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Essential and Nonessential Amino Acids Nonessential amino acids are those that are synthesized by mammals, while the essential amino acids must be obtained from dietary sources. Why would an organism evolve in such a way that it could not exist in the absence of certain amino acids? Most likely, the ready availability of these amino acids in lower organisms (plants and microorganisms) obviated the need for the higher organism to continue to produce them. The pathways for their synthesis were selected out. Not having to synthesize an additional ten amino acids (and regulate their synthesis) represents a major economy, then. Nevertheless, it remains for us to become familiar with the synthetic pathways for these essential amino acids in plants and microorganisms, and it turns out that they are generally more complicated that the pathways for nonessential amino acid synthesis and they are also species-specific. The twenty amino acids can be divided into two groups of 10 amino acids. Ten are essential and 10 are nonessential. However, this is really not an accurate dichotomy, as there is overlap between the two groups, as is indicated in the text accompanying the following two charts:
Amino acid synthesis
Amino acids are synthesized from α-ketoacids, and later transaminated from another aminoacid, usually Glutamate. The enzyme involved in this reaction is an aminotransferase. α-ketoacid + glutamate ⇄ amino acid + α-ketoglutarate Glutamate itself is formed by amination of α-ketoglutarate: α-ketoglutarate + NH+ 4 ⇄ glutamate
Introduction to Amino Acid Metabolism Essential versus Non-Essential Amino Acids Inborn Errors in Amino Acid Metabolism
Nonessential Amino Acid Biosynthesis
Amino Acid Catabolism
Glutamine/Glutamate and Aspartate/Asparagine Alanine Arginine, Ornithine and Proline Glutamate and Aspartate Serine Alanine and the Glucose-Alanine Cycle Threonine Cysteine Glycine Tyrosine Cysteine Ornithine and Proline Methionine Serine Valine, Leucine, Isoleucine Glycine Phenylalanine and Tyrosine Aspartate/Asparagine and Glutamate/Glutamine Lysine Histidine Tryptophan
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All tissues have some capability for synthesis of the non-essential amino acids, amino acid remodeling, and conversion of non-amino acid carbon skeletons into amino acids and other derivatives that contain nitrogen. However, the liver is the major site of nitrogen metabolism in the body. In times of dietary surplus, the potentially toxic nitrogen of amino acids is eliminated via transaminations, deamination, and urea formation; the carbon skeletons are generally conserved as carbohydrate, via gluconeogenesis, or as fatty acid via fatty acid synthesis pathways. In this respect amino acids fall into three categories: glucogenic, ketogenic, or glucogenic and ketogenic. Glucogenic amino acids are those that give rise to a net production of pyruvate or TCA cycle intermediates, such as α-ketoglutarate or oxaloacetate, all of which are precursors to glucose via gluconeogenesis. All amino acids except lysine and leucine are at least partly glucogenic. Lysine and leucine are the only amino acids that are solely ketogenic, giving rise only to acetylCoA or acetoacetylCoA, neither of which can bring about net glucose production. A small group of amino acids comprised of isoleucine, phenylalanine, threonine, tryptophan, and tyrosine give rise to both glucose and fatty acid precursors and are thus characterized as being glucogenic and ketogenic. Finally, it should be recognized that amino acids have a third possible fate. During times of starvation the reduced carbon skeleton is used for energy production, with the result that it is oxidized to CO2 and H2O.
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Essential vs. Nonessential Amino Acids
Nonessential Essential Alanine Asparagine Aspartate Cysteine Glutamate Glutamine Arginine* Histidine Isoleucine Leucine Lysine Methionine*
Glycine Proline Serine Tyrosine
Phenylalanine* Threonine Tyrptophan Valine
*The amino acids arginine, methionine and phenylalanine are considered essential for reasons not directly related to lack of synthesis. Arginine is synthesized by mammalian cells but at a rate that is insufficient to meet the growth needs of the body and the majority that is synthesized is cleaved to form urea. Methionine is required in large amounts to produce cysteine if the latter amino acid is not adequately supplied in the diet. Similarly, phenyalanine is needed in large amounts to form tyrosine if the latter is not adequately supplied in the diet.
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Non-Essential Amino Acid Biosynthesis Glutamate and Aspartate
Glutamate is synthesized from its' widely distributed α-keto acid precursor by a simple 1-step transamination reaction catalyzed by glutamate dehydrogenase. As discussed in the Nitrogen Metabolism page, the glutamate dehydrogenase reaction plays a central role in overall nitrogen homeostasis.
Reactions of glutamate dehydrogenase
Like glutamate. AST (formerly referred to as serum glutamate-oxalate transaminase. back to the top . aspartate is synthesized by a simple 1-step transamination reaction catalyzed by aspartate aminotransferase. SGOT). The importance of aspartate as a precursor of ornithine for the urea cycle is described in the Nitrogen Metabolism page. Aspartate can also be derived from asparagine (whose synthesis is outlined below) through the action of asparaginase.
There are 2 main pathways to production of muscle alanine: directly from protein degradation. and via the transamination of pyruvate by alanine transaminase. When alanine transfer from muscle to liver is coupled with glucose transport from liver back to muscle. Liver accumulates plasma alanine. alanine is second only to glutamine in prominence as a circulating amino acid. the process is known as the glucose-alanine cycle. alanine. In this capacity it serves a unique role in the transfer of nitrogen from peripheral tissue to the liver. and proportionately increases urea production. The pyruvate is either oxidized or converted to glucose via gluconeogenesis. where the carbon skeleton is recycled and most nitrogen eliminated. . peripheral tissue exports pyruvate and ammonia (which are potentially rate-limiting for metabolism) to the liver. reverses the transamination that occurs in muscle. in which alanine is formed from pyruvate at a rate proportional to intracellular pyruvate levels. Alanine is transferred to the circulation by many tissues. but mainly by muscle. ALT (also referred to as serum glutamate-pyruvate transaminase. The key feature of the cycle is that in 1 molecule. SGPT).Alanine and the Glucose-Alanine Cycle Aside from its role in protein synthesis.
This reaction is catalyzed by alanine transaminase. during periods of fasting. The newly formed glucose can then enter the blood for delivery back to the muscle. ALT (ALT used to be called serum glutamate-pyruvate transaminase. Glucose oxidation produces pyruvate which can undergo transamination to alanine. Within the liver alanine is converted back to pyruvate which is then a source of carbon atoms for gluconeogenesis. The alanine then enters the blood stream and is transported to the liver. Additionally. SGPT). The amino group transported from the muscle to the liver in the form of alanine is converted to urea in the urea cycle and excreted.The glucose-alanine cycle is used primarily as a mechanism for skeletal muscle to eliminate nitrogen while replenishing its energy supply. back to the top . skeletal muscle protein is degraded for the energy value of the amino acid carbons and alanine is a major amino acid in protein.
In the production of SAM all phosphates of an ATP are lost: one as Pi and two as PPi. . SAM SAM serves as a precurosor for numerous methyl transfer reactions (e. a reaction that occurs under methionine-sparing conditions and requires N5-methyl-tetrahydrofolate as methyl donor. Transmethylation reactions employing SAM are extremely important. homocysteine condenses with serine to produce cystathionine.g. In cysteine synthesis. The sum of the latter two reactions is known as trans-sulfuration. the conversion of norepinephrine to epinenephrine. Homocysteine can be converted back to methionine by methionine synthase. This reaction was discussed in the context of vitamin B12-requiring enzymes in the Vitamins page. S-adenosylhomocysteine is then cleaved by adenosylhomocyteinase to yield homocysteine and adenosine.Cysteine Biosynthesis The sulfur for cysteine synthesis comes from the essential amino acid methionine. but in this case the role of S-adenosylmethionine in transmethylation is secondary to the production of homocysteine (essentially a by-product of transmethylase activity). It is adenosine which is transferred to methionine and not AMP. The result of methyl transfer is the conversion of SAM to S-adenosylhomocysteine. see Specialized Products of Amino Acids). A condensation of ATP and methionine catalyzed by methionine adenosyltransferase yields Sadenosylmethionine (SAM or AdoMet). Biosynthesis of S-adenosylmethionine. which is subsequently cleaved by cystathionase to produce cysteine and α-ketobutyrate.
. Cystathionase is under negative allosteric control by cysteine. both use pyridoxal phosphate as a cofactor. while the α-ketobutyrate is first converted to propionyl-CoA and then via a 3-step process to the TCA cycle intermediate succinyl-CoA. although the complete syndrome is multifaceted and many individuals with this disease are mentally normal.Cysteine is used for protein synthesis and other body needs. cells contain little if any free cystine because the ubiquitous reducing agent. as well. While cysteine readily oxidizes in air to form the disulfide cystine. Genetic defects are known for both the synthase and the lyase. cysteine inhibits the expression of the cystathionine synthase gene. cystathionine synthase and cystathionase (cystathionine lyase). glutathione. Utilization of Methionine in the Synthesis of Cysteine The 2 key enzymes of this pathway. Missing or impaired cystathionine synthase leads to homocystinuria and is often associated with mental retardation. effectively reverses the formation of cystine by a non-enzymatic reduction reaction. and both are under regulatory control.
Half of the phenylalanine required goes into the production of tyrosine. and thus reduced levels of circulating homocysteine. if the diet is rich in tyrosine itself. back to the top Tyrosine Biosynthesis Tyrosine is produced in cells by hydroxylating the essential amino acid phenylalanine. Homocysteine serves as a negatively charged surface that attracts the contact phase of the intrinsic pathway of blood coagulation. it is important to ensure that proper function of the methionine synthase reaction is maintained. The reductant is the tetrahydrofolaterelated cofactor tetrahydrobiopterin. Therefore. the requirements for phenylalanine are reduced by about 50%. This relationship is much like that between cysteine and methionine. controlled studies have shown that this does not occur. Phenylalanine hydroxylase is a mixed-function oxygenase: one atom of oxygen is incorporated into water and the other into the hydroxyl of tyrosine. This genetic disease leads to methioninuria with no other consequences. . Although it would be assumed that increased intake of vitamin B12 should lead to increased conversion of homocysteine to methionine. Missing or impaired cystathionase leads to excretion of cystathionine in the urine but does not have any other untoward effects. The role of homocysteine in cardiovascular disease is related to its ability to induce a state of inflammation. which is maintained in the reduced state by the NADHdependent enzyme dihydropteridine reductase (DHPR). Elevated levels of homocysteine in the blood have been shown to correlate with cardiovascular dysfunction. Activation of the intrinsic coagulation cascade leads to inappropriate thrombolytic events as well as resulting in increases in inflammatory cytokine release from leukocytes that are activated as a result of the procoagulant state.Some instances of genetic homocystinuria respond favorably to pyridoxine therapy. suggesting that in these cases the defect in cystathionine synthase is a decreased affinity for the cofactor. Rare cases are known in which cystathionase is defective and operates at a low level.
Patients suffering from PKU have plasma phenylalanine levels >1000μM. since . and all 3 compounds appear in the urine. which is essential to normal brain development. deficiencies in DHPR can manifest with hyperphenylalaninemia. whereas the non-PKU hyperphenylalaninemias exhibit levels of plasma phenylalanine <1000μM. The product of phenylalanine transamination. the addition of tyrosine and restriction of phenylalanine from the diet can minimize the extent of mental retardation. Because of the requirement for tetrahydrobiopterin in the function of phenylalanine hydroxylase. If the problem is diagnosed early. Hyperphenylalaninemia is defined as a plasma phenylalanine concentration greater than 2mg/dL (120μM). is reduced to phenylacetate and phenyllactate. The most widely recognized hyperphenylalaninemia (and most severe) is the genetic disease known as phenlyketonuria (PKU). The presence of phenylacetate in the urine imparts a "mousy" odor. phenylpyruvic acid. This absence of α-ketoglutarate in the brain shuts down the TCA cycle and the associated production of aerobic energy. The mental retardation is caused by the accumulation of phenylalanine. Untreated PKU leads to severe mental retardation. However.Biosynthesis of Tyrosine from Phenylalanine Missing or deficient phenylalanine hydroxylase results in hyperphenylalaninemia. which becomes a major donor of amino groups in aminotransferase activity and depletes neural tissue of α-ketoglutarate.
is limited. The production of ornithine from glutamate is important when dietary arginine.g.tetrahydrobiopterin is a cofactor in several other enzyme catalyzed reactions (e. . Ornithine serves an additional important role as the precursor for the synthesis of the polyamines. see the synthesis of the tyrosine. the effects of missing or defective DHPR cause even more severe neurological difficulties than those usually associated with PKU caused by deficient phenylalanine hydroxylase activity.and tryptophan-derived neurotransmitters as well as nitric oxide in Specialized Products of Amino Acids). back to the top Ornithine and Proline Biosynthesis Glutamate is the precursor of both proline and ornithine. with glutamate semialdehyde being a branch point intermediate leading to one or the other of these 2 products. While ornithine is not one of the 20 amino acids used in protein synthesis. it plays a significant role as the acceptor of carbamoyl phosphate in the urea cycle. the other principal source of ornithine.
producing ornithine. the ornithine contributed . Ornithine production occurs from the semialdehyde via a simple glutamate-dependent transamination. When arginine concentrations become elevated.Synthesis of Ornithine and Proline from Glutamic Semialdehyde The fate of glutamate semialdehyde depends on prevailing cellular conditions.
The semialdehyde cyclizes spontaneously to Δ1-pyrroline-5-carboxylate which is then reduced to proline by an NADPH-dependent reductase. suitable for subsequent transamination. Serine Biosynthesis back to the top Glycine Biosynthesis The main pathway to glycine is a 1-step reversible reaction catalyzed by serine hydroxymethyltransferase (SHMT). 3-phosphopyruvate. This reaction involves the . serine can be derived from glycine (and visa versa) by a single step reaction that involves serine hydroxymethyltransferase and tetrahydrofolate (THF). with accumulation of the semialdehyde as a result. This enzyme is a member of the family of one-carbon transferases and is also known as glycine hydroxymethyltransferase. Aminotransferase activity with glutamate as a donor produces 3-phosphoserine. As indicated below. which is converted to serine by phosphoserine phosphatase.from the urea cycle plus that from glutamate semialdehyde inhibit the aminotransferase reaction. An NADH-linked dehydrogenase converts 3-phosphoglycerate into a keto acid. back to the top Serine Biosynthesis The main pathway to de novo biosynthesis of serine starts with the glycolytic intermediate 3phosphoglycerate.
transfer of the hydroxymethyl group from serine to the cofactor tetrahydrofolate (THF). There are mitochondrial and cytosolic versions of serine hydroxymethyltransferase. GCC) to yield a second equivalent of N5. producing glycine and N5.N10-methylene-THF. The cytosolic enzyme is referred to as SHMT1 and the mitochondrial enzyme is SHMT2.N10methylene-tetrahydrofolate as well as ammonia and CO2. Glycine produced from serine or from the diet can also be oxidized by glycine decarboxylase (also referred to as the glycine cleavage complex. .
with the amino nitrogen being donated by a number of different amino acids. it is thus a nitrogen-fixing reaction. back to the top Aspartate/Asparagine and Glutamate/Glutamine Biosynthesis Glutamate is synthesized by the reductive amination of α-ketoglutarate catalyzed by glutamate dehydrogenase. glutamate is a general collector of amino nitrogen. . Thus.Glycine is involved in many anabolic reactions other than protein synthesis including the synthesis of purine nucleotides. glutathione. heme. glutamate arises by aminotransferase reactions. In addition. creatine and serine.
oxaloacetate. and glutamate as the amino donor. AST. Aspartate can also be formed by deamination of asparagine catalyzed by asparaginase.Aspartate is formed in a transamination reaction catalyzed by aspartate transaminase. Asparagine synthetase and glutamine synthetase. Glutamine is produced from glutamate by the . catalyze the production of asparagine and glutamine from their respective α-amino acids. This reaction uses the aspartate α-keto acid analog.
Aminotransferase reactions are readily reversible. The direction of any individual transamination depends principally on the concentration ratio of reactants and products. however. asparagine can be degraded to aspartate. back to the top . and this can be considered another nitrogen fixing reaction. are considered irreversible. transamidation reactions. As indicated above. By contrast. which are dependent on ATP. the degradation of asparagine and glutamine take place by a hydrolytic pathway rather than by a reversal of the pathway by which they were formed. As a consequence. Asparagine. is formed by an amidotransferase reaction.direct incorporation of ammonia.
The catabolic path of the carbon skeletons involves simple 1-step aminotransferase reactions that directly produce net quantities of a TCA cycle intermediate. although when the energy charge of a cell is low the pyruvate will be oxidized to CO2 and H2O via the PDH complex and the TCA cycle. respectively. The glutamate dehydrogenase reaction operating in the direction of αketoglutarate production provides a second avenue leading from glutamate to gluconeogenesis. Glutaminase activity is present in many other tissues as well. This makes alanine a glucogenic amino acid. which follows the gluconeogenic pathway to glucose. making glutamine a glucogenic amino acid. although its activity is not nearly as prominent as in the kidney. . Aspartate transaminates to oxaloacetate. Glutamate and aspartate are important in collecting and eliminating amino nitrogen via glutamine synthetase and the urea cycle.Amino Acid Catabolism Glutamine/Glutamate and Asparagine/Aspartate Catabolism Glutaminase is an important kidney tubule enzyme involved in converting glutamine (from liver and from other tissue) to glutamate and NH4+. back to the top Alanine Catabolism Alanine is also important in intertissue nitrogen transport as part of the glucose-alanine cycle (see above). Generally pyruvate produced by this pathway will result in the formation of oxaloacetate. Alanine's catabolic pathway involves a simple aminotransferase reaction that directly produces pyruvate. with the NH4+ being excreted in the urine. The glutamate produced from glutamine is converted to αketoglutarate. Asparaginase (see above) is also widely distributed within the body. where it converts asparagine into ammonia and aspartate.
back to the top Arginine. Ornithine. with the production of two equivalents of N5. by a pathway that is essentially a reversal of serine biosynthesis. Thus arginine. ornithine and proline. 3phosphoglycerate. was described above in the section on glycine biosynthesis. Ornithine and Proline Catabolism The catabolism of arginine begins within the context of the urea cycle. is transaminated to form glutamate semialdehyde. Serine can be catabolized back to the glycolytic intermediate. Glutamate semialdehyde can serve as the precursor for proline biosynthesis as described above or it can be converted to glutamate. The glutamate semialdehyde generated from ornithine and proline catabolism is oxidized to glutamate by an ATP-independent glutamate semialdehyde dehydrogenase. back to the top Serine Catabolism The conversion of serine to glycine and then glycine oxidation to CO2 and NH3. are glucogenic. However. this activity of the enzyme appears to be lacking in humans. Although it has been demonstrated in mammals such as rodents and dogs that serine can be converted to pyruvate through a deamination reaction catalyzed by serine/threonine dehydratase. Proline catabolism is a reversal of its synthesis process. It is hydrolyzed to urea and ornithine by arginase. The glutamate can then be converted to α-ketoglutarate in a transamination reaction.N10-methyleneTHF. in excess of urea cycle needs. the enzymes are different. back to the top .
In humans it appears that threonine aldolase is actually encoded by a non-functional pseudogene. and vertebrates including mammals. An additional pathway occurs in the mitochondria and is initiated by threonine dehydrogenase yielding α-amino-β-ketobutyrate (2-amino-3-ketobutyrate). back to the top Glycine Catabolism Glycine is classified as a glucogenic amino acid. It appears that in newborn infants catabolism of threonine occurs exclusively via the action of the serine/threonine dehydratase. whereas. the main glycine catabolic pathway leads to the production of CO2. also called the glycine cleavage complex. Nevertheless. succinyl-CoA. The second pathway of threonine catabolism utilizes serine hydroxymethyltransferase.g. The principal threonine catabololizing pathway in humans involves glycine-independent serine/threonine dehydratase yielding α-ketobutyrate which is further catabolized to propionyl-CoA and finally the TCA cycle intermediate. it is presumed that this is the predominant threonine catabolizing pathway in humans. Thus. via the action of 2-amino-3-ketobutyrate coenzyme A ligase (also called glycine C-acetyltransfease).N10-methyleneTHF by the mitochondrial glycine decarboxylase. Therefore. it is the serine/threonine dehydratase gene that is most important in threonine catabolism in humans. this enzyme is a major threonine catabolizing enzyme in other mammals such as mice. . Serine/threonine dehydratase is expressed at high levels only in the liver. The products of this reaction are acetyl-CoA and glycine.Threonine Catabolism There are at least 3 pathways for threonine catabolism that have been identified in yeasts. and one equivalent of N5. and clawed frogs) the threonine aldolase gene encodes a functional threonine catabolizing enzyme. since it can be converted to serine by serine hydroxymethyltransferase (see above). although the latter reaction (serine to pyruvate) appears not be occur in human tissues. GCC (see above). insects. The 2-amino-3-ketobutyrate is either converted to acetyl-CoA and glycine. whereas in other mammals and vertebrates (e. or it can spontaneously degrade to aminoacetone which is converted to pyruvate. 3-phosphoglycerate or to pyruvate by serine/threonine dehydratase. The threonine dehydrogenase gene in humans appears to be nonfunctional due to the incorporation of three inactivating mutations. The glycine can be converted to serine via the same enzyme and the serine is then catabolized as described above yielding pyruvate and NH4+. zebrafish. ammonia. mice. Thus. via this catabolic pathway threonine yields ketogenic and glucogenic byproducts. and serine can be converted back to the glycolytic intermediate. As indicated above this enzyme belongs to a family of one-carbon transferases and is alternatively named glycine hydroxymethyltransferase or threonine aldolase.
the most important product of cysteine metabolism is the bile salt precursor taurine. but least important pathway is catalyzed by a liver desulfurase and produces hydrogen sulfide. The resultant sulfate is used as a precursor for the formation of 3'-phosphoadenosine-5'phosphosulfate. (PAPS). (SO4–) and H2O2. PAPS is used for the transfer of sulfate to biological molecules such as the sugars of the glycosphingolipids. The simplest. . producing the intermediate cysteinesulfinate. Catabolism of cysteinesulfinate proceeds through transamination to β-sulfinylpyruvate which then undergoes desulfuration yielding bisulfite. The enzyme sulfite oxidase uses O2 and H2O to convert HSO3– to sulfate. pyruvate. which is used to form the bile acid conjugates taurocholate and taurochenodeoxycholate. Other than protein. Cysteinesulfinate can serve as a biosynthetic intermediate undergoing decarboxylation and oxidation to produce taurine. (H2S) and pyruvate. (HSO3–) and the glucogenic product. The major catabolic pathway in animals is via cysteine dioxygenase that oxidizes the cysteine sulfhydryl to sulfinate.back to the top Cysteine Catabolism There are several pathways for cysteine catabolism.
producing many intermediates. (CN–). the latter being converted first to propionyl-CoA and then via a 3-step process to succinyl-CoA.The enzyme cystathionase can also transfer the sulfur from one cysteine to another generating thiocysteine and pyruvate. thus limiting cystathionine synthase activity. Regulation of the methionine metabolic pathway is based on the availability of methionine and cysteine. The first step in each case is a transamination using a single BCAA aminotransferase. Because this arrangement of carbon atoms cannot be made by humans. BCAAs. to produce thiosulfate. yielding the three different CoA derivatives. SAM will form only in small quantities. using N5-methylTHF and other compounds as methyl donors. Transamination of cysteine yields β-mercaptopyruvate which then reacts with sulfite. However. If both amino acids are present in adequate quantities. (S2O32–) and pyruvate. these amino acids are an essential element in the diet. if methionine is scarce. thereby detoxifying the cyanide to thiocyanate. three different α-keto acids are produced and are oxidized using a common branched-chain α-keto acid dehydrogenase (BCKD). (SO32–). encouraging the production of cysteine and αketobutyrate (both of which are glucogenic). back to the top Methionine Catabolism The principal fates of the essential amino acid methionine are incorporation into polypeptide chains. Both thiocysteine and thiosulfate can be used by the enzyme rhodanese to incorporate sulfur into cyanide. The catabolism of all three compounds initiates in muscle and yields NADH and FADH2 which can be utilized for ATP generation. Under these conditions accumulated homocysteine is remethylated to methionine. Leucine and Isoleucine Catabolism This group of essential amino acids are identified as the branched-chain amino acids. SAM accumulates and is a positive effector on cystathionine synthase. Subsequently the metabolic pathways diverge. back to the top Valine. The transulfuration reactions that produce cysteine from homocysteine and serine also produce α-ketobutyrate. . and use in the production of α-ketobutyrate and cysteine via SAM as described above. As a result. with α-ketoglutarate as amine acceptor. The catabolism of all three of these amino acids uses the same enzymes in the first two steps.
and is thus classified as strictly ketogenic. Unfortunately. dopamine. phenylalanine catabolism always follows the pathway of tyrosine catabolism. causing urine to darken on exposure to air. As in phenylketonuria (deficiency of phenylalanine hydroxylase. BCKD. Leucine gives rise to acetylCoA and acetoacetylCoA. Isoleucine catabolism terminates with production of acetylCoA and propionylCoA. The disease is known as Maple syrup urine disease because of the characteristic odor of the urine in afflicted individuals. Mental retardation in these cases is extensive. was demonstrated to be the result of a defect in phenylalanine and tyrosine catabolism.The principal product from valine is propionylCoA. deficiency of tyrosine aminotransferase (TAT) leads to hypertyrosinemia and the urinary excretion of tyrosine and the catabolic intermediates between phenylalanine and tyrosine. they cannot be heavily restricted in the diet. all three α-keto acids accumulate and are excreted in the urine. . The adverse neurological symptoms are similar for PAH and TAT deficiencies. and production of tyrosine via the tetrahydrobiopterin-requiring phenylalanine hydroxylase. Tyrosine is equally important for protein biosynthesis as well as an intermediate in the biosynthesis of several physiologically important metabolites e. There are a number of genetic diseases associated with faulty catabolism of the BCAAs. PAH). Since there is only one dehydrogenase enzyme for all three amino acids. The first inborn error in metabolism ever recognized. hypertyrosinemia leads to painful corneal eruptions and photophobia. Homogentisic acid accumulation is relatively innocuous. Thus. The most common defect is in the branched-chain α-keto acid dehydrogenase. ultimately. The main pathway for tyrosine degradation involves conversion to fumarate and acetoacetate. In addition. thus isoleucine is both glucogenic and ketogenic. back to the top Phenylalanine and Tyrosine Catabolism Phenylalanine normally has only two fates: incorporation into polypeptide chains. since these are essential amino acids. allowing phenylalanine and tyrosine to be classified as both glucogenic and ketogenic. the life of afflicted individuals is short and development is abnormal The main neurological problems are due to poor formation of myelin in the CNS. The only untoward consequence of alkaptonuria is ochronosis (bluish-black discoloration of the tissues) and arthritis. the glucogenic precursor of succinyl-CoA.g. Alkaptonuria is caused by defective homogentisic acid oxidase. but no life-threatening effects accompany the disease. alkaptonuria. norepinephrine and epinephrine (see Specialized Products of Amino Acids).
The addition of citrulline to the diet prevents the hyperammonemia. Lysine is also important as a precursor for the synthesis of carnitine. producing glutamate and α-aminoadipic semialdehyde. The lysinemia and associated lysinuria are benign. rather the modified lysine found in certain proteins. Probably more significant however. and resulting arginine deficiencies limit the quantity of ornithine available for the urea cycle. is the fact that arginine is transported on the same dibasic amino acid carrier.back to the top Lysine Catabolism Lysine catabolism is unusual in the way that the ε-amino group is transferred to α-ketoglutarate and into the general nitrogen pool. . Other serious disorders associated with lysine metabolism are due to failure of the transport system for lysine and the other dibasic amino acids across the intestinal wall. Genetic deficiencies in the enzyme α-aminoadipic semialdehyde synthase have been observed in individuals who excrete large quantities of urinary lysine and some saccharopine. Saccharopine is immediately hydrolyzed by the enzyme α-aminoadipic semialdehyde synthase in such a way that the amino nitrogen remains with the α-carbon of α-ketoglutarate. a deficiencies of its transport into the body can cause seriously diminished levels of protein synthesis. lysine is an essential amino acid. Unlike the majority of transamination reactions. Hydrolysis of proteins containing trimethyllysine provides the substrate for the subsequent conversion to carnitine. The ultimate end-product of lysine catabolism is acetoacetyl-CoA. this one does not employ pyridoxal phosphate as a cofactor. Free lysine does not serve as the precursor for this reaction. The result is severe hyperammonemia after a meal rich in protein. saccharopine. The reaction is a transamination in which the ε-amino group is transferred to the α-keto carbon of α-ketoglutarate forming the metabolite. Because this transamination reaction is not reversible. required for the transport of fatty acids into the mitochondria for oxidation. Lysine is essential for protein synthesis. Some proteins modify lysine to trimethyllysine using SAM as the methyl donor to transfer methyl groups to the ε-amino of the lysine side chain.
is not the usual α-keto acid associated with loss of α-amino nitrogens. Urocanate is converted to 4-imidazolone-5-propionate via the action of urocanate hydratase. Decarboxylation of histidine in the intestine by bacteria gives rise to histamine. The end product of histidine catabolism is glutamate. making histidine one of the glucogenic amino acids. The latter reaction is one of two routes to N5-formiminoTHF. histamine arises in many tissues by the decarboxylation of histidine. introducing a double bond into the molecule. Glutamate formiminotransferase then transfers the fomimino group to THF yielding glutamate and N5-formiminoTHF.000). Synthesis of Histamine back to the top . is most easily detected by the absence of urocanate from skin and sweat. histidase. producing the 1-carbon THF intermediate known as N5formiminoTHF. which in excess causes constriction or dilation of various blood vessels. Another key feature of histidine catabolism is that it serves as a source of ring nitrogen to combine with tetrahydrofolate (THF). The disease. urocanate. As a result. The latter product is then converted to N-formiminoglutamte via the action of imidazolone propionase. Similarly. the deaminated product. where it is normally found in relative abundance.back to the top Histidine Catabolism Histidine catabolism begins with release of the α-amino group catalyzed by histidase. The principal genetic deficiency associated with histidine metabolism is absence or deficiency of the first enzyme of the pathway. The resultant histidinemia is relatively benign. The general symptoms are those of asthma and various allergic reactions. which is of relatively high incidence (1 in 10.
Another equivalent of alanine is produced from kynurenine in a single step reaction leading to anthranilic acid. An important side reaction in liver involves a non-enzymatic cyclization to quinolate then via a transamination and several rearrangements yields limited amounts of nicotinic acid. The latter enzyme is highly inducible. The NMDA receptor is a key component of the glutaminergic neurotransmission system believed to be involved in the pathophysiology of schizophrenia. . Kynurenine is the first key branch point intermediate in the catabolic pathway leading to 3 fates: Kynurenine can undergo deamination in a standard transamination reaction yielding kynurenic acid. Oxidation of 3-hydroxyanthranilate converts it into 2-amino-3-carboxymuconic 6-semialdehyde. Kynurenic acid has been shown to act as a non-competetive antagonist at the glycine binding site of the NMDA receptor (NMDA = N-methyl-D-aspartate) which is an ionotropic (ligand-gated ion channel) receptor for glutamate. Kynurenine can also undergo a series of catabolic reactions producing 3-hydroxyanthranilic acid plus alanine. its concentration rising almost 10fold on a diet high in tryptophan. thus explaining the potential role of kynurenic acid in schizophrenia. High levels of kynurenic acid have been found in the urine of individuals suffering from schizophrenia. Kynurenic acid and metabolites have been shown to act as antiexcitotoxics and anticonvulsives.Tryptophan Catabolism A number of important side reactions occur during the catabolism of tryptophan on the pathway to acetoacetate. which has two fates. The main flow of carbon elements from this intermediate leads to acetoacetate which is why tryptophan is also a ketogenic amino acid. The first enzyme of the catabolic pathway is an iron porphyrin oxygenase that opens the indole ring. It is the production of these alanine residues that allows tryptophan to be classified among the glucogenic amino acids. which leads to production of a small amount of NAD+ and NADP+.
Nevertheless. as is indicated in the text accompanying the following two charts: The Ten "Nonessential" Amino Acids Alanine Asparagine Aspartate Cysteine Glutamate Glutamine Glycine Proline Serine Tyrosine (synthesized from phenylalanine) (requires sulfhydryl group from methionine) . tryptophan also serves as a precursor for the synthesis of serotonin and melatonin. The twenty amino acids can be divided into two groups of 10 amino acids. Why would an organism evolve in such a way that it could not exist in the absence of certain amino acids? Most likely. this is really not an accurate dichotomy.Aside from its role as an amino acid in protein biosynthesis. while the essential amino acids must be obtained from dietary sources. as there is overlap between the two groups. then. These products are discussed in Specialized Products of Amino Acids. Amino Acid Biosynthesis Essential and Nonessential Amino Acids Nonessential amino acids are those that are synthesized by mammals. Not having to synthesize an additional ten amino acids (and regulate their synthesis) represents a major economy. the ready availability of these amino acids in lower organisms (plants and microorganisms) obviated the need for the higher organism to continue to produce them. The pathways for their synthesis were selected out. However. it remains for us to become familiar with the synthetic pathways for these essential amino acids in plants and microorganisms. Ten are essential and 10 are nonessential. and it turns out that they are generally more complicated that the pathways for nonessential amino acid synthesis and they are also species-specific.
rpi. so cysteine can also be considered essential. but most of it hydrolyzed to urea and ornithine: (http://www. the carbon skeletons of these amino acids are traceable to their corresponding ketoacids. The ten "essential" amino acids are: The Ten "Essential" Amino Acids Arginine (see below) Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine Arginine is synthesized by mammals in the urea cycle.htm) Because mammals cannot synthesize enough arginine to meet the metabolic needs of infants and children. which is an essential amino acid. an essential amino acid. in animals.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/amino. Synthesis of Nonessential Amino Acids Ignoring tyrosine (as it's immediate precursor is phenylalanine. Also. the sulfhydryl group of cysteine is derived from methionine. as it is synthesized by the hydroxylation of phenylalanine. Furthermore. it could be possible to synthesize any one of the nonessential amino acids directly by transaminating its corresponding . all of the nonessential amino acids (and we will include arginine here) are synthesized from intermediates of major metabolic pathways. it is classified as an essential amino acid. an essential amino acid).Note that tyrosine is really an essential amino acid. Therefore.
is catalyzed by an aminotransferase. if that ketoacid exists as a common intermediate. in which an amino group is transferred from an amino acid to the -carbon of a ketoacid.-ketoacid. A "transamination reaction". Three very common ketoacids can be transaminated in one step to their corresponding amino acid: Pyruvate (glycolytic end product) --> alanine Oxaloacetate (citric acid cycle intermediate) --> aspartate ketoglutarate (citric acid cycle intermediate) --> glutamate The individual reactions are: .
but rather as a way to simplify the learning of synthetic pathways of the nonessential amino acids. Still. and glutamine is the amino group donor: . we will be able to trace the carbon skeletons of all of these back to an -ketoacid. Thus. asparagine and glutamine. respectively. I make this point not because of any profound implications inherent in it. Aspartate is transaminated to asparagine in an ATP-dependent reaction catalyzed by asparagine synthetase.Asparagine and glutamine are the products of amidations of aspartate and glutamate. and the remaining nonessential amino acids are not directly the result of transamination of -ketoacids because these are not common intermediates of the other pathways.
it is toxic. followed by a reaction in which NH3 displaces the phosphate group: So. We will now look into this control in more detail. although complicated. and it turns out that glutamine is the amino group donor in the formation of numerous biosynthetic products. which donates its amino group in various other reactions. Therefore. one would expect that glutamine synthetase. in which NH3 and ketoglutarate are produced. increasing the production of glutamine. To keep the level of NH3 in a controlled range. in high concentrations. the enzyme responsible for the amidation of glutamate. Xray diffraction of crystals of the enzyme reveals a . plays a central role in the regulation of nitrogen metabolism. but the accumulation of ammonia as the other product of this reaction is a problem because.The synthesis of glutamine is a two-step one in which glutamate is first "activated" to a glutamylphosphate intermediate. it is worthwhile to look at some of its features because this will give us more insight into regulation of intersecting metabolic pathways. a rising level of ketoglutarate activates glutamine synthetase. The regulation of glutamine synthetase has been studied in E. You have previously studied the oxidative deamination of glutamate by glutamate dehydrogenase. The -ketoglutarate produced is then available for accepting amino groups in other transamination reactions. the synthesis of asparagine is intrinsically tied to that of glutamine. as well as being a storage form of NH3 .Coli and. before proceeding to the biosynthesis of the remaining nonessential amino acids.
both located on the same protein. The following diagram summarizes the regulation of bacterial glutamine synthetase: see text pg 643 We can "walk through" this regulatory cascade by looking at a specific example. in turn. Uridylyltransferase is activated by -ketoglutarate and ATP.hexagonal prism structure (D6 symmetry) composed of 12 identical subunits. serine and glycine. The level of uridylylation is. depending upon the uridylylation of another Tyr residue. located on PII. 6 of which are end products of pathways involving glutamine: histidine tryptophan carbamoyl phosphate (synthesized from carbamoyl phosphate synthetase II) glucosamine-6-phosphate AMP (see next lecture) CTP (see next lecture) The other three effectors are alanine. Adenylyltransferase is the enzyme which catalyzes both the adenylylation and deadenylylation of E. regulated by the activities of the two enzymes. while it is inhibited by glutamine and Pi. the reverse occurs when UMP is covalently attached to the Tyr residue of PII. uridylyltransferase and uridylyl-removing enzyme. namely increased levels of -ketoglutarate ( reflecting a corresponding increase in NH3) levels: (1) Uridylyltransferase activity is increased (2) PII (in complex with adenylyltransferase) is uridylylated (3) Glutamine synthetase is deadenylylated . When PII is uridylylated. which results in an increase sensitivity to the cumulative feedback inhibition by the above nine effectors. glutamine synthetase is deadenylylated. and this enzyme is complexed with a tetrameric regulatory protein. The activity of the enzyme is controlled by 9 allosteric feedback inhibitors. The enzyme is also regulated by covalent modification (adenylylation of a Tyr residue). coli glutamine synthetase. which carry information regarding the cellular nitrogen level. Regulation of the adenylylation and its reverse occurs at the level of PII. PII.
Glutamate-5-semialdehyde is transaminated to ornithine and glutamate is the amino group donor. it is converted to the physiologically active amine. One branch leads to proline while the other branch leads to ornithine and arginine. To further highlight the importance of glutamate. Ornithine. The semialdehyde is a branch point. Exercise: Use the regulatory pathway to explain the effect of a rising level of glutamine on the activity of bacterial glutamine synthetase. followed by reduction to glutamate-5-semialdehyde which spontaneously cyclizes (no enzyme required) to an internal Schiff base. is converted to arginine through the urea cycle. Proline. Ornithine and Arginine are derived from Glutamate The first step involves phosphorylation of glutamate by ATP with the enzyme -glutamyl kinase. a urea cycle intermediate. the major inhibitory neurotransmitter in the brain: .(4) -ketoglutarate and NH3 form glutamine and Pi That the control of bacterial glutamine synthetase is exquisitely sensitive to the level of the cell's nitrogen metabolites is illustrated by the fact that the glutamine just produced in the above cascade is now an inhibitor of further glutamine production. however. The formation of the semialdehyde also requires the presence of either NADP or NADPH. -aminobutyric acid (GABA).
is converted to serine.The glycolytic intermediate. 3-phosphoglycerate. cysteine and glycine. .
N10 -methylene-THF hydroxymethyltransferase) Glycine is also formed in a condensation reaction as follows: N5.N10 -methylene-THF + CO2 + NH4+ --> glycine requires NADH) (enzyme: glycine synthase. (enzyme: serine Cysteine is synthesized from serine and homocysteine (methionine breakdown product): .Note the participation of glutamate as the amino group donor. Serine is converted to glycine in the following reaction: serine + THF --> glycine + N5.
ser + homocysteine -> cystathionine + H2O cystathionine + H2O --> -ketobutyrate + cysteine + NH3 Synthesis of Essential Amino Acids The synthetic pathways for the essential amino acids are: (1) present only in microorgansims (2) considerably more complex than for nonessential amino acids (3) use familiar metabolic precursors (4) show species variation For purposes of classification. Tryptophan (4) Histidine The Aspartate Family .threonine (2) Pyruvate Family: leucine. Tyrosine. isoleucine. methionine. consider the following 4 "families" which are based upon common precursors: (1) Aspartate Family: lysine. valine (3) Aromatic Family: phenylalanine.
Met and Thr is the first step. controlled as a group. catalyzed by aspartokinase: E. catalyzed by the enzyme methionine synthase : .The first committed step for the synthesis of Lys.coli has 3 isozymes of aspartokinase that respond differently to each of the 3 amino acids. in which aspartate is phosphorylated to aspartyl--phosphate. indicated in the brackets above. The biosynthesis of lysine. The pathway from aspartate to lysine has 10 steps. methionine and threonine are not. The pathway from aspartate to threonine has 5 steps The pathway from aspartate to methionine has 7 steps Regulation of the three pathways also occurs at the two branch points: -Aspartate-semialdehyde (homoserine and lysine) Homoserine (threonine and methionine) The regulation results from feedback inhibition by the amino acid products of the branches. with regard to enzyme inhibition and feedback inhibition. then. We will consider one important step in the synthesis of this group of 3 amino acids. namely the step in which homocysteine is converted to methionine.
so it is not surprising to find that SAM is a methylating agent in some reactions. unlike the carboxylations and the SAM methylations. in which the first step involves the transfer of adenosine to methionine to form SAdenosylmethionine (SAM). the THFs can transfer C1 units in more than one oxidation state. Note that the enzyme is called a "synthase" rather than a synthetase.N10-methylene-THF carries a methylene group (-CH2-) and the oxidation level is that of formaldehyde (0). This is to be compared to a "synthetase" in which an NTP is required as an energy source.This reaction can also be looked at as the transfer of a methyl group from N5-methyl-THF to homocysteine. as these reactions are seen very commonly in our study of biochemical pathways. while N5-formimino-THF transfers the formimino group (-CH=NH). in which the oxidation level of the C atom is that of formate. Tetrahydrofolates are also C1 donating agents and. N5-methyl-THF . You have already seen the transfer of a carboxyl group from the biotin cofactor of pyruvate carboxylase to pyruvate to form oxaloacetate (why isn't this called a "transferase" or a "synthase"?). The structure of THF is suited for these transfers by virtue of its N5 and N10 groups as shown in the following chemical structure: . It is reasonable to review reactions in which a C1 unit is added to a metabolic precursor . because the reaction is a condensation reaction in which ATP (or another nucleoside triphosphate) is not used as an energy source. in which the oxidation level of C is that of methanol (-4). N5. transfers the methyl group (-CH3). Formyl (-CH=O) and methenyl (-CH=) groups are also transfered by THF and these both have the C in the oxidation level of formate (+2). so another name for the enzyme catalyzing it is homocysteine methyltransferase. homocysteine is methylated to methionine.as we have just seen. You have also studied methionine breakdown. The methyl group on the sulfonium ion of SAM is highly reactive. and the C1 donor is N5-methyl-THF.In this reaction. Most carboxylation reactions use biotin as a cofactor.
and it's helpful to remember them as a group. or it can react with -ketobutyrate. but also because the disease "maple syrup urine disease" (MSUD) is a result of deficiency of branched-chain -ketoacid dehydrogenase.N10-methylene-THF is the methyl donor. Hydroxyethyl-TPP can react with another pyruvate to form -acetolactate. in which case the pathway leads to isoleucine.We will see THF again when we study the synthesis of thymidylate from dUMP. We'll just look at the beginning and the end of the pathways: The first step is common to all 3 amino acids: Pyruvate + TPP --> Hydroxyethyl-TPP (catalyzed by acetolactate synthase) Note that the central carbon atom in hydroxyethyl-TPP is a carbanion and it is stabilized by resonance forms. . not only because they all originate from the pyruvate carbon skeleton. in which case the pathway heads toward valine and isoleucine. catalyzed by the enzyme thymidylate synthase in which N5. The Pyruvate Family These are the "branched chain" amino acids. resulting in a buildup of branched-chain -keto acids.
The immediate precursor of tryptophan is indole: .Here we see another example of the importance of one particular amino acid. namely glutamate. to leucine. in one direction leads to valine and. A few high points deserve mention. in the other. The Aromatic Amino Acids: Phosphoenolpyruvate (PEP). a glycolytic intermediate. a pentose-phosphate pathway intermediate. This condensation product eventually cyclizes to chorismate. The final step in the formation of each of these amino acids involves the transfer of an amino group from glutamate to the corresponding -ketoacid of each of the 3 branched-chain amino acids. to form 2-keto-3-deoxyarabinoheptulosonate-7phosphate and inorganic phosphate. From here. and tyrosine and phenylalanine at the other end.There is a branch point at -ketoisovalerate which. ending up in the production of tryptophan at one branch end. the pathway branches. First. glutamine plays a role as the donor of an amino group to chorismate to form anthranilate at the tryptophan branch. The enzyme involved is a synthase. to the anabolic pathways for amino acids. condenses with erythrose-4-phosphate.
The only difference between the 2 resulting amino acids is that the para carbon of the benzene ring of tyrosine is hydroxylated.The "indole ring" is the characterizing feature of the tryptophan structure. dopamine. and these are LDOPA.S. in mammals. catalyzed by the enzyme phenylalanine hydroxylase. The pathway from tyrosine to norepinephrine is shown below: . Clinical Correlation: Defective or absent phenylalanine hydroxylase results in buildup of phenylalanine. The branch that leads towards tyrosine and phenylalanine has another branch point at prephenate. which is subsequently transaminated to phenylpyruvate and excreted in the urine. for this condition by blood analysis has greatly decreased the morbidity of the untreated condition. Universal screening of newborns in the U. phenylalanine is directly hydroxylated to tyrosine. Some very important physiologically active amines are derived from tyrosine. Indeed. Note that serine is the donor of the amino group to indole to form tryptophan. norepinephrine and epinephrine. The disease "phenylketonuria" rapidly leads to severe mental retardation if not treated soon after birth with a low phenylalanine diet.
The formation of epinephrine from norepinephrine involves the transfer of the highly reactive methyl group of S-adenosylmethionine to norepinephrine: .
Histidine is special in that its biosynthesis is inherently linked to the pathways of nucleotide formation. where the chemistry of the imidazole ring of histidine makes it a nucleophile and a good acid/base catalyzer. We now know that RNA can have catalytic properties. in a reaction that is driven by the subsequent hydrolysis of the pyrophosphate that condenses out. Histidine residues are often found in enzyme active sites. Glutamine again plays a role as an amino group donor. this time resulting in the formation of 5aminoamidazole-4-carboximide ribonucleotide (ACAIR). In the first step of histidine synthesis. which is an intermediate in purine biosynthesis.Histidine Biosynthesis: We will look at this pathway in a bit more detail. Perhaps the transition to protein catalysis from RNA catalysis occurred at the origin of histidine biosynthesis. N1-5'-phosphoribosyl ATP. and there has been speculation that life was originally RNA-based. because it involves the molecule 5phosphoribosyl--pyrophosphate (which we will refer to as "PRPP" from now on). . PRPP condenses with ATP to form a purine. PRPP is also involved in the synthesis of purines and pyrimidines. as we will soon see.
.The physiologically active amine. is formed from histidine: In the next lecture. this is a convenient point at which to transition from one lecture to another. histamine. Since we have just identified histidine as a likely evolutionary transition point from purines to amino acids and proteins. we will look at the synthesis of nucleotides.
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