Pyrimidine Metabolism,Metabolic

Pyrimidines are heterocyclic aromatic organic compounds similar to benzene and pyridine. Cytosine, thymine, and uracil are pyrimidine derivatives. Synthesis of the pyrimidines is less complex than that of the purines, since the base is much simpler This pathway depicts a number of processes including pyrimidine nucleotide biosynthesis, pyrimidine degradation and pyrimidine salvage. Pyrimidine nucleotide biosynthesis begins with carbamoyl phosphate. The carbamoyl phosphate used for pyrimidine nucleotide synthesis is derived from glutamine and bicarbonate and is catalyzed by carbamoyl phosphate synthetase II (CPS-II). Subsequently carbamoyl phosphate is incorporated into the pyrimidine nucleotide biosynthesis pathway through the action of aspartate transcarbamoylase, ATCase which generates carbamoyl aspartate. This is then converted to dihydroorotic acid via carbamoyl aspartate dehydrogenase, which is then converted to orotic acid via dihydroorotate dehydrogenase. The enzyme orotate phosphoribosyltransferase incorporate PRPP to produce orotidine monophosphate (OMP) which is converted to UMP (uridine monopohophsate) via orotidine-5’-phosphate carboxylase. Following completion of UMP synthesis it can be phosphorylated to UTP and utilized as a substrate for CTP synthase for the synthesis of CTP. Specifically, UMP is phosphorylated twice to yield UTP. The first phosphorylation is catalyzed by uridylate kinase and the second by ubiquitous nucleoside diphosphate kinase. Finally UTP is aminated by the action of CTP synthase, generating CTP. Uridine nucleotides are also the precursors for de novo synthesis of the thymine nucleotides. The de novo pathway to thymidine nucleotdie synthesis first requires the use of deoxyUMP from the metabolism of either UDP or CDP. The deoxyUMP is converted to deoxyTMP by the action of thymidylate synthase. The methyl group is donated by N5,N10-methylene THF. In order for the thymidylate synthase reaction to continue, THF must be regenerated from DHF. This is accomplished through the action of dihydrofolate reductase (DHFR). THF is then converted to N5,N10-THF via the action of serine hydroxymethyl transferase. The synthesis of pyrimidines differs in two significant ways from that of purines. First, the ring structure is assembled as a free base, not built upon PRPP. Second, there is no branch in the pyrimidine synthesis pathway. The salvage pathway to dTTP synthesis involves the enzyme thymidine kinase which can use either thymidine or deoxyuridine as a substrate. Uracil can be salvaged to form UMP through the concerted action of uridine phosphorylase and uridine kinase. Formation of dTMP, by salvage of dTMP requires the action of thymine phosphorylase and thymidine kinase while the salvage of deoxycytidine is catalyzed by deoxycytidine kinase. Deoxyadenosine and deoxyguanosine are also substrates for deoxycytidine kinase. In terms of the catabolism of pyrimidines, they are ultimately degraded to CO2, H2O, and urea. Cytosine can be broken down to uracil which can be further broken down to N-carbamoyl-beta-alanine and then to beta-alanine. Thymine is broken down into β-aminoisobutyrate. The β-alanine and β-aminoisobutyrate serve as -NH2 donors in the transamination of α-ketoglutarate to glutamate. A subsequent reaction converts the products to malonyl-CoA or methylmalonyl-CoA (which is converted to succinyl-CoA and can be shunted to the TCA cycle).


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Beta Oxidation of Very Long Chain Fatty Acids,Metabolic

Fatty acid degradation in most organisms occurs primarily via the beta-oxidation cycle.  In mammals, beta-oxidation occurs in both mitochondria and peroxisomes, whereas plants and most fungi harbor the beta-oxidation cycle only in the peroxisomes.  However, the oxidation ceases at octanyl CoA.  It is believed that very long chain (greater than C-22) fatty acids undergo initial oxidation in peroxisomes which is followed by mitochondrial oxidation.  One significant difference is that oxidation in peroxisomes is not coupled to ATP synthesis.  Instead, the high-potential electrons are transferred to O2, which yields H2O2.  The enzyme catalase, found exclusively in peroxisomes, converts the hydrogen peroxide into water and oxygen.  Peroxisomal β-oxidation also requires enzymes specific to the peroxisome and to very long fatty acids.  There are three key differences between the enzymes used for mitochondrial and peroxisomal β-oxidation: beta-oxidation in the peroxisome requires the use of a peroxisomal carnitine acyltransferase (instead of carnitine acyltransferase I and II used by the mitochondria) for transport of the activated acyl group into the peroxisome.  The first oxidation step in the peroxisome is catalyzed by the enzyme acyl CoA oxidase.  The beta-ketothiolase used in peroxisomal beta-oxidation has an altered substrate specificity, different from the mitochondrial beta-ketothiolase.  In mitochondria, the beta-oxidation pathway includes four reactions that occur in repeating cycles with each fatty acid molecule.  In each cycle, a fatty acid is progressively shortened by two carbons as it is oxidized and its energy captured by the reduced energy carriers NADH and FADH2.  At the end of each cycle of four reactions, one acetyl-CoA two-carbon unit is released from the end of the fatty acid, which then goes through another round of beta-oxidation, continuing to oxidize and shorten even-chain fatty acids until they are entirely converted to acetyl-CoA.  The acetyl-CoA generated in beta-oxidation enters the TCA cycle, where it is further oxidized to CO2, producing more reduced energy carriers, NADH and FADH2.  These carriers produced in the TCA cycle, along with those produced directly in beta-oxidation, transfer their energy to the electron transport chain where they drive the creation of the proton gradient that supports mitochondrial ATP production.  Another destination of acetyl-CoA is the production of ketone bodies by the liver that are transported to tissues like the heart and brain for energy.


Urea Cycle,Metabolic

About 80% of the body’s excreted nitrogen is in the form of urea which is also largely made in the liver, in a series of reactions that are distributed between the mitochondrial matrix and the cytosol. The series of reactions that form urea is known as the Urea Cycle (Ornithine Cylce) or the Krebs-Henseleit Cycle. The essential features of the urea cycle reactions and their metabolic regulation are as follows: Arginine from the diet or from protein breakdown is cleaved by the cytosolic enzyme arginase, generating urea and ornithine. In subsequent reactions of the urea cycle a new urea residue is built on the ornithine, regenerating arginine and perpetuating the cycle. Ornithine arising in the cytosol is transported to the mitochondrial matrix, where ornithine transcabamoylase catalyzes the condensation of ornithine with carbamoyl phosphate, producing citrulline. The energy for the reaction is provided by the high-energy anhydride of carbamoyl phosphate. The product, citrulline, is then transported to the cytosol, where the remaining reactions of the cycle take place. The synthesis of citrulline requires a prior activation of carbon and nitrogen as carbamoyl phosphate (CP). The activation step requires 2 equivalents of ATP and the mitochondrial matrix enzyme carbamoyl phosphate synthetase-I (CPS-I). In a 2-step reaction, catalyzed by cytosolic argininosuccinate synthetase, citrulline and aspartate are condensed to form argininosuccinate. The reaction involves the addition of AMP (from ATP) to the amido carbonyl of citrulline, forming an activated intermediate on the enzyme surface (AMP-citrulline), and the subsequent addition of aspartate to form argininosuccinate. Arginine and fumarate are produced from argininosuccinate by the cytosolic enzyme argininosuccinate lyase. In the final step of the cycle arginase cleaves urea from aspartate, regenerating cytosolic ornithine, which can be transported to the mitochondrial matrix for another round of urea synthesis. The fumarate, generated via the action of arginiosuccinate lyase, is reconverted to aspartate for use in the argininosuccinate synthetase reaction.


Tryptophan Metabolism,Metabolic

This pathway depicts the metabolic reactions and pathways associated with tryptophan metabolism in animals. Tryptophan is an essential amino acid. This means that it cannot be synthesized by humans and other mammals and therefore must be part of the diet. Unlike animals, plants and microbes can synthesize tryptophan from shikimic acid or anthranilate. As one of the 20 proteogenic amino acids, tryptophan plays an important role in protein biosynthesis through the action of tryptophanyl-tRNA synthetase. As shown in this pathway, tryptophan can be linked to the tryptophanyl-tRNA via either the mitochondrial or cytoplasmic tryptophan tRNA ligases. Also shown in this pathway map is the conversion of tryptophan to serotonin (a neurotransmitter). In this process, tryptophan is acted upon by the enzyme tryptophan hydroxylase, which produces 5-hydroxytryptophan (5HTP). 5HTP is then converted into serotonin (5-HT) via aromatic amino acid decarboxylase. Serotonin, in turn, can be converted into N-acetyl serotonin (via serotonin-N-acetyltransferase) and then melatonin (a neurohormone), via 5-hydroxyindole-O-methyltransferase. The melatonin can be converted into 6-hydroxymelatonin via the action of cytochrome P450s in the endoplasmic reticulum. Serotonin has other fates as well. As depicted in this pathway it can be converted into N-methylserotonin via Indolethylamine-N-methyltransferase (INMT) or it can be converted into formyl-5-hydroxykynurenamine via indoleamine 2,3-dioxygenase. Serotonin may also be converted into 5-methoxyindoleacetate via a series of intermediates including 5-hydroxyindoleacetaldehyde and 5-hydroxyindoleacetic acid. Tryptophan can be converted or broken down into many other compounds as well. It can be converted into tryptamine via the action of aromatic amino acid decarboxylase. The resulting tryptamine can then be converted into indoleacetaldehyde via kynurenine 3-monooxygenase and then into indoleacetic acid via the action of aldehyde dehydrogenase. Tryptophan also leads to the production of a very important compound known as kynurenine. Kynurenine is synthesized via the action of tryptophan 2,3-dioxygnase, which produces N-formylkynurenine. This compound is converted into kynurenine via the enzyme known as kynurenine formamidase (AFMID). Kynurenine has at least 3 fates. First, kynurenine can undergo deamination in a standard transamination reaction yielding kynurenic acid. Secondly, kynurenine can undergo a series of catabolic reactions (involving kynureninase and kynurenine 3-monooxygenase) producing 3-hydroxyanthranilate plus alanine. In this reaction, kynureninase catabolizes the conversion of kynurenine into anthranilic acid while kynurenine—oxoglutarate transaminase (also known as kynurenine aminotransferase or glutamine transaminase K, GTK) catabolizes its conversion into kynurenic acid. The action of kynurenine 3-hydroxylase on kynurenic acid leads to 3-hydroxykynurenine. The oxidation of 3-hydroxyanthranilate converts it into 2-amino-3-carboxymuconic 6-semialdehyde, which has two fates. It can either degrade to form acetoacetate or it can cyclize to form quinolate. Most of the body’s 3-hydroxyanthranilate leads to the production of acetoacetate (a ketone body), which is why tryptophan is also known as a ketogenic amino acid. An important side reaction in the liver involves a non-enzymatic cyclization into quinolate followed by transamination and several rearrangements to yield limited amounts of nicotinic acid, which leads to the production of a small amount of NAD+ and NADP+.


Retinol Metabolism,Metabolic

Retinol is part of the vitamin A family, and is known as vitamin A1, and in a dietary context it is a type of preformed vitamin A. As with other preformed vitamin A's, it can be obtained from animal sources, with the highest concentrations coming from animal liver, with other sources being fish and dairy products. Other forms of vitamin A include retinal, its aldehyde form, retinoic acid, its acid form, and reinyl ester, its ester form. Additionally, herbivores and omnivores can obtain provitamin A from things such as alpha-, beta- and gamma-carotene, which can be converted to retinol as needed by the body.Retinol can be used in the body to form retinyl ester via diacylglycerol O-acyltransferase 1 and acyl-CoA wax akcohol acyltransferase 1 which both use acetyl-CoA as a reactant and produce CoA in addition to the retinyl ester. IT can also be produced by lecithin retinol acyltransferase, which uses a phosphatidylcholine molecule, and produces glycerophosphocholine. All of these reactions take place in the endoplasmic reticulum. Retinyl ester can also be converted back to retinol by patatin-like phospholipase domain-containing protein 4 as the enzyme in a reaction that also converts a diacylglycerol to a triacylglycerol. Alternately, retinyl ester can interact with retinoid isomerohydrolase to form 11-cis-retinol.11-cis-retinol can be converted to retinyl palmitate by either diacylglycerol O-acyltransferase 1 or acyl-CoA wax alcohol acyltransferase 1 in the endoplasmic reticulum, which both add the acetyl group onto 11-cis-retinol, forming CoA as a side product. Alternatively, retinyl palmitate can be formed by lecithin retinol acyltransferase, which takes a molecule of phosphatidylcholine, and produces glycerophosphocholine in addition to the retinyl palmitate.Rhodopsin, a photosensitive protein found in the retina, can be converted to bathorhodopsin, which has previously been known as prelumirhodopsin. This conversion is caused by the absorption of light into the retinal portion of the protein complex, which then isomerizes, forcing the protein to change shape to accomodate this. Bathorhodopsin almost immediately converts to lumirhodopsin, which then converts to metarhodopsin, and at this point, the retinal is in its all-trans configuration. All-trans retinal can also be formed from 11-cis-retinaldehyde, also known as 11-cis-retinal, via dehydrogenase/reductase SDR family member 4 or retinol dehydrogenase 12 in the cell, as well as retinol dehydrogenases 8 and 16, short-chain dehydrogenase/reductase 3 or dehydrogenase/reductase SRD family member 9 in the endoplasmic reticulum. Two molecules of retinal can also be formed from beta-carotene, after its interaction with betabeta-carotene 15,15'-monooxygenase, or from retinol via retinol dehydrogenase 11 in the endoplasmic reticulum. Additionally, 11-cis-retinaldehyde can reversibly form all-trans retinal via interaction with alcohol dehydrogenase 1A. 11-cis-retinaldehyde is also in the conformation found in rhodopsin, and can be used to create more rhodopsin complexes. 11-cis-retinaldehyde can also be converted to 11-cis-retinol by retinol dehydrogenase in the endoplasmic reticulum.Retinol can also isomerize and form 9-cis-retinol, which can then be reversibly oxidized to form 9-cis-retinal by interacting with either retinol dehydrogenase 11 or dehydrogenase/reductase SDR family member 4. 9-cis-retinal can then be further oxidized to 9-cis-retinoic acid by retinal dehydrogenase 1 or 2. 9-cis-retinoic acid can also be formed from the isomerization of all-trans retinoic acid, which in turn is formed by the oxidation of retinol by either of retinal dehydrogenase 1 or 2.All-trans retinoic acid can also be glucuronidated to form retinoyl b-glucuronide, in a reaction catalyzed by a multiprotein chaperone complex including UDP-glucuronosyltransferase 1-1 in the endoplasmic reticulum. Finally, in the endoplasmic reticulum, all-trans-retinoic acid can undergo epoxidation to form all-trans-5,6-epoxyretinoic acid by interaction with a complex of cytochrome P450 proteins, or hydroxylated to either 4-hydroxyretinoic acid or all-trans-18-hydroxyretinoic acid by cytochrome P450 26A1. In one last reqction, 4-hydroxyretinoic acid can be oxidized once again by cytochrome P450 26A1 to form 4-oxo-retinoic acid.


Mitochondrial Electron Transport Chain,Metabolic

The electron transport chain in mitochondria leads to the transport of hydrogen ions across the inner membrane of the mitochndria, and this proton gradient is eventually used in the production of ATP. Electrons travel down a chain of electron carriers in the inner mitochondrial membrane, ending with oxygen.The outer membrane of the mitochondrion is permeable to ions and other small molecules  and nothing in this pathway requires a specific transporter to enter into the intermembrane space. However, the inner membrane is only permeable to water, oxygen and carbon dioxide, and all other molecules, including protons, require transport proteins. Phosphate is able to enter the mitochondrial matrix via the glucose-6-phosphate translocase, and ADP is able to enter the matrix as ATP leaves it via the ADP/ATP translocase 1 protein.Electrons donated by NADH can enter the electron transport chain as NADH dehydrogenase, known as complex I, facilitates their transfer to ubiquinone, also known as coenzyme Q10. As this occurs, the coenzyme Q10 becomes reduced to form ubiquinol, and protons are pumped from the intermembrane space to the matrix.Lower energy electrons can also be donated to complex II, which includes succinate dehydrogenase and contains FAD. These electrons move from succinic acid to the FAD in the enzyme complex, and then to coenzyme Q10, which is reduced to ubiquinol. Throughout this, succinic acid from the citric acid cycle is converted to fumaric acid, which then returns to the citric acid cycle. This step, unlike the others in the electron transport chain, does not result in any protons being pumped from the matrix to the intermembrane space.Regardless of which complex moved the electrons to coenzyme Q10, the cytochrome b-c1 complex, also known as complex III, catalyzes the movement of electrons from ubiquinol to cytochrome c, oxidizing ubiquinol to ubiquinone and reducing cytochrome c. This process also leads to the pumping of hydrogen ions into the intermembrane space. Finally, the transfer of electrons from the reduced cytochrome c is catalyzed by cytochrome c oxidase, also known as complex IV of the electron transport chain. This reaction oxidizes cytochrome c for further electron transport, and transfers the electrons to oxygen, forming molecules of water. This reaction also allows protons to be pumped across the membrane.The proton gradient that is built up through the electron transport chain allows protons to flow through the ATP synthase proteins in the mitochondrial inner membrane, providing the energy required to synthesize ATP from ADP.


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.


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.


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.


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.


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.


Acute Intermittent Porphyria,Disease

Acute intermittent porphyria (AIP), the second most common form of porphyria, is caused by a defect in the HMBS gene which codes for porphobilinogen deaminase. A defect in this enzyme results in accumulation of 5-aminolevulinic acid or porphobilinogen in both urine and serum. Most Patients are completely free of symptoms between attacks. Symtpoms include abdominal pain, constipation, vomitting, hypertension, muscle weakness, seizures, delirium, coma, and depression. A high-carbohydrate diet is typically recommended; in severe attacks, a glucose 10% infusion is recommended, which may aid in recovery.


Porphyria Variegata (PV),Disease

Porphyria variegata (PV) is caused by a defect in the PPOX gene which codes for protoporphyrinogen oxidase. A defect in this enzyme results in accumulation of the porphyrin precursors porphobilinogen and 5-aminolevulinic acid in plasma; increase of fecal and urinary levels of porphyrin and coproporphyrin. Symtpoms include abdominal pain, vomiting, diarrhea, constipation, muscle weakness, seizures, and mental changes such as anxiety and hallucinations. Some people with variegate porphyria have skin that is overly sensitive to sunlight. Areas of skin exposed to the sun develop severe blistering, scarring, changes in pigmentation, and increased hair growth.


Congenital Erythropoietic Porphyria (CEP) or Gunther Disease,Disease

Congenital Erythropoietic Porphyria (CEP) or Gunther Disease is a rare inborn error of porphyrin-heme synthesis inherited that is as an autosomal recessive trait. This disorder of bone marrow heme synthesis is caused by a defect in the UROS gene which codes for uroporphyrinogen-III synthase. This enzyme is involved in the fourth step of porphyrin metabolism, involved in the conversion of hydroxymethyl bilane into uroporphyrinogen III. Its defect results in accumulation of uroporphyrin III, coproporphyrin III and porphyrins; Uroporphyrin I in erythrocytes. Symptoms and signs include blistering and fragility of light-exposed skin, discolored urine, concomitant jaundice, reddish color teeth. The severe loss of bone with subsequent contractures and deformities occurs in most adults with erythropoietic porphyria.


Adrenal Hyperplasia Type 3 or Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency,Disease

Adrenal hyperplasia type 3, also called Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, is caused by a defect in the CYP21A2 gene which codes for Steroid 21-hydroxylase (21-hydroxylase). Steroid 21-hydroxylase catalyzes hydroxylation of 17-hydroxyprogesterone to 11-deoxycortisol in the glucocorticoid pathway from pregnenolone to cortisol. It also catalyzes hydroxylation of progesterone to 11-deoxycorticosterone (DOC) in the mineralocorticoid pathway on its way from pregnenolone to aldosterone. A defect in this enzyme results in accumulation of 17-Hydroxyprogesterone, progesterone and 17a-Hydroxypregnenolone, androstenedione, and testosterone; decreased levels of cortexolone, deoxycorticosterone, aldosterone and cortisol. Symptoms include salt-wasting crises in infancy due to the lack of aldosterone, like spitting, poor weight gain, vomiting, severe dehydration, and circulatory collapse. The high level of testosterone results in virilization and genital ambiguity of female infants.


Congenital Lipoid Adrenal Hyperplasia (CLAH) or Lipoid CAH,Disease

Congenital lipoid adrenal hyperplasia (CLAH; Steroid 20-22 desmolase deficiency; lipoid CAH) is caused by a defect in the CYP11A1 gene which codes for mitochondrial cholesterol side-chain cleavage enzyme. Cholesterol side-chain cleavage enzyme convertes cholesterol to pregnenolone in adrenal cortisol synthesis of all steroid hormones. A defect in this enzyme results in in impaired synthesis of all three categories of adrenal steroids (cortisol, mineralocorticoids, sex steroids) and high levels of adrenocorticotropic hormone (ACTH). Symptoms include poor feeding, vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, hypoglycemia, hyperpigmentation. Sex steroid deficiency can result in ambiguous genitalia. Patients need the mineral replacement and extra glucocorticoid. XX female patients can use estrogen replacement at or after puberty. For XY patients, the testes are uniformly nonfunctional and they are undescended, are removed when the diagnosis is made due to the risk of cancer development in these tissues.


Adrenal Hyperplasia Type 5 or Congenital Adrenal Hyperplasia Due to 17 alpha-Hydroxylase Deficiency,Disease

Adrenal hyperplasia type 5 (AH5; Congenital Adrenal Hyperplasia due to 17 Alpha hydroxylase Deficiency) is a form of congenital adrenal hyperplasia. It is caused by a defect in the CYP17A1 gene which codes for Steroid 17-alpha-hydroxylase/17,20 lyase. These 2 enzymes convert pregnenolone and progesterone to their 17-hydroxy forms in steroidogenesis and mediate three key transformations in cortisol and sex steroid synthesis. A defect in 17-alpha-hydroxylase results in decreased synthesis of both cortisol and sex steroids; increase in mineralocorticoids. Common symptoms include mild hypocortisolism, ambiguous genitalia in genetic males or failure of the ovaries to function at puberty in genetic females, and hypertension. Hypertension and mineralocorticoid excess is treated with glucocorticoid replacement. Genetically female patients need female hormone replacement to induce puberty and regulate menses. Surgery may be needed for males with ambiguous genitalia. Testosterone must be replaced for genetically males (XY) to induce puberty and continued throughout adult life.


Alkaptonuria,Disease

Alkaptonuria (Homogentisic acid oxidase deficiency) is an autosomal recessive disease caused by a mutation in the HGD gene which codes for homogentisate 1,2-dioxygenase. A mutation in this enzyme results in accumulation of homogentisic acid in urine. Symptoms, which present in adulthood, include arthritis, black or brown urine, and urolithiasis. Treatment includes a low-protein diet with vitamin C.


Hawkinsinuria,Disease

Hawkinsinuria (4-Hydroxyphenylpyruvate Hydroxylase Deficiency) is an autosomal dominant disease caused by a mutation in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. A deficiency in this enzyme results in accumulation of hawkinsin in urine and plasma; cis-4-hydroxycyclohexylacetic acid, trans-4-hydroxycyclohexylaceid, vanillactic acid, 4-hydroxyphenylpyruvic acid, pyroglutamic acid in urine; and L-tyrosine in plasma. Symptoms include ketosis, metabolic acidosis, swimming-pool odor, and mental retardation. Treatment includes a low-protein diet and vitamin C.


Tyrosinemia Type I,Disease

Tyrosinemia type I, also known as fumarylacetoacetase or FAH deficiency, is the most severe type of tyrosinemia, a buildup of tyrosine in the body. It is caused by an autosomal recessive mutation in the the FAH gene that encodes for fumarylacetoacetase, an enzyme that is responsible for the last of five steps that are involved in the metabolic breakdown of tyrosine in the liver and kidneys. The lack of this enzyme's function leads to a buildup of 4-fumarylacetoacetic acid as it couldn't be broken down to fumaric acid and acetoacetic acid. This also leads to an increased concentration of maleylacetoacetic acid. This eventually leads to the increased concentration of L-tyrosine in the body. Symptoms of tyrosinemia type I include jaundice and an enlarged liver, kidney dysfunction, as well as a failure to grow, as foods with high protein and amino acids lead to increased symptoms. Additionally, individuals are more at risk for future liver cancer.


Argininemia,Disease

Argininemia is caused by a mutation in the gene ARG, encoding liver arginase, which hydrolyses arginine to urea and ornithine in the last step of the urea cycle. A defect in liver arginase causes accumulation of ammonia in blood; arginine, creatine, guanidinoacetate, and homoarginine in plasma; urea nitrogen in serum; arginine and homoarginine in spinal fluid; and arginiosuccinate orotic acid, and uracil in urine. Symptoms include ataxia, cerebral atrophy, chorea, jaundice, and seizures.


Argininosuccinic Aciduria,Disease

Argininosuccinic Aciduria, (Argininosuccinase Deficiency, Argininosuccinate Lyase Deficiency, ASL Deficiency) is an autosomal recessive disorder caused by a mutation in the ASL gene which codes for argininosuccinate lyase. It results in accumulation of citrulline, arginosuccinic acid, L-arginine, and L-glutamic acid in plasma as well as ammonia in blood. Infants are lethargic and unwilling to eat. They may develop seizures, coma, and failure to thrive as toxic ammonia accumulates.


Citrullinemia Type I,Disease

Citrullinemia Type I, (Argininosuccinate Synthetase Deficiency, Citrullinuria, Citrullinemia, ASS) is an autosomal recessive urea cycle disorder that causes ammonia and other toxic substances to accumulate in the blood. Two forms of citrullinemia have been described, both having different signs and symptoms, and are caused by mutations in different genes. Citrullinemia belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of chemical reactions that takes place in the liver. These reactions process excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys. Citrullinemia Type I is an autosomal recessive disease caused by mutation in the ASS gene which codes for argininosuccinate synthetase. A deficiency in this enzyme results in accumulation of citruilline as well as glycine and orotic acid in urine. Infants appear normal at birth, but within the first week of life symptoms such as feeding difficulties, irritability, hypotonia, seizures, and vomiting present and eventually lead to premature death.


Ornithine Transcarbamylase Deficiency (OTC Deficiency),Disease

It is an inherited disorder which causes toxic levels of ammonia to build up in the blood.  Ornithine transcarbamylase, the defective enzyme in this disorder, is the final enzyme in the proximal portion of the urea cycle.  It is responsible for converting carbamoyl phosphate and ornithine into citrulline.  OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females.  In severely affected individuals, ammonia concentrations increase rapidly, causing ataxia, lethargy, and death without rapid intervention.  OTC deficiency is diagnosed using a combination of clinical findings and biochemical testing, while confirmation is often done using molecular genetics techniques (Wikipedia).  .


Beta-ureidopropionase deficiency (Beta Alanine-Synthase Deficiency, UPB1, BUP1) is an autosomal recessive disease caused by mutations in the UPB1 gene which codes for beta-ureidopropionase. A deficiency in this enzyme results in accumulation of N-carbamyl-beta-amino acids. Symptoms include hypotonia, dystonic movements, scoliosis, microcephaly, and severe developmental delay.


UMP Synthase Deficiency (Orotic Aciduria),Disease

Orotic Aciduria (Orotic acidemia) is caused by a defect in uridine monophosphate synthetase (UMPS) (orotate phosphoribosyl transferase and orotidine-5’-decarboxylase), an enzyme that catalyses the formation of uridine monophosphate (UMP), an energy carrying molecule in many important biosynthetic pathways. This disease is marked by very high accumulation of orotic acid in the urine, sometimes causing urinary obstruction. Symptoms include megaloblastic anemia as well as failure to thrive.


Dihydropyrimidinase Deficiency,Disease

Dihydropyrimidinase Deficiency (DHPA, Dihydropyrimidinuria Deficiency, DPH Deficiency) is an autosomal recessive disease caused by a mutation in the DPYS gene which codes for dihydropyrimidinase. A deficiency in this enzyme results in accumulation of dihydrothymine, dihydrouracil, thymine, and uracil in urine. Symptoms, which present at birth, include metabolic acidosis, difficulty feeding, and seizures.


MNGIE (Mitochondrial Neurogastrointestinal Encephalopathy),Disease

Myoneurogastrointestinal encephalopathy, or mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), is a multisystem disorder caused by mutations in the gene encoding thymidine phosphorylase, which normally uses thymidine and phosphate as substrates to catalyze the reaction between these two substrates to create thymine and 2-deoxy-alpha-D-ribose 1-phosphate. MNGIE causes accumulation of thymidine and deoxyuridine in the urine. Symptoms of MNGIE include ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility (often pseudoobstruction), diffuse leukoencephalopathy, peripheral neuropathy, and myopathy.


Carbamoyl Phosphate Synthetase Deficiency,Disease

Carbamoyl phosphate synthetase (CPS) deficiency (Carbamoyl phosphate synthetase I deficiency) is a urea cycle defect that results from a deficiency in an enzyme that mediates the normal path for incorporation of ammonia. Carbamoyl phosphate is derived from catabolism of amino acids into a 1-carbon compound, in which the carbon atom is derived from bicarbonate. The process is exclusively mitochondrial and requires the expenditure of two ATP molecules. Two hepatocellular enzymes exist: CPS I and CPS II. CPS I is exclusively intramitochondrial, and its deficiency is responsible for the disease. CPS I is the most plentiful single protein in hepatic mitochondria, accounting for about 20% of the matrix protein. CPS II is exclusively cytosolic and is an important enzyme in de novo synthesis of pyrimidine nucleotides. The regulation of CPS I activity depends on the levels of N -acetylglutamate.  In patients with homozygous CPS I deficiency, the ability to fix waste nitrogen is completely absent, resulting in increasing levels of free ammonia with the attendant effects on the CNS. A recent molecular and functional examination of the mutational effects showed that, although some mutations affect both substrate affinity and efficiency of the reaction, others affect one more than the other. Some mutations are associated with enhanced RNA instability, which leads to diminished protein synthesis.  The hepatic urea cycle is the major route for waste nitrogen disposal. Waste nitrogen is chiefly generated from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and may result in hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of N -acetylglutamate, the enzyme activator of CPS I, which initiates incorporation of ammonia into the cycle.


Congenital Bile Acid Synthesis Defect Type II,Disease

Congenital Bile Acid Synthesis Defect Type II is a congenital defect in bile acid synthesis with delta(4)-3-oxosteroid 5-beta-reductase deficiency is caused by mutation in the AKR1D1 gene. 3-oxo-5-beta-steroid 4-dehydrogenase catalyzes the bile acid intermediates 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4-cholesten-3-one. Chenodeoxycholic acid and cholic acid are decreased in plasma and urine. Symptoms of this disease include cholestatic jaundice, atypical oxo and allo bile acids in urine and serum, liver failure, and steatosis.


Congenital Bile Acid Synthesis Defect Type III,Disease

Congenital Bile Acid Synthesis Defect Type III (CBASIII) is caused by a defect in 25-hydroxycholesterol 7-alpha-hydroxylase, which plays a role in synthesis of bile acids. The synthesis of primary bile acids from cholesterol occurs via two pathways: the classic neutral pathway involving cholesterol 7-alpha-hydroxylase (CYP7A1), and the acidic pathway involving a distinct microsomal oxysterol 7-alpha-hydroxylase (CYP7B1). CBASIII is characterized by accumulation of bile acids in the urine. Symptoms include severe cholestasis, cirrhosis, and liver failure.


Familial Hypercholanemia (FHCA),Disease

Familial Hypercholanemia can be caused by mutations in the TJP2, BAAT or EPHX1 genes which code for bile acid-CoA:amino acid N-acyltransferase, which is involved in bile acid metabolism. In liver hepatocytes, it catalyzes the second step in the conjugation of C24 bile acids (choloneates) to glycine and taurine before excretion into bile canaliculi. The major components of bile are cholic acid and chenodeoxycholic acid. In a first step the bile acids are converted to an acyl-CoA thioester, either in peroxisomes (primary bile acids deriving from the cholesterol pathway), or cytoplasmic at the endoplasmic reticulum (secondary bile acids). May catalyze the conjugation of primary or secondary bile acids, or both. The conjugation increases the detergent properties of bile acids in the intestine, which facilitates lipid and fat-soluble vitamin absorption. In turn, bile acids are deconjugated by bacteria in the intestine and are recycled back to the liver for reconjugation (secondary bile acids). Bile acid-CoA:amino acid N-acyltransferase may also act as an acyl-CoA thioesterase that regulates intracellular levels of free fatty acids. Familial hypercholanemia is characterized by increased bile acids in plasma. Symptoms include rickets and steatorrhea.


Zellweger Syndrome,Disease

Zellweger syndrome, also known as cerebrohepatorenal syndrome, is an autosomal recessive peroxisome biogenesis disorder that is part of the family of Zellweger spectrum disorders. It is caused by a defect in one of 12 or more of the PEX genes (PEX1, 2, 3, 5, 6, 10, 12, 13, 14, 16, 19 and 26) that produce proteins called peroxins. Peroxins are used in the formation of peroxisomes, and can be involved in recognition of proteins targeted for the peroxisome, as well as their transport into the peroxisome. Peroxisomes typically break down both very long chain and branched fatty acids, but if they aren't present, these fatty acids build up in the blood and body, harming organs such as the brain and liver. Additionally, due to the fact that some processes, such as plasmalogen biosynthesis, occur in or using peroxisomes, and can lead to deficiencies in plasmalogens. These are important in brain and lung function, leading to other symptoms.Zellweger syndrome is characterized by an increase in levels of very long chain fatty acids in the blood plasma, as well as more visible physical symptoms, such as an abnormally large or small head at birth, characteristic facial features and poor muscle tone, which can lead to an inability of infants to feed. Other symptoms include an enlarged liver, skeletal abnormalities and low CNS function. Infants very rarely live longer than one year, and the only treatment is for symptoms the patient is experiencing, not for the syndrome itself.


Cerebrotendinous Xanthomatosis is caused by mutation in the CYP27A1 gene, which encodes sterol 27-hydroxylase. This enzyme catalyzes the first step in the oxidation of the side chain of sterol intermediates; the 27-hydroxylation of 5-beta-cholestane-3-alpha,7-alpha,12-alpha-triol. Cerebrotendinous Xanthomatosis is a rare, inherited lipid-storage disease with large deposits of cholesterol and cholestanol are found in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Symptoms include progressive neurologic dysfunction (cerebellar ataxia beginning after puberty, systemic spinal cord involvement and a pseudobulbar phase leading to death), premature atherosclerosis, and cataracts.


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.


Dihydropyrimidine Dehydrogenase Deficiency (DHPD),Disease

Dihydropyrimidine Dehydrogenase Deficiency (DHPD; Thymine-uraciluria) is a rare autosomal recessive disorder caused by a mutation in the DPYD gene which codes for dihydropyrimidine dehydrogenase. A deficiency in this enzyme results in accumulation of 5-hydroxymethyluracil, thymine, and uracil in urine. Symptoms include nystagmus, large liver, hypotonia, growth and mental retardation, and seizures.


Sarcosinemia,Disease

Sarcosinemia (SAR), also known as hypersarcosinemia, sarcosine dehydrogenase complex deficiency, SARDH deficiency, SARDHD or SARD deficiency, is an autosomal recessive metabolic disorder leading to increased levels of the amino acid sarcosine in blood plasma, as well as increased levels of sarcosine excreted in urine. SAR can be caused by a mutation, either homozygous or compound heterozygous, in the SARDH gene which codes for the sarcosine dehydrogenase enzyme. This enzyme converts sarcosine to glycine, and its absence leads to an increase in the amount of sarcosine in the body. It can also potentially be caused by a lack of folate, as folate is used in the sarcosine dehydrogenase reaction, and even with a working enzyme, the lack of substrates can prevent the conversion from occurring, leading to the same effects. The condition has been associated with mental and motor retardation, visual impairment, however other cases have been detected with no mental or physical abnormalities other than increased sarcosine levels, so it is possible that the defect is benign, or that there exist some phenotypes that are more severe than others, or unknown disorders present in the cases showing symptoms.Sarcosine can be formed from a series of reactions starting with trimethylglycine. This, along with homocysteine, react using betaine-homocysteine S-methyltransferase to form L-methionine, as well as dimethylglycine. The dimethylglycine then enters the mitochondrial matrix, and interacts with dimethylglycine dehydrogenase along with a water molecule, forming formadehyde and sarcosine. Sarcosine can also be formed in a reversible reaction from S-adenosylmethionine and glycine, using glycine N-methyltransferase as the enzyme, and forming S-adenosylhomocysteine as another product. Normally, sarcosine can interact with sarcosine dehydrogenase in the mitochondria, forming both formaldehyde and glycine. However, in this disorder, the gene encoding sarcosine dehydrogenase has been mutated and the protein is not produced, preventing this reaction from occurring. This leads to an increased concentration of sarcosine, which leads to the effects of the condition.


Galactosemia,Disease

Galactosemia (GALT Deficiency; GALT; Galactose-1-Phosphate Uridylyltransferase Deficiency) is a rare genetic disorder caused by a mutation in the GALT gene which codes for galactose-1-phosphate uridylyltransferase. A deficiency in this enzyme results in accumulation of D-galactose and galactitol in plasma and urine; bilirubin, chloride, and galactose-1-phosphate, and transaminases in serum. Symptoms, which present at birth, include jaundice, enlarged liver, anemia, weight loss, and vomiting. Treatment includes galactose-free diet, antibiotics, and vitamin K.


Gaucher Disease,Disease

Gaucher disease is caused by a defect in the GBA gene which codes for glucosylceramidase. A defect in this enzyme results in accumulation of glucosylceramide in in brain, bone marrow, liver, spleen, lungs, and other organs. Gaucher’s disease has three common clinical subtypes. Type I (or non-neuropathic type) is the most common form of the disease. Symptoms may begin early in life or in adulthood. They include enlarged liver, grossly enlarged spleen, skeletal weakness and bone disease. Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia and leukopenia. Type II (or acute infantile neuropathic Gaucher’s disease) typically begins within 6 months of birth. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age 2. Type III (the chronic neuropathic form) can begin at any time in childhood or even in adulthood. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia and respiratory problems. Patients often live into their early teen years and adulthood. For type 1 and most type 3 patients, enzyme replacement treatment with intravenous recombinant glucocerebrosidase (imiglucerase) can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. Successful bone marrow transplantation cures the non-neurological manifestations of the disease. Surgery to remove the spleen (splenectomy) may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient’s comfort. Blood transfusion may benefit some anemic patients. Other patients may require joint replacement surgery to improve mobility and quality of life. Other treatment options include antibiotics for infections, antiepileptics for seizures, bisphosphonates for bone lesions, and liver transplants. Substrate reduction therapy may prove to be effective in stopping Type 2, as it can cross through the blood barrier into the brain. There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease.


Globoid Cell Leukodystrophy,Disease

Globoid Cell Leukodistrophy, (GLD; Krabbe disease; Galactosylceramide Lipidosis) is caused by a defect in the GALC gene which codes for Galactocerebrosidase. A defect in this enzyme results in accumulation of galactosylceramide and psychosine in central nervous system. Infants with Krabbe disease are normal at birth. Symptoms begin between the ages of 3 and 6 months with irritability, fevers, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development. Other symptoms include muscle weakness, spasticity, deafness, optic atrophy and blindness, paralysis, and difficulty when swallowing. Prolonged weight loss may also occur. There are also juvenile- and adult-onset cases of Krabbe disease, which have similar symptoms but slower progression. In infants, the disease is generally fatal before age 2. Patients with late-onset Krabbe disease tend to have a slower progression of the disease and live significantly longer. Although there is no cure for Krabbe disease, bone marrow transplantation has been shown to benefit cases early in the course of the disease.


Metachromatic leukodystrophy (MLD) is caused by a defect in the ARSA gene which does for arylsulfatase A. A defect in this enzyme results in accumulation of 3-O-sulfogalactosylceramide in urine, neural and non neural tisues like kidney and gallbladder. There are several forms of MLD. In the late infantile form, which is the most common form MLD, affected children begin having difficulty walking after the first year of life. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner. Children with the juvenile form of MLD (onset between 3–10 years of age) usually begin with impaired school performance, mental deterioration, and dementia and then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset. The adult form commonly begins after age 16 as a psychiatric disorder or progressive dementia. Adult-onset MLD progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.


Glycerol Kinase Deficiency,Disease

Glycerol Kinase Deficiency (Hyperglycerolemia; Glyceroluria; GK Deficiency; GKD) is a rare metabolic disease caused by a deficiency in the GK gene which codes for glycerol kinase. A deficiency in this enzyme results in accumulation of glycerol in urine and serum. Symptoms include cryptorchism, trabismus, myopathy, lethargy, and vomiting. Treatment includes corticosteroids and acute glucose infusion.


Glycogen Storage Disease Type 1A (GSD1A) or Von Gierke Disease,Disease

Glycogen storage disease type 1A (GSD1A), or von Gierke disease, is caused by a defect in the G6PC gene which codes for Glucose-6-phosphatase. Glucose-6-phosphatase hydrolyzes glucose-6-phosphate to glucose and is responsible for the regulation of blood glucose level. A defect in this enzyme results in accumulation of glycogen in affected tissues, like liver and kidney; decreased glucose level; and accumulation of lactate. Glycogen storage disease type 1A causes clinically significant end-organ disease with significant morbidity. Usually it presents in childhood. Symptoms include seizures, irritability, pallor, hypotonia, tremors, loss of consciousness, apnea and hepatomegaly. There is no cure for glycogen storage disease type 1A. Diet therapy can help to prevent hypoglycemia and reduce the symptoms. Liver transplantation may be indicated in cases of hepatic malignancy.


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.


Malonic Aciduria,Disease

Malonic Aciduria, is an autosomal recessive metabolic disorder caused by a genetic mutation which disrupts the activity of Malonyl-Coa decarboxylase. This enzyme breaks down Malonyl-CoA (a fatty acid precursor and a fatty acid oxidation blocker) into Acetyl-CoA and carbon dioxide. A defect in Malonyl-CoA decarboxylase results in accumulation of ammonia in the blood; methylmalonic acid in the plasma; creatinine in the serum; 3-Aminoisobutyric acid, 3 Hydroxypropionic acid, 3 hydoxyvaleric acid, glycine, acylcrnitine and methylmalonic acid in the urine; and methylmalonic acid in the spinal fluid. Symptoms include cardiomyopathy, growth retardation, ketosis, nephrosis, pancreatitis, respiratory distress, and neutropenia.


Methylmalonic Aciduria Due to Cobalamin-Related Disorders,Disease

Methylcobalamin (MeCbl) is the cofactor of methionine synthase and involved in the conversion of homocysteine to methionine. Adenosylcobalamin (AdoCbl) is a cofactor for methylmalonyl CoA mutase converting methylmalonic acid into succinic acid. Methylmalonyl-CoA mutase is involved in key metabolic pathways, catalyzing the isomerization of methylmalonyl-CoA to succinyl-CoA. It requires its Vitamin B12 derived prosthetic group, adenosylcobalamin, to function.It catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. It requires its Vitamin B12 derived prosthetic group, adenosylcobalamin, to function. Defects in these cofactors for methylmalonyl CoA mutase cause accumulation of ammonia in blood; methylmalonic acid in plasma; creatinine and uric acid in serum; 3-Aminoisobutyric acid, 3-Hydroxypropionic acid, 3-Hydroxyvaleric acid, glycine, methylcitric acid and methylmalonic acid in urine; and methylmalonic acid in spinal fluid. Symptoms include anemia, dehydration, growth retardation, nephrosis, respiratory distress and metabolic acidosis.


Non-Ketotic Hyperglycinemia,Disease

Non Ketotic Hyperglycinemeia (Glycine encephalopathy; Glycine cleavage system deficiency; NKH) is caused by mutations in several genes in the mitochondrial glycine cleavage system. These include the genes encoding P protein (GLDC), T protein (GCST), and, in one case, the H protein (GCSH). Most patients with GCE (Glycine Encephalopathy, or NKH) have a defect in the GLDC gene.The enzyme system for cleavage of glycine (glycine cleavage system), which is confined to the mitochondria, is composed of 4 protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). NKH is characterized by accumulation of glycine in plasma, spinal fluid and urine. Symptoms include seizures, respiratory distress, mental retardation, chorea, visual impairment and hydrocephalus.


Vitamin A Deficiency,Disease

Vitamin A deficiency can be caused by many causes. A defect in the BCMO1 gene which codes for beta,beta-carotene 15,15’-monooxygenase is one of them. Beta,beta-carotene 15,15’-monooxygenase catalyzes the chemical reaction where the two substrates are beta-carotene and O2, whereas its product is retinal. A defect in this enzyme results in decrease of levels of retinal and vitamin A in serum; Signs and symptoms include night blindness, poor adaptation to darkness, dry skin and hair.


Hereditary Coproporphyria (HCP),Disease

Hereditary coproporphyria (HCP) is caused by a defect in the CPOX gene which codes for mitochondrial coproporphyrinogen-III oxidase. A defect in this enzyme results in accumulation of the porphyrin precursors porphobilinogen and 5-aminolevulinic acid; increase of fecal and urinary excreation of coproporphyrins. Symtpoms include reddish-purple urine, acute neurological problems (typically episodic confusion and sensory changes), and attacks of acute abdominal/nerve pain. Around 30% suffer photosensitive skin eruptions with nail involvement; these can lead to permanent scarring. While there is no cure for this condition, there are preventative measures people can take to regulate symptoms. A diet high in carbohydrates, glucose, as well as avoidance of aggravating factors (such as alcohol and drug use) can prevent attacks.


2-Hydroxyglutric Aciduria (D and L Form),Disease

L-2-Hydroxyglutaric Aciduria (D-2-Hydroxyglutaric Aciduria ) is an autosomal recessive disease caused by a mutation in the L2HGDH gene which codes for L-2-Hydroxygluarate dehydrogenase. A deficiency in this enzyme results in accumulation of L-2-Hydroxyglutaric acid in plasma, spinal fluid, and urine; and L-lysine in plasma and spinal fluid. Symptoms, which present at birth, include ataxia, hypotonia, mental retardation, and seizures. Premature death often results.  D-2-Hydroxyglutaric Aciduria is an autosomal recessive disease caused by a mutation in the D2HGDH gene which does for D-2-Hydroxygluarate dehydrogenase. A deficiency in this enzyme results in accumulation of D-2-Hydroxyglutaric acid in plasma, spinal fluid, and urine; oxoglutaric acid in urine; and gabba-aminobutyric acid in spinal fluid. Symptoms, which present at birth, include ataxia, hypotonia, mental retardation, and seizures. Premature death often results.


3-Methylglutaconic Aciduria Type IV,Disease

3-Methylglutaconic Aciduria Type IV (MGA, Type IV; MGA4) is an autosomal recessive disease caused by a mutation in an unknown gene. This disease results in an accumulation of cis and trans 3-methylglutaconic acid. Symptoms include, anemia, hyperammonemia, mental retardation, optic atrophy, hypotonia and early death.


Tay-Sachs Disease,Disease

Tay-Sachs Disease (TSD; GM2-Gangliosidosis, type I; B-Variant GM2-Gangliosidosis; Hexosaminidase A Deficiency; HEXA Deficiency; Tay-Sachs Disease Variant B1), is an autosomal recessive lysosomal storage disease. TSD is caused by a mutation in the alpha subunit of the hexosaminidase A gene (HEXA), which codes for the enzyme hexosaminidase A. HEXA degrades GM2 gangliosides and other molecules with terminal N-acetyl hexosamines in the brain and other tissues. A defect in this enzyme causes accumulation of oligosaccharides in urine. The most lethal variant of this disease is the classical infantile Tay-Sachs disease, in which children exhibit developmental retardation, dementia and blindness, finally ending in death by the second or third years. Tay-Sachs disease also has debilitating juvenile and adult forms. The majority of cases of TSD are found among (but not limited to) the Ashkenazi Jews and French Canadians in Eastern Quebec. Symptoms include ataxia, visual impairment and loss, cherry-red spot on retinal macula, dystosis multiplex, mental retardation, myoclonus, encephalopathy and psychosis.


Glucose Transporter Defect (SGLT2),Disease

SGLT2 is a sodium/glucose co-transporter that exists almost exclusively in kidney tissue. It is responsible for approximately 90% of the kidney's reabsorption of glucose, and can be found in the S1 segment of the proximal convoluted tubule of the nephron. A defect in the SLC5A2 gene that codes for SGLT2 results in glucosuria, due to the inability of most of the glucose to be reabsorbed by the kidney. There are some drugs that inhibit SGLT2 and are used to decrease blood sugar in patients with type 2 diabetes mellitus.


Hartnup Disorder,Disease

Hartunup Disorder (HND, Hartnup Disease) is an autosomal recessive disease caused by a mutation in the SLC6A19 which codes for sodium-dependent neutral amino acid transporter B(0). A deficiency in this enzyme results in accumulation of L-alanine, L-asparagine, L-histidine, indoleacetic acid, L-isoleucine, L-leucine, L-phenylalanine, L-serine, L-threonine, L-tryptophan, L-valine, and L-tyrosine in urine. Symptoms include pellagra, psychosis, ataxia, and mental retardation. Treatment includes nicotinamide.


Iminoglycinuria,Disease

Iminoglycinuria, sometimes called familial iminoglycinuria, is an autosomal recessive disorder of renal tubular transport affecting reabsorption of the amino acid glycine, and the imino acids proline and hydroxyproline, leading to accumulation of these three acids in the urine. Iminoglycinuria is a rare and complex disorder, associated with a number of genetic mutations which cause defects in both renal and intestinal transport systems of glycine and imino acids. Symptoms include urolithiasis, excessive imino acids in the urine, and mental retardation.


Lysinuric Protein Intolerance,Disease

Lysinuric protein intolerance (Hyperdibasic aminoaciduria II; Dibasic aminoaciduria II; Hyperdibasic aminoaciduria II; LPI), also called hyperdibasic aminoaciduria type 2 or familial protein intolerance, is an autosomal recessive metabolic disorder affecting amino acid transport. LPI is caused by a defect in SLC7A7, Solute carrier family 7, a cationic amino acid transporter. A defect in this enzyme results in accumulation of ammmonia and reticulocytes in blood; glutamine in plasma, carnitine and ferritin in serum, and arginine, lysine and ornithine in urine. Symptoms include bone marrow abnormality, growth retardation, hyperammoniemia, mental retardation, pancreatitis, and seizures.


Hypercholesterolemia,Disease

Hypercholesterolemia literally means high blood cholesterol. The elevated cholesterol in the blood is due to abnormalities in the levels of lipoproteins, the LDL particles that carry cholesterol in the bloodstream. This disease can usually be attributed to one’s diet, genetic factors (such as LDL receptor mutations), and the presence of other disease such as diabetes or an underactive thyroid. Metabolism of cholesterol when the patient is affected by hypercholesterolemia: the deficient enzymes are actually transport proteins that transport LDL particles into the liver, and cholesterol accumulates in the bloodstream and other tissues.


Neuron Function,Physiological

Neurons are electrically excitable cells that process and transmit information through electrical and chemical signals. A neuron consists of a cell body, branched dendrites to receive sensory information, and a long singular axon to transmit motor information. Signals travel from the axon of one neuron to the dendrite of another via a synapse. Neurons maintain a voltage gradient across their membrane using metabolically driven ion pumps and ion channels for charge-carrying ions, including sodium (Na+), potassium (K+), chloride (Cl−), and calcium (Ca2+).  The resting membrane potential (charge) of a neuron is about -70 mV because there is an accumulation of more sodium ions outside the neuron compared to the number of potassium ions inside.  If the membrane potential changes by a large enough amount, an electrochemical pulse called an action potential is generated. Stimuli such as pressure, stretch, and chemical transmitters can activate a neuron by causing specific ion-channels to open, changing the membrane potential. During this period, called depolarization, the sodium channels open to allow sodium to rush into the cell which results in the membrane potential to increase.  Once the interior of the neuron becomes more positively charged, the sodium channels close and the potassium channels open to allow potassium to move out of the cell to try and restore the resting membrane potential (this stage is called repolarization).  There is a period of hyperpolarization after this step because the potassium channels are slow to close, thus allowing more potassium outside the cell than necessary. The resting potential is restored after the sodium-potassium pump works to exchange three sodium ions out per two potassium ions in across the plasma membrane.  The action potential travels along the axon and upon reaching the end, causes neurotransmitters such as serotonin, dopamine, or norepinephrine to be released into the synapse. These neurotransmitters diffuse across the synapse and bind to receptors on the target cell, thus propagating the signal.


Benazepril Action Pathway,Drug Action

Benazepril, brand name Lotensin, belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Benazepril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form benazeprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.


Bevacizumab Action Pathway,Drug Action

Bevacizumab is a humanized anti-VEGF monoclonal antibody used in the treatment of cancer. Cancer cells tend to overexpress VEGF, which stimulates angiogenesis, facilitating cancer growth and metastasis. The majority of VEGF’s effects are mediated through its binding to the VEGFR-2 receptor on endothelial cell surfaces. Upon binding, the receptor autophosphorylates and initiates a signalling cascade, starting with the activation of CSK. CSK phosphorylates Raf-1, which subsequently phosphorylates MAP kinase kinase, which phosphorylates MAP kinase. The activated MAP kinase enters the nucleus and stimulates the expression of angiogenic factors resulting in increased cell proliferation, migration,  permeability, invasion, and survival.Binding of VEGF to VEGFR-2 also activates phospholipase C PIP2 into DAG and IP3. DAG may be involved in the activation of Raf-1 leading to angiogenesis, while IP3 activates PI3K and triggers calcium release from the endoplasmic reticulum. This ultimately leads to the activation of nitric oxide synthase and the production of nitric oxide, which stimulates vasodilation and increases vascular permeability. In cancer, VEGF has also been shown to bind to the VEGFR-1 receptor. However, its effects on angiogenesis are unclear at the moment. There are some evidence to show that VEGFR-1 may cross-talk with VEGFR-2 and initiate the signalling cascades described above.Bevacizumab exerts its effect by binding to extracellular VEGF and preventing its binding to receptors on the endothelial cell surfaces. This in turns inhibits the MAP and IP3  and supresses angiogenesis.


Vatalanib Action Pathway,Drug Action

Vatalanib is an anti-VEGFR molecule in the treatment of cancer. Cancer cells tend to overexpress VEGF, which stimulates angiogenesis, facilitating cancer growth and metastasis. The majority of VEGF’s effects are mediated through its binding to the VEGFR-2 receptor on endothelial cell surfaces. Upon binding, the receptor autophosphorylates and initiates a signalling cascade, starting with the activation of CSK. CSK phosphorylates Raf-1, which subsequently phosphorylates MAP kinase kinase, which phosphorylates MAP kinase. The activated MAP kinase enters the nucleus and stimulates the expression of angiogenic factors resulting in increased cell proliferation, migration,  permeability, invasion, and survival.Binding of VEGF to VEGFR-2 also activates phospholipase C PIP2 into DAG and IP3. DAG may be involved in the activation of Raf-1 leading to angiogenesis, while IP3 activates PI3K and triggers calcium release from the endoplasmic reticulum. This ultimately leads to the activation of nitric oxide synthase and the production of nitric oxide, which stimulates vasodilation and increases vascular permeability. In cancer, VEGF has also been shown to bind to the VEGFR-1 receptor. However, its effects on angiogenesis are unclear at the moment. There are some evidence to show that VEGFR-1 may cross-talk with VEGFR-2 and initiate the signalling cascades described above.Vatalanib exerts its effect by binding to intracellular tyrosine kinase domain of VEGFR-2 and preventing receptor autophosphorylation and activation of downstream pathways, resulting in suppression of angiogenesis.


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

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.


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.


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.