Amino acid metabolism
Amino acids are categorized into two types - non-essential amino acids (can be synthesized by the body) and essential amino acids which cannot, and have to be provided from the diet. The non-essential amino acids are glycine, alanine, serine, asparagine, aspartic acid, glutamine, glutamic acid, proline, cysteine, tyrosine and arginine. The essential amino acids include valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, threonine, lysine and histidine.
The amino acids arginine, methionine and phenylalanine are considered essential because their rate of synthesis is insufficient to meet the growth needs of the body. Most of synthesized arginine 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, phenylalanine is needed in large amounts to form tyrosine if the latter is not adequately supplied in the diet.
The amino acid pool comes from protein degradation in the gastro-intestinal tract, intracellular protein degradation and de novo synthesis and is used in protein synthesis and metabolism. Each amino acid type has its own metabolic fate and specific functions. Not only does this metabolic process generate energy, but it also generates key intermediates for the biosynthesis of certain non-essential amino acids, glucose and fat.
Synthesis of non-essential amino acids
Essential amino acids - valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, threonine, lysine and histidine - cannot be synthesized by the human body and thus have to be provided from the diet. While the amino acids arginine, methionine and phenyalanine can be synthesized by mammalian cells they are considered dietary essentials as their rate of synthesis is insufficient to meet the growth needs of the body. Methionine and phenylalanine are required in large amounts for the synthesis of cysteine and tyrosine respectively.
Figure 1. Pathways involved in the synthesis of non-essential amino acids glycine, alanine, serine cysteine, aspartic acid, asparagine, glutamic acid, glutamine, proline and ornithine. Click for enlarged view. Enzyme abreviations: ADH18-A1: aldehyde dehydrogenase 18 family, member A1; PYCR1: pyrroline-5-carboxylate reductase 1; OAT: ornithine aminotransferase. The glycolytic intermediates 3-phosphoglycerate and pyruvate are used in the synthesis of serine, glycine, cysteine and alanine. The tricarboxylic acid cycle intermediates oxaloacetate and α-ketoglutarate are involved in the synthesis of aspartic acid, glutamic acid, asparagine, glutamine, ornithine and proline. See text for details. The synthesis of non-essential amino acids glycine, alanine, serine, asparagine, aspartic acid, glutamine, glutamic acid, proline, cysteine, tyrosine is summarised in Figure 1. Glycolysis provides two intermediates for amino acid synthesis: 3-phosphoglycerate and pyruvate.
Serine, Glycine and Cysteine synthesis – The NADH-linked dehydrogenase (3-phosphoglycerate dehydrogenase) converts the glycolytic intermediate 3-phosphoglycerate into the keto acid, 3-phosphohydroxypyruvate (Figure 1). Transamination of 3-phosphohydroxypyruvate by phosphoserine aminotransferase 1, utilizing glutamate as a donor, produces 3-phosphoserine, which is converted to serine by phosphoserine phosphatase .
Glycine is synthesised from serine in a one-step reversible reaction (catalyzed by serine hydroxymethyltransferase), that involves the transfer of the hydroxymethyl group from serine to the cofactor tetrahydrofolate, producing glycine and N5,N10-methylene- tetrahydrofolate.
Serine is also involved in the synthesis of cysteine (Figure 1). The sulfur for cysteine synthesis comes from the essential amino acid methionine. A condensation of ATP and methionine, catalyzed by methionine adenosyltransferase, yields S-adenosylmethionine, a precursor for several methyl transfer reactions in the body. The result of methyl transfer is the conversion of S-adenosylmethionine to S-adenosylhomocysteine which is then cleaved by adenosylhomocysteinase to yield homocysteine and adenosine. In a reaction catalyzed by the enzyme cystathionine β-synthase, the homocysteine condenses with serine to produce cystathionine, which is subsequently cleaved by cystathionine γ-lyase to produce cysteine and α-ketobutyrate.
Synthesis of alanine. The other glycolytic product involved in amino acid synthesis is pyruvate which on transamination by alanine transaminase (also called serum glutamate-pyruvate transaminase, SGPT), again using glutamate as nitrogen donor, generates alanine and the TCA cycle intermediate α-ketoglutarate(Figure 1).
Synthesis of aspartic acid and glutamic acid. The tricarboxylic acid cycle intermediates oxaloacetate and α-ketoglutarate are the ketoacids involved in the synthesis of the amino acids aspartate and glutamate by transamination (Figure 1). The enzyme involved is aspartate aminotransferase (formerly called serum glutamic oxaloacetic transaminase (SGOT)). Glutamate alternatively can be synthesized by the reductive amination of α-ketoglutarate by glutamate dehydrogenase in a nitrogen-incorporating reaction and by other aminotransferase (transamination) reactions, with the amino nitrogen being donated by a number of different amino acids. Examples in Figure 1 are alanine aminotransferase and ornithine aminotransferase. Thus, glutamate is a general collector of amino nitrogen. Glutamate can also be formed by the deamination of glutamine by the enzyme glutaminase  (Figure 1).
As mentioned above aspartate is formed in a transamination reaction catalyzed by aspartate transaminase, where oxaloacetate is the amino acceptor and glutamate is the amino donor. Aspartate can also be formed by deamination of asparagine catalyzed by asparaginase  (Figure 1).
Synthesis of asparagine and glutamine. As shown in Figure 1, asparagine and glutamine can be synthesised from their respective α-amino acids (aspartate and glutamate) by the enzymes asparagine synthetase and glutamine synthetase .
Glutamine is produced from glutamate by the direct incorporation of ammonia, another nitrogen incorporating reaction. Asparagine, however, is formed by a different reaction, catalyzed by an amidotransferase. In contrast to aminotransferase (transamination) reactions (which are readily reversible), transamidation reactions are dependent on ATP and considered irreversible. As a consequence, the degradation of asparagine and glutamine take place by a hydrolytic pathway rather than by a reversal of the synthetic pathway by which they were formed. As discussed in the previous subsection, asparagine can be degraded to aspartate by the enzyme asparaginase with the release of ammonia (Figure 1).
Proline and ornithine biosynthesis. Glutamate is also the precursor of both proline and ornithine with Δ1-pyrroline-5-carboxylate serving as a branch point intermediate leading to one or the other of these two products (Figure 1). 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 (generated from ammonia, CO2 and ATP) in the urea cycle, the cycle used by humans and animals to quickly detoxify ammonia formed as a result of amino acid catabolism (see below). The production of ornithine from glutamate is important when dietary arginine, the other principal source of ornithine, is limited. The synthesis of ornithine from glutamate occurs only in the intestines.
Tyrosine synthesis. Tyrosine is produced in cells by hydroxylating the essential amino acid phenylalanine. The enzyme involved is the mixed-function oxygenase phenylalanine hydroxylase . Half of the daily requirement for phenylalanine is for the production of tyrosine; if the diet is rich in tyrosine itself, the requirements for phenylalanine can be reduced by about 50%.
Amino acid catabolism
The catabolism of amino acids accounts for 10 to 15% of the human body’s energy production. The liver is the major site of nitrogen metabolism in the body with the potentially toxic nitrogen of amino acids eliminated via transaminations, deamination, and urea formation.
The urea cycle
The urea cycle (Figure 2) mediates the removal of ammonia as urea in the amount of 10 to 20 g per day in the healthy adult. This cycle was the first metabolic cycle discovered (Hans Krebs and Kurt Henseleit, 1932), five years before the discovery of the tricarboxylic acid cycle. In mammals, the urea cycle takes place primarily in the liver, and to a lesser extent in the kidney.
The initial two steps of the urea cycle occur in the mitochondria. The first by carbamyl phosphate synthetase, mediates the formation of carbamyl phosphate from NH3−, HCO3− and ATP. The second step is the condensation of ornithine with carbamyl phosphate by the enzyme ornithine transcarbamylase to form citrulline. The activity of this enzyme is directly related to dietary protein.
Figure 2. The urea cycle which serves to excrete excess nitrogen as urea in most vertebrates. Click for enlarged view. The first two steps occur in the mitochondria, the remainder in the cytosol. See text for details. Based on Hauke, 2002. Citrulline is released to the cytosol, where it condenses with aspartate to form argininosuccinate via the enzyme argininosuccinate synthetase. Argininosuccinate is cleaved in the cytosol by argininosuccinate lyase, to yield fumarate, which is oxidized in the TCA cycle, and arginine, which is rapidly cleaved to urea and ornithine via the hepatic enzyme arginase. Both argininosuccinate lyase and arginase are induced by starvation, dibutyryl cAMP and corticosteroids.
Glucogenic and ketogenic amino acids
Depending on their metabolic fates, amino acids are referred to as ‘glucogenic’, ‘ketogenic’ or ‘glucogenic and ketogenic’.Glucogenic amino acids are broken down into one of the following metabolites: pyruvate, α-ketoglutarate, succinyl CoA, fumarate or oxaloacetate which can be oxidized into CO2 and H2O to generate ATP via the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation. Alternatively the carbon skeletons from these metabolites can be used to synthesise glucose by the process of gluconeogenesis hence the term glucogenic amino acids.
In contrast ketogenic amino acids are broken down into acetyl-CoA and or the ketone body acetoacetate, neither of which can bring about net glucose production in humans. A third group of amino acids are catabolised to both glucogenic and ketogenic intermediates. Thirteen amino acids: glycine, alanine, serine, aspartic acid, asparagine, glutamic acid, glutamine, proline, valine, methionine, cysteine, histidine and arginine, are purely ‘glucogenic’; five amino acids: tryptophan, phenylalanine, tyrosine, isoleucine and threonine are both ‘glucogenic and ketogenic’; while the remaining two amino acids - lysine and leucine - are purely ‘ketogenic’.
Catabolism of the glucogenic amino acids
Glucogenic amino acids catabolised to pyruvate: alanine, serine, glycine and cysteine
Alanine catabolism. Alanine is second only to glutamine in prominence as a circulating amino acid. In this capacity it serves a unique role in the transfer of nitrogen from peripheral tissues to the liver. Alanine is transferred to the circulation by many tissues, but mainly by muscle, in which alanine is formed from pyruvate (by transamination) at a rate proportional to intracellular pyruvate levels generated by the catabolism of glycogen (glycogenolysis) and glucose (glycolysis).
Figure 3. The glucose-alanine cycle. The glucose-alanine cycle is used primarily as a mechanism for skeletal muscle to eliminate nitrogen while replenishing its energy supply. Glucose oxidation produces pyruvate which can undergo transamination to alanine. Additionally, during periods of fasting, skeletal muscle protein is degraded for the energy value of the amino acid carbons and alanine is a major amino acid in protein. The alanine then enters the blood stream and is transported to the liver. Within the liver alanine is converted back to pyruvate which is then a source of carbon atoms for gluconeogenesis. The newly formed glucose can then enter the blood for delivery back to the muscle. 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.As summarised in Figure 3, the liver accumulates alanine from the blood, uses alanine transaminase to reverse the transamination that occurs in muscle regenerating pyruvate for further oxidation by the tricarboxylic acid cycle or conversion to glucose (gluconeogenesis), and proportionately increases the elimination of unwanted nitrogen (ammonia) via the urea cycle (Figure 3). When alanine transfer from muscle to liver is coupled with glucose transport from liver back to muscle, the process is known as the glucose-alanine cycle (Figure 3). The key feature of the cycle is that through a single molecule, alanine, peripheral tissues export pyruvate and ammonia to the liver, where the carbon skeleton is recycled and most nitrogen eliminated.
Serine catabolism – Serine catabolism involves its conversion to pyruvate and ammonia by the enzyme serine dehydratase which catalyses the β-elimination of the hydroxyl group of serine to form an amino acrylate intermediate which tautomerizes into the imine which is then hydrolyzed to produce ammonia and pyruvate. Serine is glucogenic as it can be metabolized back to the glycolytic intermediate, 3-phosphoglycerate, by a pathway that is essentially a reversal of serine biosynthesis (Figure 1). However, the enzymes are different.
Glycine catabolism - The main glycine catabolic pathway leads to the production of CO2, ammonia, one equivalent of N5,N10-methylene tetrahydrofolate and NADH + H+. The oxidative decarboxylation is catalysed by the mitochondrial enzyme, glycine dehydrogenase (decarboxylating) which is also called the glycine cleavage complex (GCC). Glycine is classified as a glucogenic amino acid since, as shown in Figure 1, it can be converted to serine (by serine hydroxymethyltransferase) which can be converted back to the glycolytic intermediate, 3-phosphoglycerate as mentioned in the previous paragraph.
Cysteine catabolism - The major cysteine catabolic pathway in humans occurs via the action of cysteine dioxygenase type 1 (CDO1). CDO1 oxidizes the sulfhydryl group of cysteine to sulfinate, producing the intermediate cysteine sulfinate. Catabolism of cysteine sulfinate proceeds through transamination (catalyzed by cytosolic aspartate transaminase) to β-sulfinylpyruvate (3-sulfinylpyruvate) which then undergoes desulfuration yielding pyruvate and bisulfite, (HSO3–) which is in equilibrium with sulfite (SO32–) at pH 7.2. The enzyme sulfite oxidase then catalyzes the conversion of sulfite to sulfate.
The enzyme cysteine desulfurase is another important enzyme associated with cysteine catabolism as it removes the sulfur from cysteine yielding alanine. The sulfur remains associated with cysteine desulfurase and is subsequently transferred to numerous enzymes that possess iron-sulfur clusters for their activity. Other than protein, the most important metabolic products derived from cysteine are glutathione (GSH), the bile salt modifying compound, taurine, and as a source of the sulfur for coenzyme-A synthesis.
Glucogenic amino acids catabolised to oxaloacetate or α-ketoglutarate: aspartic acid, asparagine, glutamic acid, glutamine, histidine, proline, ornithine and arginine
Aspartic and glutamic acid catabolism. The acidic amino acids aspartic acid and glutamic acid are important in collecting amino nitrogen (ammonia) via the enzymes asparagine synthetase and glutamine synthetase  (see Figure 1). They are also important in eliminating ammonia via the urea cycle (see Figure 2). The catabolic path of the carbon skeletons involves simple 1-step aminotransferase reactions that directly produce net quantities of a TCA cycle intermediate, oxaloacetate or α-ketoglutarate. The glutamate dehydrogenase reaction operating in the direction of α-ketoglutarate production provides a second avenue leading from glutamate to gluconeogenesis (Figure 1).
Asparagine catabolism begins with the enzyme asparaginase which converts asparagine into ammonia and aspartate. Aspartate can serve as an amino donor in transamination reactions yielding oxaloacetate, which follows the gluconeogenic pathway to glucose (Figure 1).
Glutamine catabolism involves the enzyme glutaminase, an important kidney tubule enzyme, that converts glutamine (from liver and from other tissues) to glutamate and NH4+, with the NH4+ being excreted in the urine. Glutaminase activity is present in many other tissues as well, although its activity is not nearly as prominent as in the kidney. The glutamate produced from glutamine is converted to α-ketoglutarate via the action of glutamate dehydrogenase, making glutamine a glucogenic amino acid.
Histidine catabolism proceeds via a 4-step pathway to glutamate which begins with release of the α-amino group catalyzed by histidine ammonia-lyase (also called histidase), introducing a double bond into the molecule. As a result, the deaminated product, urocanate, is not the usual α-keto acid associated with loss of α-amino nitrogens. The end product of histidine catabolism is glutamate, making histidine one of the glucogenic amino acids. The process of histidine catabolism represents, not only a catabolic reaction pathway, but a major folic acid derivative biosynthesis pathway. In the course of the catabolism, a portion of the carbon skeleton of histidine is transferred to tetrahydrofolate (THF) forming the folate derivative, N5-formimino-THF.
Ornithine and proline catabolism is essentially a reversal of their synthesis from glutamate (see Figure 1). Proline is oxidized back to Δ1-pyrroline-5-carboxylate via the action of proline dehydrogenase. Ornithine can be deaminated to Δ1-pyrroline-5-carboxylate via a reversal of the ornithine aminotransferase reaction. The resulting Δ1-pyrroline-5-carboxylate is oxidized to glutamate via the action of aldehyde dehydrogenase 4 family, member A1, (also called delta-1-pyrroline-5-carboxylate dehydrogenase).
Arginine catabolism involves several pathways, with the major catabolic pathway being its cleavage by the enzyme arginase  to form ornithine and urea in the urea cycle (Figure 2). The enzyme ornithine δ-aminotransferase transfers the δ-aminogroup of ornithine to α-ketoglutarate to form glutamate and glutamate γ-semialdehyde, the latter being converted to a second molecule of glutamate by the enzyme glutamate-5-semialdehyde dehydrogenase  (Figure 1). The glutamate can be converted to α-ketoglutarate for further metabolism as described above.
In some tissues arginine serves as the precursor for nitric oxide (NO) production via the action of nitric oxide synthase . The citrulline byproduct of the NOS reaction can feed back into arginine synthesis via the hepatic urea cycle enzymes argininosuccinate synthetase (ASS1) and argininosuccinate lyase (ASL). Arginine also serves as the precursor for creatine synthesis and, therefore, arginine can be excreted in the urine as the creatine byproduct, creatinine. The cycling of citrulline back to arginine involves the urea cycle enzymes, argininosuccinate synthetase and argininosuccinate lyase  (Figure 2).
Glucogenic amino acids catabolised to succinyl CoA: methionine, valine and in humans, threonine
Methionine catabolism involves nine steps. The first step is catalyzed by methionine adenosyl transferase which tranfers the adenosyl group of ATP to the sulfur of methionine to form S-adenosylmethionine (SAM). SAM methylase transfers the activated methyl group to an acceptor to form S-adenosylhomocysteine which is hydrolyzed by adenosylhomocysteinase to form homocysteine. Cystathionine β-synthase catalyzes the condensation of a serine residue with homocysteine to form cystathionine. Cystathioniine γ-lyase cleaves cystathionine into cysteine and α-ketobutyrate, the latter being converted into propionyl CoA by α-ketobutyrate dehydrogenase .
The propionyl-CoA is converted, via a mitochondrially-localized three reaction ATP-dependent pathway, to succinyl-CoA which can then enter the TCA cycle for further oxidation. The enzymes required for this conversion are propionyl-CoA carboxylase, methylmalonyl-CoA epimerase, and methylmalonyl-CoA mutase, respectively. This propionyl-CoA conversion pathway to succinyl CoA is also required for the metabolism of the amino acids valine, isoleucine, and threonine and the odd-chain fatty acids.
Valine catabolism. The catabolism of valine is similar to that of the other branched chain amino acids, isoleucine (a ‘glucogenic and ketogenic’ amino acid) and leucine (a ‘ketogenic’ amino acid)  as shown in Figure 4.
Figure 4. The catabolism of branched-chain amino acids valine, isoleucine and leucine[5,6]. Click for enlarged view. The first two steps involve the same enzymes for all three amino acids, after that the pathways diverge and use different enzymes. See text for details. While most amino acid catabolism occurs in the liver, that of branched-chain amino acids such as isoleucine, leucine and valine is not, due to the absence in liver of the first enzyme in their catabolic pathways - branched chain amino acid transferase (BCAT) . Valine, isoleucine and leucine are catabolized mainly in muscle, adipose tissue, kidney and brain. Branched-chain amino acid (BCAA) catabolism yields both NADH and FADH2 which can be utilized for ATP generation which is a primary reason for their high rates of catabolism in skeletal muscle.
The catabolism of all three of these amino acids uses the same enzymes in the first two steps. The first step in each case is a transamination using one of two branched-chain aminotransferase, (BCATc or BCATm) with α-ketoglutarate as amine acceptor (Figure 4). The resulting α-ketoacids are then oxidatively decarboxylated via the action of the enzyme complex, branched-chain ketoacid dehydrogenase (BCKD). The BCKD reaction generates the CoA derivatives of the decarboxylated ketoacids while also generating the reduced electron carrier, NADH. After these first two reactions the catabolic pathways for the three amino acids diverge (Figure 4). The third reaction of valine amino acid catabolism involves a dehydrogenation step catalysed by isobutyryl-CoA dehydrogenase (IBD)  to form mathylacrylyl CoA and the reduced electron carrier FADH2. As shown in Figure 4 the catabolism of valine involves four additional enzymic reactions carried out by the enzymes methacrylyl CoA hydratase, hydroxyisobutyryl CoA hydrolase and methylmalonate semialdehyde dehydrogenase, that culminate in the production of propionyl CoA. The propionyl CoA can be then converted to succinyl-CoA via a mitochondrially-localized three reaction ATP-dependent pathway involving propionyl-CoA carboxylase, methylmalonyl-CoA epimerase, and methylmalonyl-CoA mutase. Succinyl CoA can enter the TCA cycle for further oxidation or after conversion to oxaloacetate, be metabolised to glucose via gluconeogenesis.
Threonine catabolism. While there are three catabolic pathways for threonine in mammals only one appears important in humans. This pathway involves glycine-independent serine/threonine dehydratase yielding α-ketobutyrate which is further catabolized to propionyl-CoA. Serine/threonine dehydratase is expressed at high levels only in the liver. The resulting propionyl-CoA is converted to succinyl-CoA for further oxidation or conversion to glucose as discussed above.
A second threonine catabolism pathway in mammals involves the enzymes threonine dehydrogenase and α-amino-β-ketobutyrate lyase resulting in the conversion of threonine to acetyl CoA (a ketogenic product) and glycine (a glucogenic product that can be converted to serine and then back to the glycolytic intermediate 3-phosphoglycerate by a pathway that is essentially a reversal of the serine biosynthesis pathway (Figure 1)). However the enzymes are different. This pathway, that yields both ketogenic and glucogenic products, does not appear to be functional in humans because the human gene for threonine dehydrogenase contains three inactivating mutations and is non-functional. Thus in humans threonine can be considered purely glucogenic.
Catabolism of the ‘glucogenic and ketogenic’ amino acids: threonine, isoleucine, phenylalanine, tyrosine and tryptophan.
Threonine catabolism. There are alternate catabolic pathways for threonine in mammals that lead to the production of either propionyl CoA (glucogenic) or acetyl CoA (ketogenic), and glycine (glucogenic) as end products. However, as discussed in the preceding section, only one, the glucogenic propionyl CoA pathway, appears to be important in humans.
Isoleucine catabolism is similar to that of the other branched-chain amino acids (BCAA) valine (glucogenic) and leucine (ketogenic) and occurs predominantly in skeletal muscle. BCAA catabolism yields both NADH and FADH2 which can be utilized for ATP generation which is a primary reason for their high rates of catabolism in skeletal muscle. As summarized in Figure 5, the first step in the catabolism of isoleucine is a transamination using a pyridoxal phosphate-dependent BCAA aminotransferase (termed a branched-chain aminotransferase, BCAT), with α-ketoglutarate as amine acceptor. The resulting α-keto-β-methylvalerate is then oxidatively decarboxylated via the action of the enzyme complex, branched-chain ketoacid dehydrogenase (BCKD). The BCKD reaction generates α-methylbutyryl CoA and NADH. The third reaction of branched-chain amino acid catabolism involves a dehydrogenation step carried out by the enzyme short/branched-chain acyl-CoA dehydrogenase (SBCAD) yielding tiglyl CoA and FADH2. The final three reactions in isoleucine catabolism involve the three enzymes involved in the terminal steps of fatty acid oxidation - enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase which convert tiglyl CoA to acetyl CoA (ketogenic) and propionyl CoA (glucogenic). The former can gives rise to ketone bodies while the latter can be converted to succinyl CoA for further oxidation or conversion to glucose as discussed above in the section on valine catabolism. The second last reaction, by 3-hydroxyacyl-CoA dehydrogenase, generates NADH + H+ for ATP synthesis via oxidative phosphorylation.
Figure 5. Catabolic pathway for phenylalanine and tyrosine catabolism. Click to enlarge. See text for details. Source: ref .Phenylalanine and tyrosine catabolism. The degradation of aromatic amino acids requires molecular oxygen to break down the aromatic rings. As shown in Figure 5 the degradation of phenylalanine begins with a monooxygenase, phenylalanine hydroxylase which adds a hydroxyl group to phenylalanine to form tyrosine. From there the remaining five catabolic pathways for phenylalanine and tyrosine are the same. Tyrosine aminotransferase deaminates tyrosine to form p-hydroxyphenylpyruvate which is converted into homogentisate by the enzyme p-hydroxyphenylpyruvate dioxygenase . The final three steps in the catabolism of tyrosine and phenylalanine are carried out by the enzymes homogentisate 1,2-dioxygenase, maleylacetoacetate isomerase and fumarylacetoacetate hydrolase resulting in the production of fumarate (glucogenic) and acetoacetate (ketogenic).
Tryptophan catabolism. The catabolism of tryptophan in humans is complex with one major pathway resulting in the formation of acetoacetyl CoA, the precursor of ketone bodies - acetoacetate, 3-hydroxybutyrate and acetone. As shown in Figure 6, tryptophan catabolism includes the generation of the glucogenic amino acid alanine, which allows tryptophan to be classified as a ‘glucogenic and ketogenic’ amino acid. The tryptophan catabolic pathway starts with either tryptophan 2,3-dioxygenase, or indoleamine 2,3-dioxygenase 1 which open the indole ring to form N-formyl-kynurenine. N -formyl-kynurenine is then converted to kynurenine by the enzyme, arylformamidase (also called kynurenine formamidase ) .
Figure 6. Simplified pathway of tryptophan catabolism. Click for enlarged view. See text for details. Source: ref .As shown in Figure 6, kynurenine then undergoes a series of catabolic reactions resulting in complete oxidation to acetoacetyl-CoA. The first is catalyzed by kynurenine hydroxylase (also called kynurenine 3-monooxygenase) forming 3-hydroxykynurenine. The next step in the pathway is catalyzed by kynureninase and produces 3-hydroxyanthranilic acid and the amino acid alanine hence the classification of tryptophan as a ‘glucogenic and ketogenic’ amino acid. The next step in the pathway is the conversion of 3-hydroxyanthranilic acid to 2-amino-3-carboxymuconate-6-semialdehyde (ACMS) and quinolinic acid by the enzyme 3-hydroxyanthranilate 3,4-dioxygenase. ACMS can be metabolized via the action of the enzyme ACMS decarboxylase followed by 10 other enzymes to acetoacetyl-CoA, the end product of complete tryptophan catabolism.
Aside from its role as an amino acid in protein biosynthesis, tryptophan also serves as a precursor for the synthesis of the neurotransmitters serotonin and melatonin and kynurenine also serves as an important intermediate in the pathway for the synthesis of the nicotinamide adenine dinucleotide co-factors, NAD+ and NADP+.
Catabolism of the ketogenic amino acids lysine and leucine.
Lysine catabolism. Lysine and leucine are the only two amino acids that are purely ketogenic. The primary pathway of lysine catabolism in the liver is one that begins with the formation of the adduct between lysine and α-ketoglutarate called saccharopine. The formation of saccharopine and its hydrolysis to α-aminoadipic-6-semialdehyde is catalyzed by the bifunctional enzyme α-aminoadipic semialdehyde synthase. This reaction results in the amino nitrogen remaining with the α-carbon of α-ketoglutarate, producing glutamate and α-aminoadipic-6-semialdehyde. Because this transamination reaction is not reversible, lysine is an essential amino acid . The ultimate end-product of lysine catabolism is acetoacetyl CoA which can be further converted in the liver to the Ketone bodies acetoacetate, 3-hydroxybutyrate and acetone.
Leucine catabolism As summarised in Figure 4, leucine catabolism, like that of the other branched-chain amino acids valine and isoleucine, begins with transamination by a branched amino acid aminotransferase to form α-ketoisocaproate which is then oxidatively decarboxylated to form isovaleryl CoA by the branched chain α-ketoacid dehydrogenase complex . In the next step isovaleryl CoA is dehydrogenated to form 3-methylcrotonyl CoA. The enzyme that catalyzes this dehydrogenation is isovaleryl CoA dehydrogenase. 3-Methylcrotonyl CoA is then carboxylated by a biotin containing enzyme called methylcrotonyl CoA carboxylase. This two-step reaction involves the ATP-dependent carboxylation of the biotin cofactor with bicarbonate serving as the source of CO2 and the transfer of the carboxyl group to 3-methylcrotonyl CoA to form 3-methylglutaconyl CoA. 3-methylglutaconyl CoA is then hydrated by 3-methylglutaconyl CoA hydratase to form 3-hydroxy-3-methylglutaryl CoA which can be cleaved into acetyl CoA and acetoacetate by the enzyme 3-hydroxy-3-methylglutaryl CoA lyase  (Figure 4).
^ Protein Degradation https://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/protease.htm
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^ Miles B, Amino acid degradation - https://www.google.com.au/?gws_rd=ssl#q=Miles+Amino+acid+catabolism
^ Taniguchi K et al., The valine catabolic pathway in human liver: effect of cirrhosis on enzyme activities. Hepatology 1996; 24:1395-1398.
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