Alanine Metabolism,Metabolic

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Alanine (L-Alanine) is an α-amino acid that is used for protein biosynthesis. Alanine transaminase can facilitate the reductive amination of pyruvate to produce alanine. L-Alanine can be converted to pyruvic acid by alanine aminotransferase 1 reversibly coupled with interconversion of oxoglutaric acid and L-glutamic acid. L-Alanine can also be produced by alanine-glyoxylate transaminase with coupled interconversion of glyoxylate and glycine. L-Alanine will be coupled with alanyl tRNA by alanyl-tRNA synthetase to perform protein biosynthesis. Alanine constitutes about 8% of human proteins. Under fasting conditions, alanine, derived from protein breakdown, can be converted to pyruvate and used to synthesize glucose via gluconeogenesis in the liver. Alternately, alanine, after conversion to pyruvate, can be fully oxidized via the TCA cycle in other tissues.


Aspartate Metabolism,Metabolic

Aspartate is synthesized by transamination of oxaloacetate by aspartate aminotransferase or amino acid oxidase. Aspartyl-tRNA synthetase can then couple aspartate to aspartyl tRNA for protein synthesis. The aspartate content in human proteins is about 7%. Asparagine synthase can convert aspartate to the polar amino acid asparagine. Aspartate is also a precursor for cellular signaling compounds such as, N-acetyl-aspartate, beta-alanine, adenylsuccinate, arginino-succinate and N-carbamoylaspartate. Aspartate is also a metabolite in the urea cycle and involved in gluconeogenesis. Additionally, aspartate carries the reducing equivalents in the mitochondrial malate-aspartate shuttle, which utilizes the ready interconversion of aspartate and oxaloacetate. The conjugate base of L-aspartic acid, aspartate, also acts as an excitatory neurotransmitter in the brain which activates NMDA receptors.


Glutamate Metabolism,Metabolic

Glutamate is one of the non-essential amino acids that is produced by the body. Glutamate is precursor for many nucleic acids and proteins in addition to its role in the central nervous system. It is an excitatory neurotransmitter and has a role in neuronal plasticity, affecting memory and learning.  Glutamate plays a role in numerous metabolic pathways. Dysfunctional glutamate metabolism may cause disorders such as: gyrate atrophy, hyperammonemia, γ-hydoxybutyric aciduria, hemolytic anemia, and 5-oxoprolinuria.


Glutathione Metabolism,Metabolic

Glutathione (GSH) is an low-molecular-weight thiol and antioxidant in various species such as plants, mammals and microbes. Glutathione plays important roles in nutrient metabolism, gene expression, etc. and sufficient protein nutrition is important for maintenance of GSH homeostasis. Glutathione is synthesized from glutamate, cysteine, and glycine sequentially by gamma-glutamylcysteine synthetase and GSH synthetase. L-Glutamic acid and cysteine are synthesized to form gamma-glutamylcysteine by glutamate-cysteine ligase that is powered by ATP. Gamma-glutamylcysteine and glycine can be synthesized to form glutathione by enzyme glutathione synthetase that is powered by ATP, too. Glutathione exists oxidized (GSSG) states and in reduced (GSH) state. Oxidation of glutathione happens due to relatively high concentration of glutathione within cells.


Citric Acid Cycle,Metabolic

The citric acid cycle, which is also known as the tricarboxylic acid cycle (TCA cycle) or the Krebs cycle, is a connected series of enzyme-catalyzed chemical reactions of central importance to all aerobic organisms (i.e. organisms that use oxygen for cellular respiration). The citric acid cycle is named after citrate or citric acid, a tricarboxylic acid that is both consumed and regenerated through this pathway. The citric acid cycle was discovered in 1937 by Hans Adolf Krebs while he worked at the University of Sheffield in England (PMID: 16746382). Krebs received the Nobel Prize for his discovery in 1953. Krebs’ extensive work on this pathway is also why the citric acid or TCA cycle is often referred to as the Krebs cycle. Metabolically, the citric acid cycle allows the release of energy (ultimately in the form of ATP) from carbohydrates, fats, and proteins through the oxidation of acetyl-CoA. The citric acid cycle also produces CO2, the precursors for several amino acids (aspartate, asparagine, glutamine, proline) and NADH – all of which are used in other important metabolic pathways, such as amino acid synthesis and oxidative phosphorylation (OxPhos). The net yield of one “turn” of the TCA cycle in terms of energy-containing compounds is one GTP, one FADH2, and three NADH molecules.  The NADH molecules are used in oxidative phosphorylation to generate ATP. In eukaryotes, the citric acid cycle occurs in the mitochondrial matrix. In prokaryotes, the citric acid cycle occurs in the cytoplasm.  In eukaryotes, the citric acid or TCA cycle has a total of 10 steps that are mediated by 8 different enzymes.  Key to the whole cycle is the availability of acetyl-CoA. One of the primary sources of acetyl-CoA is from the breakdown of glucose (and other sugars) by glycolysis. This process generates pyruvate. Pyruvate is decarboxylated by pyruvate dehydrogenase to generate acetyl-CoA. The citric acid cycle begins with acetyl-CoA transferring its two-carbon acetyl group to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate) through the enzyme citrate synthase. The resulting citrate is then converted to cis-aconitate and then isocitrate via the enzyme aconitase.  The resulting isocitrate then combines with NAD+ to form oxalosuccinate and NADH, which is then converted into alpha-ketoglutarate (and CO2) through the action of the enzyme known as isocitrate dehydrogenase. The resulting alpha-ketoglutarate combines with NAD+ and CoA-SH to produce succinyl-CoA, NADH, and CO2. This step is mediated by the enzyme alpha-ketoglutarate dehydrogenase. The resulting succinyl-CoA combines with GDP and organic phosphate to produce succinate, CoA-SH, and GTP. This phosphorylation reaction is performed by succinyl-CoA synthase. The resulting succinate then combines with ubiquinone to produce two compounds, fumarate and ubiquinol through the action of the enzyme succinate dehydrogenase.  The resulting fumarate is then hydrated by the enzyme known as fumarase to produce malate. The resulting malate is oxidized via NAD+ to produce oxaloacetate and NADH. This oxidation reaction is performed by malate dehydrogenase.  The resulting oxaloacetate can then combine with acetyl-CoA and the TCA reaction cycle begins again. Overall, in the citric acid cycle, the starting six-carbon citrate molecule loses two carboxyl groups as CO2, leading to the production of a four-carbon oxaloacetate. The two-carbon acetyl-CoA that is the “fuel” for the TCA cycle can be generated by several metabolic pathways including glucose metabolism, fatty acid oxidation, and the metabolism of amino acids.  The overall reaction for the citric acid cycle is as follows: acetyl-CoA + 3 NAD+ + FAD + GDP + P + 2H2O = CoA-SH + 3NADH + FADH2 + 3H+ + GTP + 2CO2. Many molecules in the citric acid cycle serve as key precursors for other molecules needed by cells.  The citrate generated via the citric acid cycle can serve as an intermediate for fatty acid synthesis; alpha-ketoglutarate can serve as a precursor for glutamate, proline, and arginine; oxaloacetate can serve as a precursor for aspartate and asparagine; succinyl-CoA can serve as a precursor for porphyrins; and acetyl-CoA can serve as a precursor fatty acids, cholesterol, vitamin D, and various steroid hormones. There are several variations to the citric acid cycle that are known. Interestingly, most of the variation lies with the step involving succinyl-CoA production or conversion.  Humans and other animals have two different types of succinyl-CoA synthetases. One produces GTP from GDP, while the other produces ATP from ADP (PMID: 9765291). On the other hand, plants have a succinyl-CoA synthetase that produces ATP (ADP-forming succinyl-CoA synthetase) (Jones RC, Buchanan BB, Gruissem W. (2000). Biochemistry & molecular biology of plants (1st ed.). Rockville, Md: American Society of Plant Physiologists. ISBN 0-943088-39-9.). In certain acetate-producing bacteria, such as Acetobacter aceti, an enzyme known as succinyl-CoA:acetate CoA-transferase performs this conversion (PMID: 18502856) while in Helicobacter pylori succinyl-CoA:acetoacetate CoA-transferase is responsible for this reaction (PMID: 9325289). The citric acid cycle is regulated in a number of ways but the primary mechanism is by product inhibition. For instance, NADH inhibits pyruvate dehydrogenase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, and citrate synthase. Acetyl-CoA inhibits pyruvate dehydrogenase, while succinyl-CoA inhibits alpha-ketoglutarate dehydrogenase and citrate synthase.  Additionally, ATP inhibits citrate synthase and alpha-ketoglutarate dehydrogenase. Calcium is another important regulator of the citric acid cycle. In particular, it activates pyruvate dehydrogenase phosphatase, which then activates pyruvate dehydrogenase. Calcium also activates isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase (PMID: 171557).


Alpha Linolenic Acid and Linoleic Acid Metabolism,Metabolic

Linoleic acid (LNA) is a polyunsaturated fatty acid (PUFA) precursor to the longer n−6 fatty acids commonly known as omega-6 fatty acids. Omega-6 fatty acids are characterized by a carbon-carbon double bond at the sixth carbon from the methyl group. Similarly, the PUFA alpha-linoleic acid (ALA) is the precursor to n-3 fatty acids known as omega-3 fatty acids which is characterized by a carbon-carbon double bond at the third carbon from the methyl group. Both LNA and ALA are essential dietary requirements for all mammals since they cannot be synthesized natively in the body. Both undergo a series of similar conversions to reach their final fatty acid form. LNA enters the cell and is catalyzed to gamma-linolenic acid (GLA) by acyl-CoA 6-desaturase (delta-6-desaturase/fatty acid desaturase 2). GLA is then converted to dihomo-gammalinolenic acid (DGLA) by elongation of very long chain fatty acids protein 5 (ELOVL5). DGLA is then converted to arachidonic acid (AA) by acyl-CoA (8-3)-desaturase (delta-5-desaturase/fatty acid desaturase 1). Arachidonic acid is then converted to a series of short lived metabolites called eicosanoids before finally reaching it's final fatty acid form.


Selenoamino Acid Metabolism,Metabolic

Selenoamino acids include selenocysteine, selenohomocysteine and selenomethionine, amino acids containing a selenium in place of a sulfur. Selenium has important biological functions but may be toxic at high doses. It is believed its toxicity arises from its induction of oxidative stress. Many selenoproteins are antioxidants. Due to its antioxidant effects selenium has become an of interest supplement to prevent diseases and cancers. Selenium and sulfur are very similar chemically, thus sulfur metabolism enzymes will act on selenium as well to form selenoamino acids which then may replace other amino acids  in protein synthesis.


Amino Sugar Metabolism,Metabolic

Amino sugars are sugar molecules containing an amine group. They make up many polysaccharides including, glycosaminoglycans or mucopolysaccharides.


Ammonia Recycling,Metabolic,Ammonia can be rerouted from the urine and recycled into the body for use in nitrogen metabolism. Glutamate and glutamine play an important role in this process. There are many other processes that act to recycle ammonia. asparaginase recycles ammonia from asparagine. Glycine cleavage system generates ammonia from glycine. Histidine ammonia lyase forms ammonia from histidine. Serine dehydratase also produces ammonia by cleaving serine.


Arginine and Proline Metabolism,Metabolic

The arginine and proline metabolism pathway illustrates the biosynthesis and metabolism of several amino acids including arginine, ornithine, proline, citrulline, and glutamate in mammals. In adult mammals, the synthesis of arginine takes place primarily through the intestinal-renal axis (PMID: 19030957). In particular, the amino acid citrulline is first synthesized from several other amino acids (glutamine, glutamate, and proline) in the mitochondria of the intestinal enterocytes (PMID: 9806879). The mitochondrial synthesis of citrulline starts with the deamination of glutamine to glutamate via mitochondrial glutaminase. The resulting mitochondrial glutamate is converted into 1-pyrroline-5-carboxylate via pyrroline-5-carboxylate synthase (P5CS). Alternately, the 1-pyrroline-5-carboxylate can be generated from mitochondrial proline via proline oxidase (PO). Ornithine aminotransferase (OAT) then converts the mitochondrial 1-pyrroline-5-carboxylate into ornithine and the enzyme ornithine carbamoyltransferase (OCT -- using carbamoyl phosphate) converts the ornithine to citrulline (PMID: 19030957). After this, the mitochondrial citrulline is released from the small intestine enterocytes and into the bloodstream where it is taken up by the kidneys for arginine production. Once the citrulline enters the kidney cells, the cytosolic enzyme argininosuccinate synthetase (ASS) will combine citrulline with aspartic acid to generate argininosuccinic acid. After this step, the enzyme argininosuccinate lyase (ASL) will remove fumarate from argininosuccinic acid to generate arginine. The resulting arginine can either stay in the cytosol where it is converted to ornithine via arginase I (resulting in the production of urea) or it can be transported into the mitochondria where it is decomposed into ornithine and urea via arginase II.  The resulting mitochondrial ornithine can then be acted on by the enzyme ornithine amino transferase (OAT), which combines alpha-ketoglutarate with ornithine to produce glutamate and 1-pyrroline-5-carboxylate.  The mitochondrial enzyme pyrroline-5-carboxylate dehydrogenase (P5CD) acts on the resulting 1-pyrroline-5-carboxylate (using NADPH as a cofactor) to generate glutamate. Alternately, the mitochondrial 1-pyrroline-5-carboxylate can be exported into the kidney cell’s cytosol where the enzyme pyrroline-5-carboxylate reductase (P5CR) can convert it to proline. While citrulline-to-arginine production primarily occurs in the kidney, citrulline is readily converted into arginine in other cell types, including adipocytes, endothelial cells, myocytes, macrophages, and neurons.  Interestingly, chickens and cats cannot produce citrulline via glutamine/glutamate due to a lack of a functional pyrroline-5-carboxylate synthase (P5CS) in their enterocytes (PMID: 19030957).


beta-Alanine Metabolism,Metabolic

Beta-alanine, 3-aminopropanoic acid, is a non-essential amino acid. Beta-Alanine is formed by the proteolytic degradation of beta-alanine containing dipeptides: carnosine, anserine, balenine, and pantothenic acid (vitamin B5). These dipeptides are consumed from protein-rich foods such as chicken, beef, pork, and fish. Beta-Alanine can also be formed in the liver from the breakdown of pyrimidine nucleotides into uracil and dihydrouracil and then metabolized into beta-alanine and beta-aminoisobutyrate. Beta-Alanine can also be formed via the action of aldehyde dehydrogenase on beta-aminoproionaldehyde which is generated from various aliphatic polyamines. Under normal conditions, beta-alanine is metabolized to aspartic acid through the action of glutamate decarboxylase. It addition, it can be converted to malonate semialdehyde and thereby participate in propanoate metabolism. Beta-Alanine is not a proteogenic amino acid. This amino acid is a common athletic supplementation due to its belief to improve performance by increased muscle carnosine levels.


Betaine Metabolism,Metabolic

Betaine (or trimethylglycine) is similar to choline (trimethylaminoethanol) but differs in choline's terminal carboxylic acid group trimethylglycine is reduced to a hydroxyl group. Betaine is obtained from diet as betaine or compounds containing choline in foods such as whole grains, beets and spinach. Betaine can also be synthesized from choline in the liver and kidney.  First, choline is oxidized to betaine aldehyde by mitochondrial choline oxidase (choline dehydrogenase). Then, betaine aldehyde dehydrogenase oxidizes betaine aldehyde to betaine in the mitochondria or cytoplasm. In the liver, betaine functions as a methyl donor similar to choline, folic acid, S-adenosyl methionine and vitamin B12. Methyl donors are important for liver function, cellular replication and detoxification reactions. Betaine is also involved in the production of carnitine to protect from kidney damage and functions as an osmoprotectant in the inner medulla.


Biotin Metabolism,Metabolic

Biotin is a vitamin that is an essential nutrient for humans. Biotin can be absorbed from consuming various foods such as: legumes, soybeans, tomatoes, romaine lettuce, eggs, cow's milk, oats and many more. Biotin acts as a cofactor for enzymes to catalyze carboxylation reactions involved in gluconeogenesis, amino acid catabolism and fatty acid metabolism. Biotin deficiency has been associated with many human diseases. These diseases may be caused by dysfunctional biotin metabolism due to enzyme deficiencies. Some research suggests biotin may play a role in transcription regulation or protein expression which may lead to biotin related diseases.


Butyrate Metabolism,Metabolic

Butyrate metabolism (Butanoate metabolism) describes the metabolic fate of a number of short chain fatty acids or short chain alcohols that are typically produced by intestinal fermentation. Many of these molecules are eventually used in the production of ketone bodies, the creation of short-chain lipids or as precursors to the citrate cycle, glycolysis or glutamate synthesis. The molecule for which this pathway is named, butyric acid, is a four-carbon fatty acid that is formed in the human colon by bacterial fermentation of carbohydrates (including dietary fiber). It is found in rancid butter, parmesan cheese, and vomit, and has an unpleasant odor and acrid taste, with a sweet aftertaste (similar to ether).


Caffeine Metabolism,Metabolic

Caffeine is obtained from diet including coffee and other beverages and is absorbed in the stomach and small intestine. In the liver, the cytochrome P450 oxidase enzyme system and specifically CYP1A2 metabolizes caffeine into paraxanthine to increase lipolysis and increase free fatty acids and glycerol levels in the blood, theobromine to dilate blood vessels and increase urine volume and theophylline which relaxes bronchi smooth muscles. In the lysosome, these metabolites undergo further metabolism into methyluric acids before being excreted in the urine. There is genetic variability in the metabolism of caffeine due to the polymorphism of CYP1A2. This variability can affect the pharmacokinetic and pharmacodynamic properties of caffeine and may affect an individual's consumption.


Carnitine Synthesis,Metabolic

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


Catecholamine Biosynthesis,Metabolic

The Catecholamine Biosynthesis pathway depicts the synthesis of catecholamine neurotransmitters. Catecholamines are chemical hormones released from the adrenal glands as a response to stress that activate the sympathetic nervous system. They are composed of a catechol group and are derived from amino acids. The commonly found catecholamines are epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine. They are synthesized in catecholaminergic neurons by four enzymes, beginning with tyrosine hydroxylase (TH), which generates L-DOPA from tyrosine. The L-DOPA is then converted to dopamine via aromatic L-amino acid decarboxylase (AADC), which becomes  norepinephrine via dopamine beta-hydroxylase (DBH); and finally is converted to epinephrine via phenylethanolamine N-methyltransferase (PNMT).


Cysteine Metabolism,Metabolic,The semi-essential amino aid cysteine is tightly regulated in the body to ensure proper levels for metabolism but maintaining levels below toxic thresholds. Cysteine can be obtained from diet or synthesized from  O-acetyl-L-serine. Cystine is the dimeric form of cysteine. Cysteine is a precursor for protein synthesis and an antioxidant. Impaired cysteine metabolism has been linked with neurodegenerative disorders.


D-Arginine and D-Ornithine Metabolism,Metabolic

D-Amino acids have been show to be present in high concentrations in humans and play a role in biological functions. D-Amino may have negative effects as they can be found in some bacteria or form spontaneously in certain reactions. D-Amino acid oxidase (DAAO) is one of the main enzymes that metabolize D-Amino acids via deamination. DAAO is highly specific towards D-amino acids and favours free neutral D-amino acids or those with hydrophobic, polar or aromatic groups. Acidic amino acids are not catalyze by DAOO.


Degradation of Superoxides,Metabolic

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


Ethanol Degradation,Metabolic

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


Fatty Acid Elongation in Mitochondria,Metabolic

Cells typically contain large amounts of C18 and C20 fatty acids. Longer chain fatty acids are found in certain specialized tissues (myelin contains high amounts of C22 and C24 components). Even longer chain fatty acids are derived from either dietary sources or from elongation of C16-CoA or C18-CoA formed by the cytoplasmic fatty acid synthetase system. All of the fatty acids needed by the body can be synthesized from palmitate (C16:0) except the essential, polyunsaturated fatty acids such as linoleate and linolenate. To create longer, shorter, oxidized, reduced fatty acids, palmitic acid is subjected to enzymatic reactions by reductases, hydroxylases, elongases and mixed function oxidases. There are 3 major processes that modify palmitic acid: elongation, desaturation and hydroxylation. Elongation of fatty acids may occur at endoplasmic reticulum where fatty acid molecules of length up to C24 may be produced. Mitochondrial elongation may result in fatty acids up to C16 in length. Fatty acid elongation in mitochondria is essentially the reverse of beta-oxidation for fatty acid oxidation. In particular, both pathways make use of acetyl-CoA acyltransferase, 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase. The final step of fatty acid elongation uses enoyl-CoA reductase (not part of the beta-oxidation pathway). The elongation takes place in the mitochondrial matrix. In liver and kidney fatty acid elongation operates best in the presence of both NADH and NADPH, whereas in heart and skeletal muscle, only NADH is required. The mitochondrial pathway is important for elongating fatty acids containing 14 or fewer carbon atoms. Short chain fatty acids (SCFA) are fatty acids with aliphatic tails of less than six carbons. Medium chain fatty acids (MCFA) are fatty acids with aliphatic tails of 612 carbons. Long chain fatty acids (LCFA) are fatty acids with aliphatic tails longer than 12 carbons. Very Long chain fatty acids (VLCFA) are fatty acids with aliphatic tails longer than 22 carbons.


Fatty Acid Metabolism,Metabolic

Fatty acids constitute a large energy source for the body. The cellular membrane is also made up of fatty acids. During starvation times, fatty acids can provide energy to humans for numerous days. Fatty acid metabolism is also known as beta-oxidation. During metabolism, acetyl CoA is produced that can then enter the citric acid cycle. When ATP is needed, ATP may be generated by increasing fatty acid metabolism. Fatty acid metabolism is essentially the reverse reaction of fatty acid synthesis.


Folate Metabolism,Metabolic

The 1-carbon transformations require folic acid (folate). Folic acid participates in both the activation of single carbons as well as in the oxidation and reduction of single carbons. Folate-dependent single-carbon reactions are important in amino acid metabolism and in biosynthetic pathways leading to DNA, RNA, membrane lipids, and neurotransmitters. To carry out the transfer of 1-carbon units, NADPH must reduce folic acid two times in the cell. The pyrazine ring of the 6-methylpterin is reduced at each of the two N-C double bonds. More precisely, the pathway leading to the formation of tetrahydrofolate (THF) begins when folate (F) is reduced to dihydrofolate (DHF) which is then reduced to THF. Dihydrofolate reductase catalyses the last step. Vitamin B3 in the form of NADPH is a necessary cofactor for both steps of the synthesis. The resulting 5,6,7,8-tetrahydrofolate (THF) is the acceptor of 1-carbon groups. Tetrahydrofolate accepts methyl groups, usually from serine. The product, N5,N10-methylene-tetrahydrofolate, is the central compound in 1-carbon metabolism. Methylene-THF (CH2FH4) is formed from THF by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Tetrahydrofolate can also accept a methyl group from the complete breakdown of glycine. The N5,N10-methylene-tetrahydrofolate can either donate its single-carbon group directly, be oxidized by NADP to the methenyl form, or be reduced by NADH to the methyl form. Depending on the biosynthetic pathway involved, any of these species can donate the 1-carbon group to an acceptor. The methylene form donates its methyl group during the biosynthesis of thymidine nucleotides for DNA synthesis, the methenyl form donates its group as a formyl group during purine biosynthesis, and the methyl form is the donor of the methyl group to sulfur during methionine formation. Methyl tetrahydrofolate (CH3-THF) can be made from methylene-THF by reduction of the methylene group with NADPH. Another form of THF, formyl-THF or folinic acid) results from oxidation of methylene-THF or is formed from formate donating formyl group to THF. Finally, histidine can donate a single carbon to THF to form methenyl-THF.


Fructose and Mannose Degradation,Metabolic

Fructose and mannose are monosaccharides that can be found in many foods. Fructose can join with glucose to form sucrose. Mannose can be converted to glucose. Both may be used as food sweeteners. Fructose is well absorbed, especially in the presence of glucose. Fructose causes less of an insulin response compared to glucose and thus may be a preferred sugar for diabetics. In contrast to fructose, humans do not metabolize mannose well with the majority of it being excreted unchanged. Mannose in the urine can be beneficial in treating urinary tract infections caused be E. coli. However, mannose can be detrimental to humans by causing diabetic complications.


Glycerol Phosphate Shuttle,Metabolic,The glycerol phosphate shuttle also known as the glycerophosphate shuttle. It shuttles electrons to mitochondrial carriers in the oxidative phosphorylation pathway from cytosolic NADH. This shuttle relies on mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH). This is also a common process for the cell  to regenerate cytosolic NAD+ for other processes.


Homocysteine Degradation,Metabolic

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


Ketone Body Metabolism,Metabolic

Ketone bodies are consisted of acetone, beta-hydroxybutyrate and acetoacetate. In liver cells' mitochondria, acetyl-CoA can synthesize acetoacetate and beta-hydroxybutyrate; and spontaneous decarboxylation of acetoacetate will form acetone. Metabolism of ketone body (also known as ketogenesis) contains several reactions. Acetoacetic acid (acetoacetate) will be catalyzed to form acetoacetyl-CoA irreversibly by 3-oxoacid CoA-transferase 1 that also coupled with interconversion of succinyl-CoA and succinic acid. Acetoacetic acid can also be catalyzed by mitochondrial D-beta-hydroxybutyrate dehydrogenase to form (R)-3-Hydroxybutyric acid with NADH. Ketogenesis occurs mostly during fasting and starvation.  Stored fatty acids will be broken down and mobilized to produce large amount of acetyl-CoA for ketogenesis in liver, which can reduce the demand of glucose for other tissues. Acetone cannot be converted back to acetyl-CoA; therefore, they are either breathed out through the lungs or excreted in urine.


Lysine Degradation,Metabolic

The degradation of L-lysine happens in liver and it is consisted of seven reactions. L-Lysine is imported into liver through low affinity cationic amino acid transporter 2 (cationic amino acid transporter 2/SLC7A2). Afterwards, L-lysine is imported into mitochondria via mitochondrial ornithine transporter 2.  L-Lysine can also be obtained from biotin metabolism. L-Lysine and oxoglutaric acid will be combined to form saccharopine by facilitation of mitochondrial alpha-aminoadipic semialdehyde synthase, and then, mitochondrial alpha-aminoadipic semialdehyde synthase will further breaks saccharopine down to allysine and glutamic acid. Allysine will be degraded to form aminoadipic acid through alpha-aminoadipic semialdehyde dehydrogenase. Oxoadipic acid is formed from catalyzation of mitochondrial kynurenine/alpha-aminoadipate aminotransferase on aminoadipic acid. Oxoadipic acid will be further catalyzed to form glutaryl-CoA, and glutaryl-CoA converts to crotonoyl-CoA, and crotonoyl-CoA transformed to 3-hydroxybutyryl-CoA. 3-Hydroxybutyryl-CoA will form Acetyl-CoA as the final product through the intermediate compound: acetoacetyl-CoA. Acetyl-CoA will undergo citric acid cycle metabolism. Carnitine is another key byproduct of lysine metabolism (not shown in this pathway).


Malate-Aspartate Shuttle,Metabolic

The malate-aspartate shuttle (also known as the malate shuttle) is used by mitochondria for translocating electrons produced during glycolysis across the impermeable inner membrane for oxidative phosphorylation. This allows the hydrogen ions of the cofactor NADH produced in the cytosol to reach the electron transport chain in the mitochondria and generate ATP. The shuttle system is required because the inner membrane is impermeable to NADH and its oxidized form NAD+. NAD+/NADH does not cross the membrane, only ions (attached to malate) cross it. In this particular shuttle process, oxaloacetate on the cytoplasmic side is first reduced by NADH, creating malate and NAD+. Malate and the electrons it carries are transported into the mitochondria across the inner mitochondrial membrane, in exchange for alpha-ketoglutarate, which is transported out of the mitochondria. Once inside, the energy in malate is extracted again by reducing NAD+ to make NADH, thereby regenerating oxaloacetate. This NADH is then free to transfer its electrons to the electron transport chain. The oxaloacetate is transaminated with glutamate to make aspartate and alpha-ketoglutarate. Aspartate is returned to the cytosol by the aspartate-glutamate transporter, which moves glutamate into the mitochondria as it transports aspartate out. The net result is that NADH is transported into the mitochondria, generating 3 ATP molecules for every NADH transported in from the cytosol.


Nucleotide Sugars Metabolism,Metabolic

Nucleotide sugars are defined as any nucleotide in which the distal phosphoric residue of a nucleoside 5'-diphosphate is in glycosidic linkage with a monosaccharide or monosaccharide derivative. There are nine sugar nucleotides and they can be classified depending on the type of the nucleoside forming them: UDP-Glc, UDP-Gal, UDP-GlcNAc, UDP-GlcUA, UDP- Xyl, GDP-Man, GDP-Fuc and CMP-NeuNAc. Turning back now to the pathway in question, namely the nucleotide sugar metabolism pathway, it should be noted that the nucleotide sugars play an important role. Indeed, they are donors of certain important residues of sugar which are vital to glycosylation and by extension tot the production of polysaccharides. This process produces the substrates for glycosyltransferases. These sugars have several additional roles. For example, nucleotide sugars serve a vital purpose as the intermediates in interconversions of nucleotide sugars that result in the creation and activation of certain sugars necessary in the glycosylation reaction in certain organisms. Moreover, the process of glycosylation is attributed mostly (though not entirely) to the endoplasmic reticulum/golgi apparatus. Logically then, due to the important role of nucleotide sugars in glycosylation, a plethora of transporters exist which displace the sugars from their point of production, the cytoplasm, to where they are needed. In the case, the endoplasmic reticulum and golgi apparatus.


Pantothenate and CoA Biosynthesis,Metabolic

Panthothenate (vitamin B5) is the precursor of coenzyme A and is the prosthetic group of acyl carrier protein (ACP). Its name is derived from the Greek pantothen meaning "from everywhere" and small quantities of pantothenic acid are found in nearly every foodstuff. Coenzyme A (CoA) may act as an acyl group carrier to form acetyl-CoA and other related compounds and is used as a way to transport carbon atoms within the cell. CoA is important in energy metabolism for pyruvate to enter TCA cycle as acetyl-CoA, and for α-ketoglutarate to be transformed to succinyl-CoA in the cycle. CoA is also important in the biosynthesis of many important compounds such as fatty acids, cholesterol, and acetylcholine. About 85% of dietary pantothenic acid is as CoA or phosphopentetheine. In the intestinal lumen, these undergo hydrolysis to phosphopantetheine, then pantetheine. Intestinal mucosal cells have high pantetheinase activity and rapidly hydrolyze pantetheine to yield free pantothenic acid. Coenzyme A is synthesized in a five-step process from pantothenate. First, antothenate (Vitamin B5) is phosphorylated to 4'-phosphopantothenate by the enzyme pantothenate kinase, next a cysteine is added to 4'-phosphopantothenate by the enzyme phosphopantothenoylcysteine synthetase to form 4'-phospho-N-pantothenoylcysteine (PPC). In the next step, PPC is decarboxylated to 4'-phosphopantetheine by phosphopantothenoylcysteine decarboxylase. In the fourth step, 4'-phosphopantetheine is adenylylated to form dephospho-CoA by the enzyme phosphopantetheine adenylyl transferase. Finally, dephospho-CoA is phosphorylated using ATP to coenzyme A by the enzyme dephosphocoenzyme A kinase. CoA undergoes dephosphorylation, catalyzed by lysosomal acid phosphatasae to dephospho-CoA, followed by pyrophosphatase action to release 4’-phosphotantetheine and 5’AMP. Red blood cells contain pantothenic acid, pantetheine 4’-phosophate and pantetheine.


Phenylacetate Metabolism,Metabolic

Phenylacetate (or phenylacetic acid) metabolism involves two steps. The first step is the conversion of phenylacetate into phenylacetyl-CoA which is catalyzed by acyl-coenzyme A synthetase ACSM1 or acyl-coenzyme A synthetase ACSM2B. Coenzyme A and ATP are also involved in this first step and AMP and pyrophosphate will be generated during the first step of metabolism. In the second step, phenylacetyl-CoA and L-glutamine interacts with glycine N-acyltransferase to generate coenzyme A as well as phenylacetylglutamine, of which the latter will be excreted in the urine. Phenylacetate metabolism provides a route that facilitates the excretion of nitrogen for patients with urea cycle defects; hence, it is important for clinical purposes.


Pyruvaldehyde Degradation,Metabolic

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


Riboflavin Metabolism,Metabolic

Riboflavin (vitamin B2) is an important part of the enzyme cofactors FAD (flavin-adenine dinucleotide) and FMN (flavin mononucleotide).  The name "riboflavin" actually comes from "ribose" and "flavin".  Like the other B vitamins, riboflavin is needed for the breaking down and processing of  ketone bodies, lipids, carbohydrates, and proteins.  Riboflavin is found in many different foods, such as meats and vegetables.As the digestion process occurs, many different flavoproteins that come from food are broken down and riboflavin is reabsorbed. The reverse reaction is mediated by acid phosphatase 6. FMN can be turned into to FAD via FAD synthetase, while the reverse reaction is mediated by nucleotide pyrophosphatase.  FAD and FMN are essential hydrogen carriers and are involved in over 100 redox reactions that take part in energy metabolism.


Thiamine Metabolism,Metabolic

Thiamin(e), also known as vitamin B1, is known to play a fundamental role in energy metabolism. It consists of a pyrimidine ring (2,5-dimethyl-6-aminopyrimidine) and a thiazolium ring (4-methyl-5-hydroxy ethyl thiazole) joined by a methylene bridge. Thiamine is found in a wide variety of foods at low concentrations. Yeast and pork are the most highly concentrated sources of thiamine. Cereal grains, however, are generally the most important dietary sources of thiamine, by virtue of their ubiquity. Of these, whole grains contain more thiamine than refined grains. Thiamine is released by the action of phosphatase and pyrophosphatase in the upper small intestine. At low concentrations the process is carrier mediated and at higher concentrations, absorption occurs via passive diffusion. Active transport is greatest in the jejunum and ileum (it is inhibited by alcohol consumption and by folic deficiency). The majority of thiamine in serum is bound to proteins, mainly albumin. Uptake of thiamine by cells of the blood and other tissues occurs via active transport and passive diffusion. About 80% of intracellular thiamine is phosphorylated and most is bound to proteins. Thiamine and its acid metabolites (2-methyl-4-amino-5-pyrimidine carboxylic acid, 4-methyl-thiazole-5-acetic acid and thiamine acetic acid) are excreted principally in the urine. Thiamine is mainly the transport form of the vitamin, while the active forms are phosphorylated thiamine derivatives. There are four known natural thiamine phosphate derivatives: thiamine monophosphate (ThMP), thiamine diphosphate (ThDP), also sometimes called thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), and the recently discovered adenosine thiamine triphosphate (AThTP) and adenosine thiamine diphosphate (AThDP). Thiamine monophosphate (TMP) is an intermediate to facilitate the synthesis of free thiamine to thiamine diphosphate and triphosphate. The synthesis of thiamine diphosphate (ThDP), also known as thiamine pyrophosphate (TPP) or cocarboxylase, is catalyzed by an enzyme called thiamine diphosphokinase. TPP activates decarboxylation of pyruvate in the pyruvate dehydrogenase complex. This complex is a group of enzymes and cofactors that form acetyl CoA that condenses with oxaloacetate to form citrate, the first component of the citric acid cycle.


Spermidine and Spermine Biosynthesis,Metabolic

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


Taurine and Hypotaurine Metabolism,Metabolic

There is an organic acid known as Taurine, which is a derivative product of sulfhydryl amino acid (which contains sulfur), as well as cysteine.  The synthesis or metabolism in mammalian systems of this acid transpires within the pancreas in such a fashion that it utilizes a pathway known as the cysteine sulfinic acid pathway.To put this process in context, its occurrence is often seen in vivo, in hepatocytes, and is fundamental in the cyclical process of recovering bile acids from the intenstine, turning them back into salts and returning them to the bile. In essence the cysteine pathway induces a sulfhydryl group to be oxidized, creating cysteine sulfinic acid, by utilizing the appropriate enzymes (ie cysteine dioxygenase). This new acid undergoes decarboxylation creating a new compound: hypotaurine. This process goes on as Taurine now is subjected to conjugation vis a vis its amino terminal group. This includes acids such as chenodeoxycholic acid and cholic acid, and in turn the formation of bile salts occurs.Moreover, this entire process can be catalyzed via bile acid and a special amino acid N-acetyltransferase.


Ubiquinone Biosynthesis,Metabolic

Ubiquinone is also known as coenzyme Q10. It is a 1,4-benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the isoprenyl chemical subunits. Ubiquinone is a carrier of hydrogen atoms (protons plus electrons) and functions as an ubiquitous coenzyme in redox reactions, where it is first reduced to the enzyme-bound intermediate radical semiquinone and in a second reduction to ubiquinol (Dihydroquinone; CoQH2). Ubiquinone is not tightly bound or covalently linked to any known protein complex but is very mobile. In eukaryotes ubiquinones were found in the inner mito-chondrial membrane and in other membranes such as the endoplasmic reticulum, Golgi vesicles, lysosomes and peroxisomes. The benzoquinone portion of Coenzyme Q10 is synthesized from tyrosine, whereas the isoprene sidechain is synthesized from acetyl-CoA through the mevalonate pathway. The mevalonate pathway is also used for the first steps of cholesterol biosynthesis. The enzyme para-hydroxybenzoate polyprenyltransferase catalyzes the condensation of p-hydroxybenzoate with polyprenyl diphosphate to generate ubiquinone.


Sulfate/Sulfite Metabolism,Metabolic

This pathway illustrates the conversion of sulfite to sulfate (via sulfate oxidase) and subsequent generation of adenylylsulfate (APS) via 3'-phosphoadenosine 5'-phosphosulfate synthase 2. APS is converted to phosphoadenylyl-sulfate (PAPS) via adenylylsulfate kinase. APS can also be regenerated from PAPS by 3'(2'), 5'-bisphosphate nucleotidase 1. PAPS is eventually converted to adenosine bisophosphate (PAP) through the action of several different enzymes including aryl sulfotransferase, chondroitin 4-sulfotransferase 13 and estrone sulfotransferase. The metabolism pathway in question is important for many reasons. Recall, that the sulfite ion is in fact the conjugate base of sulfurous acid. Moreover, this ion is found naturally in one of the worlds most popular beverages, wines. Beyond its natural occurence, sulfite ion had the property of stopping fermentation. As such, the addition of it to products such as wine can be used either as a preservative or to stop the fermentation process at a moment which is of interest. Finally, this preservation property goes beyond merely wines, and finds utility in dried fruits, potatoes, etc.


Phytanic Acid Peroxisomal Oxidation,Metabolic

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


Phenylalanine and Tyrosine Metabolism,Metabolic

In man, phenylalanine is an essential amino acid which must be supplied in the dietary proteins.  Once in the body, phenylalanine may follow any of three paths.  It may be (1) incorporated into cellular proteins, (2) converted to phenylpyruvic acid, or (3) converted to tyrosine.  Tyrosine is found in many high protein food products such as soy products, chicken, turkey, fish, peanuts, almonds, avocados, bananas, milk, cheese, yogurt, cottage cheese, lima beans, pumpkin seeds, and sesame seeds.  Tyrosine can be converted into L-DOPA, which is further converted into dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline).  Depicted in this pathway is the conversion of phenylalanine to phenylpyruvate (via amino acid oxidase or tyrosine amino transferase acting on phenylalanine), the incorporation of phenylalanine and/or tyrosine into polypeptides (via tyrosyl tRNA synthetase and phenylalyl tRNA synthetase) and the conversion of phenylalanine to tyrosine via phenylalanine hydroxylase.  This reaction functions both as the first step in tyrosine/phenylalanine catabolism by which the body disposes of excess phenylalanine, and as a source of the amino acid tyrosine.  The decomposition of L-tyrosine begins with an α-ketoglutarate dependent transamination through the tyrosine transaminase to para-hydroxyphenylpyruvate.  The next oxidation step catalyzed by p-hydroxylphenylpyruvate-dioxygenase creates homogentisate.  In order to split the aromatic ring of homogentisate, a further dioxygenase, homogentistate-oxygenase, is required to create maleylacetoacetate.  Fumarylacetate is created by the action maleylacetoacetate-cis-trans-isomerase through rotation of the carboxyl group created from the hydroxyl group via oxidation.  This cis-trans-isomerase contains glutathione as a coenzyme.  Fumarylacetoacetate is finally split via fumarylacetoacetate-hydrolase into fumarate (also a metabolite of the citric acid cycle) and acetoacetate (3-ketobutyroate).


Histidine Metabolism,Metabolic

Histidine is unique in that its biosynthesis is inherently linked to the pathways of nucleotide formation.  The biosynthesis of histidine in adults begins with the condensation of ATP and PRPP (phosphoribosyl pyrophosphate) to form N-5-phosphoribosyl 1-pyrophosphate (phosphoribosyl-ATP).  It is also worth noting that PRPP is the starting point for purine and pyrimidine biosynthesis.  Subsequent histidine biosynthetic steps (from phosphoribosyl-ATP onwards) likely take place in the intestinal microflora.  Elimination of the phosphate and the opening of the ring in phosphoribosyl-ATP forms phosphoribosyl-forminino-5-aminoimidazole-4-carboxamide ribonucleotide (phosphoribosyl-formimino-AICAR-phosphate).  This is subsequently converted to 5-phosphoribulosyl-forminino-5-aminoimidazole-4-carboxamide ribonucleotide.  Cleavage of this intermediate results in the formation of imidazole glyercol phosphate and AICAR (aminoimidazolecarboxamide ribonucleotide) with glutamine playing a role as an amino group donor.  AICAR is recycled through the purine pathway while the imidazole glycerol phosphate is converted to imidazole acetal phosphate.  Transamination yields histidinol phosphate which is converted to histidinol and finally to histidine.  Histidine catabolism begins with release of the α-amino group catalyzed by histidase, leading to the deaminated product, urocanate.  Urocanate is converted to 4-imidazolone-5-propionate via the action of urocanate hydratase.  The latter product is then converted to N-formiminoglutamte via the action of imidazolone propionase.  The enzyme formiminotransferase cyclodeaminase then removes the formimino group to yield glutamate.  Because the end product of histidine catabolism is glutamate this makes histidine one of the glucogenic amino acids.  Another key feature of histidine catabolism is that it serves as a source of ring nitrogen to combine with tetrahydrofolate (THF), producing the 1-carbon THF intermediate known as N5-formiminoTHF.  The latter reaction is one of two routes to N5-formiminoTHF.  Decarboxylation of histidine in the intestine by bacteria gives rise to histamine.  Similarly, histamine arises in many tissues by the decarboxylation of histidine, which in excess causes constriction or dilation of various blood vessels.  Once histamine is generated it can be converted to several breakdown products including N-methylhistamine, imidazole acetaldehyde, methylimidazole acetaldehyde and methylimidazole-acetic acid.  Histidine is also a precursor for carnosine biosynthesis (via carnosine synthase), with beta-alanine being the rate limiting precursor.   Anserine can be synthesized either from carnosine via carnosine N-methyltransferase or from 1-methylhistidine via carnosine synthase.   Inversely, cytosolic non-specific dipeptidase catalyzes the synthesis of 1-methylhistidine from anserine.


Arachidonic Acid Metabolism,Metabolic

This pathway describes the production and subsequent metabolism of arachidonic acid, an omega-6 fatty acid. In resting cells arachidonic acid is present in the phospholipids (especially phosphatidylethanolamine and phosphatidylcholine) of membranes of the body’s cells, and is particularly abundant in the brain. Typically a receptor-dependent event, requiring a transducing G protein, initiates phospholipid hydrolysis and releases the fatty acid into the intracellular medium. Three enzymes mediate this deacylation reaction including phospholipase A2 (PLA2), phospholipase C (PLC), and phospholipase D (PLD). Once released, free arachidonate has three possible fates: 1) reincorporation into phospholipids, 2) diffusion outside the cell, and 3) metabolism. Arachidonate metabolism is carried out by three distinct enzyme classes: cyclooxygenases, lipoxygenases, and cytochrome P450’s. Specifically, the enzymes cyclooxygenase and peroxidase lead to the synthesis of prostaglandin H2, which in turn is used to produce the prostaglandins, prostacyclin, and thromboxanes. The enzyme 5-lipoxygenase leads to 5-HPETE, which in turn is used to produce the leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and lipoxins. Some arachidonic acid is converted into midchain HETEs, omega-chain HETEs, dihydroxyeicosatrienoic acids (DHETs), and epoxyeicosatrienoic acids (EETs) by cytochrome P450 epoxygenase hydroxylase activity. Several products of these pathways act within neurons to modulate the activities of ion channels, protein kinases, ion pumps, and neurotransmitter uptake systems, affecting processes such as cellular proliferation, inflammation, and hemostasis. The newly formed eicosanoids may also exit the cell of origin and bind to G-protein-coupled receptors present on nearby neurons or glial cells.


Androgen and Estrogen Metabolism,Metabolic

This pathway describes the inactivation and catabolism of male (androgen) and female (estrogen) hormones. Many steroid hormones are transformed by sulfatases, dehydrogenases and glucuronide transferases to enhance their solubility and to facilitate their elimination. Inactivation refers to the metabolic conversion of a biologically active compound into an inactive one. Peripheral inactivation (e.g. by liver enzymes) is required to ensure steady-state levels of plasma androgens and estrogens. Specifically, if an androgen or estrogen is to act as a " chemical signal ", its half-life in the circulation must be limited, so that any change in secretion rate is immediately reflected by a change in its plasma concentration. But hormone inactivation can also occur in target tissues, notably after the hormone has triggered the relevant biological effects in order to ensure termination of hormone action. The main site of peripheral androgen/estrogen inactivation and catabolism is the liver, but some catabolic activity also occurs in the kidneys. Inactive androgens and estrogens are mainly eliminated as urinary (mostly conjugated) metabolites. This elimination requires conversion to hydrophilic compounds in order to ensure their solubility in biological fluids at rather high concentrations. Depending on the structure of the starting steroid there may be: 1) Reduction of a double bond at C-4 and reduction of an oxo(keto) group at C-3 to a secondary alcoholic group; 2) Reduction of an oxo group at C-20 to a secondary alcoholic group; 3) Oxidation of a 17ß-hydroxyl group; 4) Further hydroxylations at various positions of the steroid nucleus (e.g. 7-hydroxylation of 5a-reduced androgens) or 5) Conjugation (sulphate and/or glucuronide derivatives).


Glucose-Alanine Cycle,Metabolic

The glucose-alanine cycle—also referred to in the literature as the Cahill cycle or the alanine cycle—involves muscle protein being degraded to provide more glucose to generate additional ATP for muscle contraction. It allows pyruvate and glutamate to be transported out of muscle tissue to the liver where gluconeogenesis takes place to supply the muscle tissue with more glucose as mentioned previously. To initiate the cycle, muscle and tissues that catabolize amino acids for fuel generate amino groups—most commonly in the form of glutamate—through the process of transamination. These amino groups are transferred via alanine aminotransferase to pyruvate (a product of glycolysis) to form alanine and alpha-ketoglutarate. Alanine subsequently moves through the circulatory system to the liver where the reaction previously catalyzed by alanine aminotransferase is reversed to produce pyruvate. This pyruvate is converted into glucose through the process of gluconeogenesis which subsequently is transported back to the muscle tissue. Meanwhile, glutamate dehydrogenase in the mitochondria catabolizes glutamate into ammonium. Ammonium moves on to form urea in the urea cycle.


Vitamin K Metabolism,Metabolic

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


Phospholipid Biosynthesis,Metabolic

This pathway describes the synthesis of the common phospholipids, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and cardiolipins. Phospholipids can be synthesized by two mechanisms. One utilizes a CDP-activated polar head group for attachment to the phosphate of phosphatidic acid. The other utilizes CDP-activated 1,2-diacylglycerol and an inactivated polar head group. Phospholipids are synthesized in the ER membrane from cytosolic precursors. Two fatty acids linked to coenzyme A (CoA) carriers are first joined to glycerol-3-phosphate, yielding phosphatidic acid, which is simultaneously inserted into the membrane. A phosphatase then converts phosphatidic acid to diacylglycerol. The attachment of different polar head groups to diacylglycerol then results in formation of phosphatidylcholine, phosphatidylethanolamine, or phosphatidylserine. Phosphatidylinositol is formed from phosphatidic acid, rather than from diacylglycerol. Initially, most phospholipids have a saturated fatty acid on C-1 and an unsaturated fatty acid on C-2 of the glycerol backbone. However, the fatty acid distribution at the C–1 and C–2 positions of glycerol within phospholipids is continually in flux, owing to phospholipid degradation and the continuous phospholipid remodeling that occurs while these molecules are in membranes. In many cases the acyl group which was initially transferred to glycerol, by the action of the acyl transferases, is not the same acyl group present in the phospholipid when it resides within a membrane. The remodeling of acyl groups in phospholipids is the result of the action of phospholipase A1 (PLA1) and phospholipase A2 (PLA2). The most commonly added alcohols (serine, ethanolamine and choline) also contain nitrogen that may be positively charged, whereas, glycerol and inositol do not.


Lactose Synthesis,Metabolic

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


Steroid Biosynthesis,Metabolic

The steroid biosynthesis (or cholesterol biosynthesis) pathway is an anabolic metabolic pathway that produces steroids from simple precursors. It starts with the mevalonate pathway, where acetyl-CoA and acetoacetyl-CoA are the first two building blocks. These compounds are joined together via the enzyme hydroxy-3-methylgutaryl (HMG)-CoA synthase to produce the compound known as hydroxy-3-methylgutaryl-CoA (HMG-CoA). This compound is then reduced to mevalonic acid via the enzyme HMG-CoA reductase. It is important to note that HMG-CoA reductase is the protein target of many cholesterol-lowering drugs called statins (PMID: 12602122). The resulting mevalonic acid (or mevalonate) is then phosphorylated by the enzyme known as mevalonate kinase to form mevalonate-5-phosphate, which is then phosphorylated again by phosphomevalonate kinase to form mevolonate-5-pyrophsophate. This pyrophosphorylated compound is subsequently decarboxylated via the enzyme mevolonate-5-pyrophsophate decarboxylase to form isopentylpyrophosphate (IPP). IPP can also be isomerized (via isopentenyl-PP-isomerase) to form dimethylallylpyrophosphate (DMAPP). IPP and DMAPP can both donate isoprene units, which can then be joined together to make farnesyl and geranylgeranyl intermediates. Specifically, three molecules of IPP condense to form farnesyl pyrophosphate through the action of the enzyme known as geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form a molecule known as squalene by the action of the enzyme known as squalene synthase in the cell’s endoplasmic reticulum. The enzyme oxidosqualene cyclase then cyclizes squalene to form lanosterol. Lanosterol is a tetracyclic triterpenoid, and serves as the framework from which all steroids are derived. 14-Demethylation of lanosterol by a cytochrome P450 enzyme known as CYP51 eventually yields cholesterol. Cholesterol is the central steroid in human biology. It can be obtained from animal fats consumed in the diet or synthesized de novo (as described above). Cholesterol is an essential constituent of lipid bilayer membranes (where it forms cholesterol esters) and is the starting point for the biosynthesis of steroid hormones, bile acids and bile salts, and vitamin D. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (via glucocorticoids such as cortisol), salt balance (mineralocorticoids such as aldosterone), and sexual development and function (via androgens such as testosterone and estrogens such as estradiol). Bile acids and bile salts (such as taurocholate) are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Cholesterol is the main constituent of atheromas. These are the fatty lumps found in the walls of arteries that occur in atherosclerosis and, when ruptured, can cause heart attacks.


Purine Metabolism,Metabolic

Purines are heterocyclic aromatic organic compounds, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines, are the most widely distributed kind of nitrogen-containing heterocycle in nature. The two most important purines are adenine and guanine. Other notable purines are hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine. Purines are found in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. This pathway depicts a number of processes including purine nucleotide biosynthesis, purine degradation and purine salvage. The major site of purine nucleotide synthesis is in the liver. Synthesis of the purine nucleotides begins with PRPP and leads to the first fully formed nucleotide, inosine 5'-monophosphate (IMP). IMP synthesis begins with 5-phospho-α-ribosyl-1-pyrophosphate, PRPP. Through a series of reactions utilizing ATP, tetrahydrofolate (THF) derivatives, glutamine, glycine and aspartate this pathway yields IMP. The rate limiting reaction is catalyzed by glutamine PRPP amidotransferase which drives the reaction with PRPP and glutamine yielding 5-phosphoribosylamine (PRA). 5-phosphoribosylamine is converted to glycinamide ribotide (GAR) then to formyglycinamide ribotide (FGAR). This set of reactions is catalyzed by a trifunctional enzyme containing GAR synthetase, GAR transformylase and AIR synthetase. FGAR is converted to formylglycinamidine-ribonucleotide (FGAM) by formylglycinamide synthase. FGAM is then converted by aminoimidzaole ribotide synthase to 5-aminoimidazole ribotide (AIR) then carboxylated by aminoimidazole ribotide carboxylase to carboxyaminoimidazole ribotide (CAIR). CAIR is then converted to succinylaminoimidazole carboxamide ribotide (SAICAR) by succinylaminoimidazole carboxamide ribotide synthase followed by conversion to AICAR (via adenylsuccinate lyase) then to FAICAR (via aminoimidazole carboxamide ribotide transformylase). FAICAR is finally converted to inosine monophosphate (IMP) by IMP cyclohydrolase. Because of the complexity of this synthetic process, the purine ring is actually composed of atoms derived from many different molecules. The N1 atom arises from the amine group of Asp, the C2 and C8 atoms originate from formate, the N3 and N9 atoms come from the amide group of Gln, the C4, C5 and N7 atoms come from Gly and the C6 atom comes from CO2. IMP represents a branch point for purine biosynthesis, because it can be converted into either AMP or GMP through two distinct reaction pathways. AMP is generated from IMP via adenylsuccinate synthetase (which adds aspartate) and adenylsuccinate lyase. GMP is generated via the action of IMP dehydrogenase and GMP synthase. Catabolism of purine nucleotides ultimately leads to the production of uric acid. Beginning from AMP, the enzymes AMP deaminase and nucleotidase work in concert to generate inosine. Alternately, AMP may be dephosphorylate by nucleotidase and then adenosine deaminase (ADA) converts the free adenosine to inosine. The enzyme purine nucleotide phosphorylase (PNP) converts inosine to hypoxanthine, while xanthine oxidase converts hypoxanthine to xanthine and finally to uric acid. GMP and XMP can also be converted to uric acid via the action of nucleotidase, PNP, guanine deaminase and xanthine oxidase. The synthesis of nucleotides from the purine bases and purine nucleosides takes place in a series of steps known as the salvage pathways. The free purine bases, adenine, guanine, and hypoxanthine, can be reconverted to their corresponding nucleotides by phosphoribosylation. Two key transferase enzymes are involved in the salvage of purines: adenosine phosphoribosyltransferase (APRT), which catalyzes the conversion of adenine to AMP and hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which catalyzes the conversion of hypoxanthine to IMP.


Vitamin B6 Metabolism,Metabolic

As is commonly known there are many vitamins, the vitamin B complex group being one of the most well known. An important vitamin B complex group vitamin is vitamin B6, which is water-soluble. Moreover, this vitamin comes in various forms, one of which is an active form, known by the name pyridoxal phosphate or PLP. PLP serves as cofactor in a variety of reactions including from amino acid metabolism, (in particular in reactions such as transamination, deamination, and decarboxylation). To complicate matters however, there are in fact seven alternate forms of this same vitamin. These include pyridoxine (PN), pyridoxine 5’-phosphate (PNP), pyridoxal (PL), pyridoxamine (PM), pyridoxamine 5’-phosphate (PMP), 4-pyridoxic acid (PA), and the aforementioned pyridoxal 5’-phosphate (PLP). One of these forms, PA, is in fact a catabolite whose presence is found in excreted urine. For a person to absorb some of these active forms of vitamin B6 such as PLP or PMP they must first be dephosphorylized. This done via an alkaline enzyme phosphatase. There are a wide variety of biproducts from the metabolism in question, most of which find there ways into the urine and from there are excreted. One such biproduct is 4-pyridoxic acid. In fact this last biproduct is found in such large quantities that estimates of vitamin B6 metabolism birproducts show that 4-pyridoxic acid is as much as 40-60% of all the biproducts.Of course, it is not the only product of metabolism. Others include,include pyridoxal, pyridoxamine, and pyridoxine.


Pyruvate Metabolism,Metabolic

Pyruvate is an intermediate compound in the metabolism of fats, proteins, and carbohydrates. It can be formed from glucose via glycolysis or the transamination of alanine. It can be converted into Acetyl-CoA to be used as the primary energy source for the TCA cycle, or converted into oxaloacetate to replenish TCA cycle intermediates. Pyruvate can also be used to synthesize carbohydrates, fatty acids, ketone bodies, alanine, and steroids. In conditions of inssuficient oxygen or in cells with few mitochondria, pyruvate is reduced to lactate in order to re-oxidize NADH back into NAD+Pyruvate participates in several key reactions and pathways. In glycolysis, phosphoenolpyruvate (PEP) is converted to pyruvate by pyruvate kinase in an highly exergonic and irreversible reaction. In gluconeogenesis, pyruvate carboxylase and PEP carboxykinase are needed to catalyze the conversion of pyruvate to PEP. In fatty acid synthesis, the pyruvate dehydrogenase complex decarboxylates pyruvate to produce acetyl-CoA. In gluconeogenesis, the carboxylation by pyruvate carboxylase produces oxaloacetate. The fate of pyruvate depends on the cell energy charge. In cells or tissues with a high energy charge pyruvate is directed toward gluconeogenesis, but when the energy charge is low pyruvate is preferentially oxidized to CO2 and H2O in the TCA cycle, with generation of 15 equivalents of ATP per pyruvate. The enzymatic activities of the TCA cycle are located in the mitochondrion. When transported into the mitochondrion, pyruvate encounters two principal metabolizing enzymes: pyruvate carboxylase (a gluconeogenic enzyme) and pyruvate dehydrogenase (PDH). With a high cell-energy charge, acetyl-CoA, is able allosterically to activate pyruvate carboxylase, directing pyruvate toward gluconeogenesis. When the energy charge is low CoA is not acylated, pyruvate carboxylase is inactive, and pyruvate is preferentially metabolized via the PDH complex and the enzymes of the TCA cycle to CO2 and H2O.


Pentose Phosphate Pathway,Metabolic

The pentose phosphate pathway—also referred to in the literature as the phosphogluconate pathway, the hexose monophosphate shunt, or the pentose phosphate shunt—is involved in the generation of NADPH as well as pentose sugars. Of the total cytoplasmic NADPH used in biosynthetic reactions, a significant proportion of it is generated through the pentose phosphate pathway. Ribose 5-phosphate is also another essential product generated by this pathway which is employed in nucleotide synthesis. The pentose phosphate pathway is also involved in the digestive process as the products of nucleic acid catabolism can be metabolized through the pathway (pentose sugars are usually yielded in the breakdown) while the carbon backbones of dietary carbohydrates can be converted into glycolytic/gluconeogenic intermediates. The pentose phosphate pathway is interconnected to the glycolysis pathway through the shared use of three intermediates: glucose 6-phosphate, glyceraldehyde 3-phosphate, and fructose 6-phosphate.The pathway can be described as eight distinct reactions (see below) and is separated into an oxidative phase and a non-oxidative phase. Reactions 1-3 form the oxidative phase and generate NADPH and pentose 5-phosphate. Reactions 4-8 form the non-oxidative phase and converts pentose 5-phosphate into other pentose sugars such as ribose 5-phosphate, but generates no NADPH. The eight reactions are as follows: reaction 1 converts glucose 6-phosphate into D-glucono-1,5-lactone 6-phosphate with NADPH formation; reaction 2 converts D-glucono-1,5-lactone 6-phosphate into 6-phospho-D-gluconate; reaction 3 converts 6-phospho-D-gluconate into ribulose 5-phosphate with NADPH formation; reaction 4 converts ribulose 5-phosphate into xylulose 5-phosphate; reaction 5 converts ribulose 5-phosphate into ribose 5-phosphate; reaction 6 rearranges ribose 5-phosphate and xylulose 5-phosphate to form sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate; reaction 7 rearranges sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate to form erythrose 4-phosphate and fructose 6-phosphate; and reaction 8 rearranges xylulose 5-phosphate and erythrose 4-phosphate to form glyceraldehyde 3-phosphate and fructose-6-phosphate.


Methionine Metabolism,Metabolic

Methionine metabolism in mammals consists of 2 pathways, the methionine cycle and the transsulfuration sequence. These pathways share 3 common reactions with both including the conversion of methionine to S-adenosylmethionine (SAM),the utilization of SAM in diverse transmethylation reactions yielding a methylated product plus S-adenosylhomocysteine, and the cleavage of S-adenosylhomocysteine to yield homocysteine and adenosine. The transulfuration reactions that produce cysteine from homocysteine and serine also produce α-ketobutyrate, the latter being converted first to propionyl-CoA and then via a 3-step process to succinyl-CoA. Regulation of the methionine metabolic pathway is based on the availability of methionine and cysteine. If both amino acids are present in adequate quantities, SAM accumulates and is a positive effector on cystathionine synthase, encouraging the production of cysteine and α-ketobutyrate (both of which are glucogenic). However, if methionine is scarce, SAM will form only in small quantities, thus limiting cystathionine synthase activity.


Primary Hyperoxaluria Type I,Disease

Type I primary hyperoxaluria (Glycolicaciduria) is caused by mutation in the gene encoding alanine-glyoxylate aminotransferase (AGXT). AGXT normally catalyzes the reaction from L-serine and pyruvate to 3-hydroxypyruvate and L-alanine and the reaction from L-alanine and glyoxylate to pyruvate and glycine. A defect in AGXT results in accumulation of glycolic acid, glyoxylic acid, and oxalate in urine. Symptoms include hematuria, myocarditis, nephrocalcinosis, peripheral neuropathy, and renal failure.


Pyruvate Carboxylase Deficiency,Disease

Pyruvate carboxylase deficiency is caused by mutation in the pyruvate carboxylase gene. Serine—pyruvate aminotransferase catalyzes the reaction of serine and pyruvate to produce 3-hydroxypyruvate and L-alanine, as well as the reaction from L-alanine and glyodxylate to pyruvate and glycine. A defect in this results in accumulation of ammonia, glucose and pyruvate in blood; proline, lysine, citrulline, and alanine in plasma; and 2-oxoglutaric acid, fumaric acid, ketone bodies and succinate in urine. Symptoms include ataxia, lactic acidosis, mental retardation, metabolic acidosis, siezures, and dyspnea.


17-beta Hydroxysteroid Dehydrogenase III Deficiency,Disease

Defects in 17-beta hydroxysteroid dehydrogenase III (HSD17B3) are the cause of male pseudohermaphrodism with gynecomastia. These individuals have unambiguous female external genitalia at birth, but fail to menstruate at the time of expected puberty and instead virilize as evidenced by growth of the phallus. A defect in HSD17B3 causes accumulation of dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) as well as androstenedione in plasma.


beta-Ketothiolase Deficiency,Disease

beta-Ketothiolase Deficiency (2-Methyl-3-Hydroxybutyric Acidemia; Mitochondrial Acetoacetyl-CoA Thiolase Deficiency; MAT Deficiency; T2 Deficiency; 3-KTD Deficiency; 3-Ketothiolase Deficiency) is an autosomal recessive disease caused by a mutation in the HADHB gene which codes for beta-ketathiolase. A deficiency in this enzyme results in accumulation of ammonia and ketone bodies in blood; and 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, 3-hydroxybutyric acid, tiglylglycine, and ketone bodies in urine. Symptoms include ketosis, seizures, organic acids in urine, and hyperammonemia. Treatment includes a low protein diet and L-carnitine.h3. h2.


2-Methyl-3-hydroxybutyryl CoA dehydrogenase deficiency (Hydroxyl-CoA dehydrogenase deficiency; MHBD) is a rare inborn disease of metabolism caused by a mutation in the HSD17B10 gene which codes for 3-hydroxyacyl-CoA dehydrogenase type-2. A deficiency in this enzyme results in accumulation of L-lactic acid in blood, spinal fluid, and urine; 2-ethylhydracrylic acid, 2-methyl-3-hydroxybutyric acid, and tiglylglycine in urine. Symptoms include cerebal atrophy, motor and mental retardation, overactivity and behavior issues, seizures and progressive neurological defects leading to early death. Treatment includes a high carbohydrate and low protein diet.


Propionic Acidemia,Disease

Propionic acidemia (Ketotic hyperglycinemia) is caused by mutation in the genes encoding propionyl-CoA carboxylase, PCCA or PCCB. The break down of Propionyl-CoA is catalyzed by Propionyl-CoA carboxylase (PCC). Propionyl-CoA plays an important role in amino acid metabolism. A mutation in this enzyme causes accumulation of ammonia and propionylcarnitine (C3) in the blood; carnitine , glutamine, glycine, and propionic acid in the plasma; 3-hydroxypropionic acid, 3-hydroxyvaleric acid, 5-oxoproline, acylcarnitin, glycine, methylcitric acid, propionylglycine and tiglylcine in the urine. Symptoms include cardio myopathy, growth retardation, hypothermia, ketosis, neutropenia, strokelike episodes, pyloric stenosis and spastic diplegia/quadriplegia.


3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (3-Hydroxy-3-methylglutaric acidemia; Leucine metabolism, defect in, HMG-CoA lyase deficiency) is an autosomal recessive disease caused by a mutation in the HMGCL gene which codes for hydroxymethylglutaryl-CoA lyase. A deficiency in this enzyme results in accumulation of 3-hydroxymethylglutaric acid, 3-hydroxyisovaleric acid, 3-methylcrotonylglycine and 3-methylglutaconic acid (cis and trans form), and methylglutaric acid in urine; and ammonia in blood. Symptoms include cardiomyopathy, dehydration, hypotonia, lactic acidosis, and pancreatitis. Treatment includes a low-fat, low-protein, high-carbohydrate diet.


Maple Syrup Urine Disease,Disease

Maple Syrup Urine Disease (Branched-chain alpha-keto acid dehydrogenase deficiency, MSUD) is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase enzyme complex (BCKDH), which normally degrades the branched chain amino acids leucine, isoleucine, and valine. The disease is characterized in an infant by the presence of sweet-smelling urine, with an odor similar to that of maple syrup. Increased amounts of valine, leucine and isoleucine and their toxic byproducts accumulate in the blood, plasma, and urine. Symptoms include ataxia, encephalopathy, ketosis, mental retardation, seizures, and a maple syrup or caramel odor.


3-Methylcrotonyl-CoA Carboxylase Deficiency Type I,Disease

3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency Type I (3-MCC Deficiency; MCCD Type I; Methylcrotonylglycinuria Type I; 3-Methylcrotonylglycinuria I) is caused by a defect in the MCCC1 and MCCC2 genes. 3-methylcrotonyl-coenzyme A carboxylase plays an essential role in breaking down proteins from the diet. Specifically, the enzyme is responsible for the fourth step in processing leucine. If a mutation in the MCCC1 or MCCC2 gene reduces or eliminates the activity of 3-methylcrotonyl-CoA carboxylase, the body is unable to process leucine properly. As a result, toxic byproducts of leucine processing build up to harmful levels, damaging the brain and nervous system. Symptoms include recurring episodes of vomiting and diarrhea, lethargy, hypotonia, seizures, and coma.


3-Methylglutaconic Aciduria Type I,Disease

3-Methylglutaconic aciduria type 1 (3-Methylglutaconicaciduria; Aciduria, 3-methylglutaconic type I) is an autosomal recessive disease caused by a mutation in the AUH gene which codes for methylglutaconyl-CoA hydratase. A deficiency in this enzyme results in accumulation of 3-hydroxyisovaleric acid, 3-methylglutaconic acid, and methylglutaric acid in urine. Symptoms include hypoglycemia, low birth weight, coma, seizures, and mental retardation. Treatment includes a low protein diet.


3-Methylglutaconic Aciduria Type III,Disease

3-Methylglutaconic aciduria type 3 (Costeff syndrome; Optic atrophy plus syndrome) is an autosomal recessive disease caused by a deficiency in the OPA3 code which does for optic atrophy 3 protein. A deficiency of this enzyme results in accumulation of 3-methylglutaconic acid and methylglutaric acid. Symptoms include ataxia, dysarthria, optic atrophy, and neurological deterioration.


Methylmalonate Semialdehyde Dehydrogenase Deficiency,Disease

Methylmalonate Semialdehyde Dehydrogenase Deficiency (MMSDH Deficiency; Aldehyde Dehydrogenase 6 Family, Member A1; ALDH6A1 Deficiency)is caused by a defect in methylmalonate semialdehyde dehydrogenase, which catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA, respectively. A defect in methylmalonate semialdehyde dehydrogenase causes accumulation of 3-Aminoisobutyric acid, 3-Hydroxyisobutyric acid, 3-hydroxypropionic acid, beta-Alanine, lactate, and methylmalonic acid in urine. Symptoms inclue failure to thrive, large liver, mental and motor retardation and vomiting.


Methylmalonic Aciduria,Disease

Methylmalonic acidemia cause defects (Methylmalonaciduria due to methylmalonic CoA mutase; Acidemia, methylmalonic; MMA) in the metabolic pathway where methylmalonyl-coenzyme A (CoA) is converted into succinyl-CoA by the enzyme methylmalonyl-CoA mutase. Defects in the enzyme Methylmalonyl-CoA mutase causes 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.


4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency,Disease

4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency (SSADH; Gamma-hydroxybutyric acidemia) inhibits the formation of succinate from GABA. This deficiency results in urinary excretion of 4-hydroxybutyric acid. In vivo proton MR also indicates elevated GABA levels as compared with an age-matched control. Symptoms include ataxia, chorea or athetosis, motor retardation, seizures, macrocephaly and delayed or abnormal speech development.


Homocarnosinosis,Disease

Homocarnosinosis is caused by an inherited defect in serum carnosinase, which converts homocarnosine to GABA (gamma aminobutyric acid). A defect in serum carnosinase causes accumulation of the brain specific dipeptide homocarnosine (Hca), in the CSF and brain. Symptoms include hypotonia, mental retardation, retinitis pigmentosa and spastic diplegia/quadriplegia.


Hyperinsulinism-hyperammonemia syndrome (HHS; Glutamate dehydrogenase 1; GLUD1), an inherited condition, is caused by a defect in the GLUD1 gene which codes for mitochondrial glutamate dehydrogenase 1. It is a mitochondrial matrix enzyme, with a key role in the nitrogen and glutamate (Glu) metabolism and the energy homeostasis. An excessive activity of this enzyme results in high insulin and ammonia levels in blood; decrease level of glucose in blood. Symptoms and signs include shakiness, weakness, seizure, rapid pulse and confusion. Maintain normoglycemia is essencial to prevent neurologic damage. Some medications can be used to suppress insulin secretion.


Glutathione Synthetase Deficiency (5-Oxoprolinuria; Pyroglutamic Aciduria) is caused by a defect in the GSS gene which codes for glutathione synthetase. Glutathione synthetase is the second enzyme in the glutathione biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione. A defect in this enzyme results in accumulation of pyroglutamic acid and gamma-glutamylcysteine in urine and blood; decrease level of glutathione in erythrocytes; increase urinary excretion of 5-oxoproline. Glutathione synthetase deficiency can be classified into three types: mild, moderate and severe. Mild glutathione synthetase deficiency usually results in the destruction of red blood cells (hemolytic anemia). Rarely, affected people also excrete large amounts of a compound called 5-oxoproline in their urine (5-oxoprolinuria). This compound builds up when glutathione is not processed correctly in cells. Individuals with moderate glutathione synthetase deficiency may experience symptoms beginning shortly after birth including hemolytic anemia, 5-oxoprolinuria, and elevated acidity in the blood and tissues (metabolic acidosis). In addition to the features present in moderate glutathione synthetase deficiency, individuals affected by the severe form of this disorder may experience neurological symptoms. These problems may include seizures; a generalized slowing down of physical reactions, movements, and speech (psychomotor retardation); mental retardation; and a loss of coordination (ataxia). Some people with severe glutathione synthetase deficiency also develop recurrent bacterial infections.


5-Oxoprolinuria (5-Oxoprolinase deficiency) is a result of a defect in the gamma-glutamyl cycle due to either 5-oxoprolinase or glutathione synthetase deficiency. In the case of glutathione synthetase deficiency, the glycine is not incorporated into gamma-glutamylcysteine. In the case of 5-oxoprolinase, however, pyroglutamic acid accumulates. Symptoms include anemia, mental retardation, metabolic acidosis, respiratory distress and urolithiasis.


Adenosine Deaminase Deficiency,Disease

Adenosine deaminiase deficiency (immunodeficiency) is an autosomal recessive disease caused by a muation in the ADA gene which codes for adenosine deaminase. A deficiency in this enzyme results in immunodeficiency and a decreased concentration of lymphocytes in blood. Symptoms include diarrhea, severe or recurrent infections, vomiting and early onset in children, infants and newborns. Treatment includes bone-marrow transplants and enzyme replacement therapy.


Adenylosuccinate Lyase Deficiency. (Adenylosuccinase Deficiency ; Adenylosuccinate monophosphate lyase deficiency) is a rare autosomal recessive disease caused by a mutation in the ADSL gene which codes for adenylosuccinate lyase. A deficiency in this enzyme results in accumulation of succinyladenosine in plasma, spinal fluid, and urine. Symptoms, which present at birth, include hyptonia, seizures, mental retardation, and encephalopathy. Treatment includes allopurinol.


Gout or Kelley-Seegmiller Syndrome,Disease

Gout, or Kelley-Seegmiller syndrome, is caused by a partial defect in the HPRT1 gene which codes for hypoxanthine-guanine phosphoribosyltransferase. Hypoxanthine-guanine phosphoribosyltransferase is an enzyme in purine metabolism. Its primarily functions to salvage purines from degraded DNA to renewed purine synthesis. In this role, it acts as a catalyst in the reaction between guanine and phosphoribosyl pyrophosphate (PRPP) to form GMP. A partial deficiency in this enzyme causes overproduction of uric acid, therefore it results in accumulation of uric acid in serum and increase urinary excretion of uric acid. Symptoms and signs include excruciating, sudden, unexpected, burning pain, as well as swelling, redness, warmth, and stiffness in the affected joint, usually in the great toe, tophi in the helix or antihelix of the ear, along the ulnar surface of the forearm, in the olecranon bursa, or in other tissues. Treatment has three objectives: manage symptoms of acute attacks, prevent acute attacks, and reduce serum uric acid.


Lesch-Nyhan Syndrome (LNS),Disease

Lesch-Nyhan Syndrome (LNS; Hypoxanthin guanine phosphoribosyltransferase deficiency) is caused by a complete defect in the HPRT1 gene which codes for hypoxanthine-guanine phosphoribosyltransferase. Hypoxanthine-guanine phosphoribosyltransferase is an enzyme in purine metabolism. Its primarily functions to salvage purines from degraded DNA to renewed purine synthesis. In this role, it acts as a catalyst in the reaction between guanine and phosphoribosyl pyrophosphate (PRPP) to form GMP. A complete deficiency in this enzyme causes overproduction of uric acid, therefore it results in accumulation of uric acid in serum and increase urinary excretion of uric acid. Symptoms and signs include severe gout and kidney problems, poor muscle control, and moderate mental retardation. These complications usually appear in the first year of life. A striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting, that begin in the second year of life. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington’s disease. Treatment for LNS is symptomatic. Gout can be treated with allopurinol to control excessive amounts of uric acid. Kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. There is no standard treatment for the neurological symptoms of LNS. Some may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol.


Molybdenum Cofactor Deficiency,Disease

Molybdenium cofactor deficiency (Sulfite oxidase deficiency) is caused by mutations in the genes MOCS1 and MOCS2 in the formation of molybdenum cofactor. A molybdenum-containing cofactor is essential to the function of 3 enzymes: sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Xanthine dehydrogenase is a molybdenum-containing hydroxylase involved in the oxidative metabolism of purines. Defects in this enzyme cause accumulation of hypoxanthine,, s-s-sulfocysteine, taurine, and xanthine in the urine. Symptoms include hemorrhage, cerebral atrophy, encephalopathy, lactic acidosis, nystagmus, spastic diplegia/quadriplegia, and vomiting.


Xanthine Dehydrogenase Deficiency (Xanthinuria),Disease

The rare genetic disorder, Xanthinuria (also referred to as xanthine oxidase deficiency) results from a deficiency of the enzyme xanthine oxidase. This enzyme deficiency causes the accumulation of: xanthine in the plasma, uric acid in serum or hypoxanthine, uric acid and xanthine in the urine. The disorder has symptoms including arthralgia, hematuria, mental retardation, stomatisis, and urolithiasis.


Purine Nucleoside Phosphorylase Deficiency,Disease

Purine nucleoside phosphorylase deficiency (Nucleoside phosphorylase; Immunodeficiency) is a rare disease causing severe immunodeficiency. The disease is caused by a mutation in the enzyme purine nucleoside phosphorylase. The enzyme is necessary for purine breakdown. The mutation causes deoxy-GTP (dGTP) to accumulate which causes T-cell toxicity. The disease results in accumulation of guanosine, inosine, and uric acid in serum; and orotic acid in some cases in the urine. Symptoms include anemia, ataxia, hypotonia, lymphopenia, mental retardation, and tremor or twitching.


AICA-Ribosiduria,Disease

AICA-ribosiduria is a metabolic disease caused by a defect in final steps of purine de novo biosynthesis. This defect is caused by a mutation in the ATIC which codes for bifunctional purine biosynthesis protein PURH. A deficiency in this enzyme results in accumulation of 5-aminoimidazole-4-carboxamide in urine. Symptoms include mental retardation, epilepsy, dysmorphic features, and congenital blindness.


Prolidase Deficiency (PD),Disease

Prolidase deficiency is an autosomal recessive disorder. The enzyme prolidase cleaves iminodipeptides with N-terminal proline or hydroxyproline. Collagen has high levels of iminoacids therefore, these dipeptidases are important for collagen metabolism. A defect in this enzyme causes accumulation of imidodipeptides in urine. Symptoms include skin lesions, anemia, dysmorphism, mental retardation, and ptosis (drooping eyelid).


Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency),Disease

Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency, Creatine Deficiency Syndrome, Creatine Deficiency due to AGAT Deficiency, GATM Deficiency) is caused by mutation in the GATM gene, which codes for L-arginine:glycine amidinotransferase, which catalyzes the reaction between L-arginine and glycine, transferring an amidino group from L-arginine to glycine, producing L-ornithine and guanidinoacetate, a precursor of creatine. A defect in this enzyme causes a decrease in concentration of creatine and guanidinoacetate in plasma and urine. Symptoms include mental and motor retardation, seizures, and delayed or abnormal speech development.


Hyperprolinemia Type II,Disease

Hyperprolinemia (prolinemia Type II, HPII, prolinuria) is caused by mutation in the pyrroline-5-carboxylate dehydrogenase gene (P5CDH), which encodes pyrroline-5-carboxylate dehydrogenase. This enzyme assists in the metabolism of pyrroline-5-carboxylate, converting it to the amino acid glutamine. The conversion between proline and glutamine, and the reverse reaction controlled by different enzymes, are essential factors required to maintain proper metabolism and protein production. A defect in this enyzme causes accumulation of proline in plasma; ornithine in serum; and glycine, hydroxyproline and proline in urine. Symptoms include mental retardation, acute and chronic renal failure and seizures.


Hyperprolinemia Type I,Disease

Hyperprolinemia type I (HPI, proline oxidase deficiency) is caused by mutation in the proline dehydrogenase gene (PRODH), which codes for proline dehydrogenase (proline oxidase). This enzyme converts proline to delta-1-pyrroline-5-carboxylate. A defect in proline dehydrogenase causes accumulation of proline in plasma, and glycine, hydroxyproline, and proline in urine. Symptoms include mental retardation, renal cysts, and seizures.


Prolinemia Type II,Disease

Prolinemia Type II is caused by mutation in the pyrroline-5-carboxylate dehydrogenase gene (P5CDH) mitochondrial matrix NAD-dependent dehydrogenase. This dehydrogenase is a catalyst for converting pyrroline-5-carboxylate to glutamate in the proline degradation pathway. An enzyme defect causes accumulation of glycine, hydroxyproline and proline in the urine, ornithine in the serum and proline in plasma. Symptoms include mental retardation, acute and chronic renal failure, and seizures.