methoxy-4-hydroxyphenylglycolaldehyde in a reaction catalyzed by aldehyde dehydrogenase.