Amino Acid Metabolism, Third Edition

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AccessEmergency Medicine. Case Files Collection. Clinical Sports Medicine Collection. Davis AT Collection. Davis PT Collection. Murtagh Collection. About Search. Enable Autosuggest. Previous Chapter. Next Chapter. Janson L. Lee W. Janson, and Marc E. Accessed September 21, MLA Citation. Download citation file: RIS Zotero.

Effect of starvation on branched-chain alpha-keto acid dehydrogenase activity in rat heart and skeletal muscle. Changes in the concentration of specific amino acids in the serum of experimentally malnourished pigs. The plasma aminogram in kwashiorkor. Reeds PJ. The catabolism of valine in the malnourished rat.

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Nutr Rev. Am J Physiol Endocrinol Metab. Blomstrand E. Amino acids and central fatigue. Amino Acids. Dasarathy S, Hatzoglou M. Hyperammonemia and proteostasis in cirrhosis. Hyperammonemia-induced depletion of glutamate and branched-chain amino acids in muscle and plasma. J Hepatol. Effect of hyperammonemia on leucine and protein metabolism in rats. Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle. Plasma amino acids in four models of experimental liver injury in rats.

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Branched-chain amino acid supplementation in treatment of liver cirrhosis: updated views on how to attenuate their harmful effects on cataplerosis and ammonia formation. Rodney S, Boneh A. Amino acid profiles in patients with urea cycle disorders at admission to hospital due to metabolic decompensation. JIMD Rep. Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy-therapeutic perspectives. Metab Brain Dis. Acute effects of phenylbutyrate on glutamine, branched-chain amino acid and protein metabolism in skeletal muscles of rats.

Int J Exp Pathol. Phenylbutyrate therapy for maple syrup urine disease. Hum Mol Genet. Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients. Mol Genet Metab. Dietary management of urea cycle disorders: European practice. Blood levels of branched-chain amino acids and alpha-ketoacids in uremic patients given keto analogues of essential amino acids.

Peripheral metabolism of branched-chain keto acids in patients with chronic renal failure. Miner Electrolyte Metab. Leucine and protein metabolism in rats with chronic renal insufficiency. Exp Toxicol Pathol. Plasma and muscle free amino acids in uremia: influence of nutrition with amino acids. Clin Nephrol. Acidosis, not azotemia, stimulates branched-chain, amino acid catabolism in uremic rats. Kidney Int.

Metabolic acidosis accelerates whole body protein degradation and leucine oxidation by a glucocorticoid-dependent mechanism. Effect of a keto acid-amino acid supplement on the metabolism and renal elimination of branched-chain amino acids in patients with chronic renal insufficiency on a low protein diet. Wien Klin Wochenschr. Management of protein-energy wasting in non-dialysis-dependent chronic kidney disease: reconciling low protein intake with nutritional therapy.

Free plasma levels and urinary excretion of eighteen amino acids in normal and diabetic dogs. Plasma and skeletal muscle free amino acids in type I, insulin-treated diabetic subjects. The increased skeletal muscle protein turnover of the streptozotocin diabetic rat is associated with high concentrations of branched-chain amino acids. Biochem Mol Med. Effects of streptozotocin-induced diabetes in domestic pigs with focus on the amino acid metabolism.

Lab Anim. Blood and tissue branched-chain amino and alpha-keto acid concentrations: effect of diet, starvation, and disease. Effects of diabetes on the activity and content of the branched-chain alpha-ketoacid dehydrogenase complex in liver. Arch Biochem Biophys. Effects of diabetes and starvation on skeletal muscle branched-chain alpha-keto acid dehydrogenase activity. Amino acid and protein metabolism in diabetes mellitus. Arch Intern Med. Amino acids and free fatty acids in plasma in diabetes.

The effect of insulin on the arterial levels. Acta Med Scand. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Regulation of branched-chain amino acid catabolism in rat models for spontaneous type 2 diabetes mellitus. Biochem Biophys Res Commun. Metabolite profiles and the risk of developing diabetes. Nat Med. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance.

Dietary leucine - an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS One. The effects of branched-chain amino acid granules on the accumulation of tissue triglycerides and uncoupling proteins in diet-induced obese mice. Endocr J. DNA damage in an animal model of maple syrup urine disease. Activation of branched-chain keto acid dehydrogenase by exercise.

Effect of exercise on glutamine synthesis and transport in skeletal muscle from rats. Clin Exp Pharmacol Physiol. Branched-chain alpha-keto acid dehydrogenase complex in rat skeletal muscle: regulation of the activity and gene expression by nutrition and physical exercise. Distribution of plasma amino acids in humans during submaximal prolonged exercise. Changes in plasma amino acid distribution and urine amino acids excretion during prolonged heavy exercise.

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Splanchnic and leg metabolism of glucose, free fatty acids, and amino acids. The effects of 8 weeks of heavy resistance training and branched-chain amino acid supplementation on body composition and muscle performance. Nutr Health.

The effect of acute branched-chain amino acid supplementation on prolonged exercise capacity in a warm environment. Eur J Appl Physiol. Effects of diets supplemented with branched-chain amino acids on the performance and fatigue mechanisms of rats submitted to prolonged physical exercise. Stress-induced intracellular glutamine depletion.

The potential use of glutamine-containing peptides in parenteral nutrition. Beitr Infusionther Klin Ernahr. Hardy G, Hardy IJ. Can glutamine enable the critically ill to cope better with infection? Holecek M, Sispera L. Glutamine deficiency in extracellular fluid exerts adverse effects on protein and amino acid metabolism in skeletal muscle of healthy, laparotomized, and septic rats.

Amino Acid Metabolism

Current concepts of protein turnover and amino acid transport in liver and skeletal muscle during sepsis. Arch Surg. Gardiner K, Barbul A. Intestinal amino acid absorption during sepsis. Use of a branched chain amino acid enriched solution in patients under metabolic stress. Am J Surg. Branched-chain amino acid support of stressed patients. Prospective study on the efficacy of branched-chain amino acids in septic patients.

J Parenter Enter Nutr. Therapeutic use of branched-chain amino acids in burn, trauma, and sepsis. Branched-chain amino acids. J Gastroenterol Hepatol. Branched-chain amino acid supplementation: impact on signaling and relevance to critical illness. J Cell Physiol. Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Human mild traumatic brain injury decreases circulating branched-chain amino acids and their metabolite levels. J Neurotrauma. Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury.

Arch Phys Med Rehabil. In addition to glycine, the GlyR can be activated by several other small amino acids such as alanine and taurine. Glycine is also involved in the modulation of excitatory neurotransmission exerted via glutamate binding to N -methyl-D-aspartate NMDA type glutamate receptors. Glutaminase is an important kidney tubule enzyme involved in the process of renal ammoniagenesis.

Glutaminase activity is present in many other tissues in addition to the kidney, such as the liver, small intestine, and neurons where its role is nearly as significant as it is within the kidney tubule. GLS encoded kidney-type glutaminase is the amino acid isoform 1 protein and GLS encoded glutaminase C is the amino acid isoform 2 protein.

Asparaginase see above is also widely distributed within the body, where it converts asparagine into ammonia and aspartate. Aspartate can serve as an amino donor in transamination reacions yielding oxaloacetate, which follows the gluconeogenic pathway to glucose. Glutamate and aspartate are important in collecting and eliminating amino nitrogen via glutamine synthetase and the urea cycle , respectively.

The catabolic path of the carbon skeletons involves simple 1-step aminotransferase reactions that directly produce net quantities of a TCA cycle intermediate. Alanine is also important in intertissue nitrogen transport as part of the glucose-alanine cycle see above that delivers waste nitrogen from skeletal muscle to the liver where it can be incorporated into urea. The alanine catabolic pathway involves a simple aminotransferase reaction that directly produces pyruvate. The transamination is carried out by alanine transaminase, ALT also called alanine aminotranserase.

Generally, the pyruvate produced from alanine has two distinct fates that are controlled by the energy demands of the liver and the metabolic needs of the organism as a whole. Altrenatively, during the fasted state when blood glucose levels are low, the pyruvate is diverted into the gluconeogenic pathway so that the liver can release glucose to the blood. This makes alanine a glucogenic amino acid. The catabolism of arginine begins within the context of the urea cycle.

It is ultimately hydrolyzed to urea and ornithine by arginase. Proline catabolism involves a two-step process that is essentially a reversal of its synthesis process outlined above. Therefore, ornithine and proline are both glucogenic. Since arginine is metabolized to urea and ornithine, and the resulting ornithine is a glucogenic precursor, arginine is also a glucogenic amino acid.

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Catabolism of arginine, ornithine, and proline. The catabolism of ornithine and proline is essentially a reversal of their synthesis from glutamate. In some tissues arginine serves as the precursor for nitric oxide NO production via the action of nitric oxide synthases NOS. 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 creatine byproduct, creatinine.

The cycling of citrulline back to arginine involves the urea cycle enzymes, argininosuccinate synthetase ASS1 and argininosuccinate lyase ASL. The catabolism of serine in humans involves the conversion of serine to glycine and then glycine oxidation to CO 2 and NH 3 , with the production of two equivalents of N 5 , N 10 -methyleneTHF, as was described above in the section on glycine biosynthesis. Serine can be catabolized back to the glycolytic intermediate, 3-phosphoglycerate, by a pathway that is essentially a reversal of serine biosynthesis, however, the enzymes are different.

There are at least three pathways for threonine catabolism that have been identified in yeasts, insects, and vertebrates including mammals. Therefore, it is presumed that this is the predominant threonine catabolizing pathway in humans. The enzymes required for this conversion are propionyl-CoA carboxylase, methylmalonyl-CoA epimerase, and methylmalonyl-CoA mutase, respectively. This propionyl-CoA conversion pathway is also required for the metabolism of the amino acids valine, isoleucine, and methionine see below , and odd-chain fatty acids.

For this reason this three-step reaction pathway is often remembered by the mnemonic as the VOMIT pathway, where V stands for valine, O for odd-chain fatty acids, M for methionine, I for isoleucine, and T for threonine. The PCCA gene is located on chromosome 13q The PCCB gene is located on chromosome 3q Mutations in the MMUT gene are one cause of the methylmalonic acidemias.

The second pathway of threonine catabolism utilizes serine hydroxymethyltransferase SHMT. As indicated above in the Glycine Biosynthesis section, this enzyme belongs to a family of one-carbon transferases and is alternatively named glycine hydroxymethyltransferase or threonine aldolase.

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The products of this reaction are acetyl-CoA and glycine. Thus, via this catabolic pathway threonine yields ketogenic and glucogenic byproducts. In humans it appears that threonine aldolase is actually encoded by a non-functional pseudogene, whereas in other mammals and vertebrates e. The 2-aminoketobutyrate is either converted to acetyl-CoA and glycine, via the action of 2-aminoketobutyrate coenzyme A ligase also called glycine C-acetyltransfease , or it can spontaneously degrade to aminoacetone which is converted to pyruvate.

The threonine dehydrogenase gene in humans appears to be non-functional due to the incorporation of three inactivating mutations. Nevertheless, the main glycine catabolic pathway leads to the production of CO 2 , ammonia, and one equivalent of N 5 , N 10 -methyleneTHF by the mitochondrial enzyme, glycine dehydrogenase decarboxylating which is also called the glycine cleavage complex, GCC. The GCC is composed of four mitochondrial proteins encoded by four genes. The protein components of the GCC are the actual glycine decarboxylase subunit identified as the P subunit: pyridoxal phosphate-dependent , a lipoic acid-containing subunit the H subunit , a tetrahydrofolate-requiring enzyme called aminomethyltransferase the T subunit , and dihydrolipoamide dehydrogenase the L subunit.

The T subunit aminomethyltransferase is encoded by the AMT gene located on chromosome 3p The L subunit is encoded by the DLD gene which is located on chromosome 7q Deficiencies in the H, P, or T proteins results in glycine encephalopathy which is characterized by nonketotic hyperglycinemia. These gene defects result in severe mental retardation that is due to highly elevated levels of glycine in the CNS. There are several pathways for non-protein disposition of cysteine that include both metabolism and catabolism. The major cysteine catabolic pathway in humans occurs via the action of cysteine dioxygenase type 1 gene symbol: CDO1.

CDO1 oxidizes the sulfhydryl group of cysteine to sulfinate, producing the intermediate cysteine sulfinate. The CDO1 gene is located on chromosome 5q The enzyme sulfite oxidase gene symbol: SUOX then catalyzes the conversion of sulfite to sulfate. The SUOX gene is located on chromosome 12q The enzyme cysteine desulfurase encoded by the NFS1 gene is another important enzyme associated with cysteine catabolism. Cysteine desulfurase removes the sulfur from cyteine yielding alanine. The sulfur remains associated with cysteine desulfurase and is subsequently transferred to numerous enzymes that possess iron-sulfur clusters for their activity.

Cysteine desulfurase is a member of the pyridoxal phosphate B 6 -dependent aminotransferase family. The NFS1 gene is located on chromosome 20q The use of these alternative translational start sites generates mitochondrial and cytoplasmic or nuclear forms of the enzyme. 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.

Taurine is used to form the bile acid conjugates taurocholate and taurochenodeoxycholate. Taurine synthesis occurs primarily in the liver since this is the only bile acid synthesizing tissue in the body However, taurine can be transported to the blood and disseminated to other tissues. Taurine is derived from the cysteine catabolism intermediate, cysteine sulfinate. Cysteine sulfinate is converted to hypotaurine by the rate-limiting enzyme in taurine synthesis, cysteine sulfinic acid decarboxylase, CSAD also called sulfinoalanine decarboxylase. The CSAD gene is located on chromosome 12q Oxidation of hypotaurine to taurine is thought to occur spontaneously, i.

Pathways of cysteine catabolism. Catabolism of cysteine is responsible for the release and or transfer of the sulfur from this amino acid. The catabolism of cysteine can also involve a metabolic pathway as is the case for taurine synthesis. Cysteine catabolism and taurine synthesis both begin with the oxidation to cysteine sulfinic acid catalyzed by cysteine dioxygenase. Cysteine sulfinate is converted to taurine via the action of cysteinesulfinate decarboxylase.

Catabolism of cysteine sulfinate to sulfate ion first involves a transamination that releases 3-sulfinpyruvate that spntaneously decomposes to bisulfite ion and pyruvate. The transaminase responsible for this reaction is the soluble form of aspartate transaminase which is encoded by the GOT1 gene.

The bisulfite ion is in ionic equilibrium with sulfite ion which is then converted to the sulfate ion via the action of sulfite oxidase. Both thiocysteine and thiosulfate can be used by sulfurtransferases to incorporate sulfur into cyanide ion, CN — , thereby detoxifying the cyanide to thiocyanate. These sulfurtransferase enzymes contain domains called rhodanese domains since they were first identifed in a mitochondrial enzyme that was originally called rhodanese thiosulfate sulfurtransferase, TST.

Another rhodanese domain-containing enzyme that is located in the cytosol is called mercaptopyruvate sulfurtransferase MPST. One of the important uses of the sulfate that is derived from the catabolism of cysteine is as a precursor for the formation of 3'-phosphoadenosine-5'-phosphosulfate , PAPS. PAPS is used for the transfer of sulfate to biological molecules such as the sugars of the glycosphingolipids.

Two-step reaction for synthesis of PAPS. The clinical significance of methylmalonyl-CoA mutase in this pathway is that it is one of only two enzymes that requires a vitamin B 12 -derived co-factor for activity. The other B 12 -requiring enzyme is methionine synthase see the Cysteine Synthesis section above. This propionyl-CoA conversion pathway is also required for the metabolism of the amino acids valine, isoleucine, and threonine and fatty acids with an odd number of carbon atoms. Regulation of the methionine metabolic pathway is based on the availability of methionine and cysteine.

Under these conditions accumulated homocysteine is remethylated to methionine, using N 5 -methyl-THF as the methyl donor. This group of essential amino acids is identified as the branched-chain amino acids, BCAAs. Because this arrangement of carbon atoms cannot be made by humans, these amino acids are an essential element in the diet.

The catabolism of all three amino acids occurs in most cells but at highest rates in skeletal muscle. The catabolism of all three of these amino acids uses the same enzymes in the first two steps. Humans express two genes that encode BCAT activity. The BCAT1 gene is located on chromosome 12p BCAT1 isoform 1 is a amino acid protein. BCAT1 isoform 2 is a amino acid protein. BCAT1 isoform 3 is a amino acid protein. BCAT1 isoform 4 is a amino acid protein. BCAT1 isoform 5 is a amino acid protein.

The BCAT2 gene is located on chromosome 19q The isoform b protein is found in the cytosol. BCAT2 isoform c is a amino acid protein. Expression of the BCAT1 gene is restricted to only a few tissues types. Expression of BCAT2 is widely distributed among numerous tissues. Although detectable in the fetal liver, the adult liver does not express either BCAT gene. The metabolism of the branched-chain amino acids is critical to overall nitrogen homeostasis in the brain and to the maintenance of proper levels of the excitatory neurotransmitter, glutamate.

Amino Acid Metabolism, 3rd Edition

Within the brain different populations of cells express predominantly BCATc while others express predominantly BCATm and this differential distribution is what is important in overall neuronal nitrogen homeostasis. Subsequently the metabolic pathways diverge, producing many intermediates. The other two dehydrogenase complexes are the PDHc and the 2-oxoglutarate dehydrogenase complexes associated with the TCA cycle. The BCKD complex is a multimeric enzyme composed of three catalytic subunits.

The E2 portion is a dihydrolipoamide branched-chain transacylase composed of 24 lipoic acid-containing polypeptides. The E3 portion is a homodimeric flavoprotein identified as dihydrolipoamide dehydrogenase, DLD. The E2 gene symbol: DBT is located on chromosome 1p The E3 gene symbol: DLD is located on chromosome 7q The DLD gene encodes the same dihydrolipoamide dehydrogenase subunits found in the PDHc and the 2-oxoglutarate dehydrogenase complexes. Regulation of BCKD activity is exerted via phosphorylation and dephosphorylation similarly to the regulation of the activity of the PDHc.

The phosphorylation of BCKD inhibits the enzyme, whereas, dephosphorylation activates it. Phosphorylation of BCKD is catalyzed by the kinase, branched chain ketoacid dehydrogenase kinase [commonly referred to as BDK; originally identified as 3-methyloxobutanoate dehydrogenase lipoamide kinase] which is encoded by the BCKDK gene. The PPM1K gene is located on chromosome 4q Catabolism of the branched-chain amino acids.

The three branched-chain amino acids, isoleucine, leucine, and valine enter the catabolic pathway via the action of the same two enzymes. After these first two reactions the remainder of the catabolic pathways for the three amino acids diverges.

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The third reaction of branched-chain amino acid catabolism involves a dehydrogenation step that involve three distinct enzymes, one for each of the CoA derivatives generated via the BCKD reaction. This latter dehydrogenation step also yields additional reduced electron carrier as FADH 2.

These CoA dehydrogenases belong to the same family of enzymes involved in the process of mitochondrial fatty acid oxidation. The principal catabolic by-product from valine is propionylCoA, the glucogenic precursor of succinyl-CoA. Isoleucine catabolism terminates with production of acetyl-CoA and propionyl-CoA; thus isoleucine is both glucogenic and ketogenic. Leucine gives rise to acetyl-CoA and acetoacetyl-CoA, and is thus classified as strictly ketogenic.

As pointed out above for the catabolism of methionine, the resulting propionyl-CoA is converted , via a mitochondrially-localized, three reaction, ATP-dependent pathway, to succinyl-CoA. There are a number of genetic diseases associated with faulty catabolism of the branched-chain amino acids BCAA. 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. Unfortunately, since these are essential amino acids, they cannot be heavily restricted in the diet.

The main neurological problems are due to poor formation of myelin in the CNS. Although the outcomes for afflicted individuals used to quite severe with abnormal development and a short life-span, many advances in the treatment of MSUD in recent years have improved the clinical picture.

Liver transplantation can result in a relatively normal life for MSUD patients. Additional disorders that are associated with defects in BCAA metabolism include isovaleric acidemia and 3-methylcrotonylglycinuria. Both of these disorders are the result of defects in leucine catabolism. The IVD gene is located on chromosome 15q Mutations in the IVD gene lead to the accumulation of isovaleryl-CoA which is toxic to the central nervous system and is a fatal disorder in its most severe form if not correctly diagnosed.

Although there are variabilities in the symptoms of isovaleric acidemia, in the infantile severe form the symptoms initially present as poor feeding, vomiting, seizures, and lethargy. These symptoms can progress to seizures, coma, and death. Isovaleric acidemia is inherited as an autosomal recessive disorder. The other major leucine metabolic defect is 3-methylcrotonylglycinuria which results from defects in either of the two subunits of 3-methylcrotonyl-CoA carboxylase 3MCC.

The function of 3-methylcrotonyl-CoA carboxylase is to catalyze the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA during the catabolism of leucine. The 3-methylcrotonyl-CoA is the product of isovaleryl-CoA dehydrogenase which catalyzes the previous reaction in leucine catabolism.

The activity of 3MCC is dependent on biotin. The MCCC1 gene is located on chromosome 3q The MCCC2 gene is located on chromosome 5q Inheritance of 3-methylcrotonylglycinuria also referred to as 3MCC deficiency occurs in an autosomal recessive manner. The symptoms that result from defects in either of the two genes encoding 3MCC can range from benign to profound metabolic acidosis and early death. In the more severe forms of 3MCC deficiency infants appear normal at birth but will develop symptoms during the first year of life or possibly not until early childhood.

The characteristic features of the severe forms of 3MCC deficiency include difficulty feeding, recurrent episodes of vomiting and diarrhea, lethargy, and hypotonia. If left undiagnosed or untreated, 3MCC deficiency can lead to delayed development, seizures, and coma and ultimately death. Numerous studies have shown that diets high in protein increase fatty acid oxidation and overall energy expenditure and thus, promote weight loss. In addition, high protein diets are known to improve glucose homeostasis and therefore, can have a positive impact on insulin sensitivity and diabetes.

In animal models of obesity and diabetes, increasing the protein to carbohydrate ratio in a high-fat diet results in a delay in the development of obesity while simultaneously improving glucose tolerance. In studies on obese humans, subjects that consumed a milk whey-protein-enriched diet exhibited demonstrable improvement in fatty liver symptoms hepatic steatosis and reduced plasma lipid profiles.

In studies examining the effects of dietary protein on energy expenditure, appetite suppression, and weight loss, whey protein is the more beneficial source when comparing the effects of consumption of whey proteins, soy proteins, or casein. Whey proteins are enriched in the branched-chain amino acids BCAA leucine, isoleucine, and valine and are thus, excellent sources of energy production in skeletal muscle as well as serving as building blocks for muscle protein synthesis.

Leucine has been proposed to be the primary mediator of the metabolic changes that occur when consuming a high protein diet. At the molecular level, leucine has been shown to activate the metabolic regulatory kinase known as mammalian target of rapamycin, mTOR. Activation of skeletal muscle mTOR results in increased protein synthesis and thus, increased energy expenditure.

Hypothalamic mTOR activation is also involved in the regulation of feeding behaviors. Of note is the fact that direct injection of leucine into the hypothalamus results in increased mTOR signaling leading to decreased feeding behavior and body weight. This effect is unique to leucine, as direct injection of valine, another BCAA, does not result in hypothalamic mTOR activation nor reductions in food intake or body weight.

The effects of leucine supplementation, on the above described parameters, are not as pronounced as the effects observed when consuming a high-protein diet. This suggests that additional factors are likely involved in the effects of high-protein diets. One of these factors may be that consuming a high protein diet is associated with a reduction in total carbohydrate intake. The reduced carbohydrate intake would thus, be associated with a reduction in hepatic lipogenesis and an increase in adipose tissue lipolysis. Although leucine alone is not as effective as high-protein diets at reducing body weight and food intake it cannot be discounted as an important dietary supplement.

However, it must be pointed out that some controversy surrounds the role of high protein consumption, and in particular leucine intake, in overall metabolic homeostasis. This is due to the fact that some studies in laboratory animals have shown that leucine supplementation results in insulin resistance. This latter effect would certainly lead to an increased likelihood for development of type 2 diabetes.

In the typical Western diet consisting of high dairy and meat, the role of leucine in the pathogeneis of type 2 diabetes is suggested by the consequent over activation of mTOR. With respect to diabetes, activation of mTOR results in phosphorylation and activation of the kinase, p70S6K, which in turn phosphorylates the insulin receptor substrate 1 IRS In addition, increased mTOR activation leads to adipogenesis which can lead to obesity-mediated insulin resistance.

Most of the work in laboratory animals demonstrates that the positive effects of increased leucine intake or high-protein diets are most pronounced when the animals are also consuming a high-fat diet. However, although high-protein diets or leucine supplementation are important considerations in a healthy diet, the total amount consumed must be taken into account so as not to lead to excess mTOR activation. Phenylalanine normally has only two fates: incorporation into polypeptide chains, and hydroxylation to tyrosine via the tetrahydrobiopterin-requiring phenylalanine hydroxylase PAH reaction.

Thus, phenylalanine catabolism always ensues in the pathway of tyrosine biosynthesis followed by tyrosine catabolism. Tyrosine is equally important for protein biosynthesis as well as an intermediate in the biosynthesis of the catecholamines: dopamine, norepinephrine and epinephrine see Specialized Products of Amino Acids. The pathway of tyrosine degradation involves conversion to fumarate and acetoacetate, allowing phenylalanine and tyrosine to be classified as both glucogenic and ketogenic. The catabolism of tyrosine involves five reactions, four of which have been shown to associated with inborn errors in metabolism and three of these result in clinically significant disorders.

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  6. The first reaction of tyrosine catabolism involves the nuclear genome encoded mitochondrial enzyme tyrosine aminotransferase and generates the corresponding ketoacid, p -hydroxyphenylpyruvic acid. Tyrosine aminotransferase is encoded by the TAT gene on chromosome 16q The second reaction of tyrosine catabolism is catalyzed by 4-hydroxyphenylpyruvate dioxygenase which is encoded by the HPD gene located on chromosome 12q The product of the HPD reaction is homogentisic acid.

    Homogentisate is oxidized by the second dioxygenase enzyme of tyrosine catabolism, homogentisate oxidase. Homogentisate oxidase is encoded by the homogentisate 1,2-dioxygenase gene symbol: HDG located on chromosome 3q Glutathione S-transferase zeta 1 was formerly called 4-maleylacetoacetate isomerase or maleylacetoacetate cis - trans -isomerase. The GSTZ1 gene is located on chromosome 14q Fumarylacetoacetate is hydrolyzed to fumarate and acetoacetate by the enzyme fumarylacetoacetate hydrolase which is encoded by the FAH gene located on chromosome 15q The fumarate end product of tyrosine catabolism feeds directly into the TCA cycle for further oxidation.

    Pathway of phenylalanine and tyrosine catabolism. Phenylalanine becomes tyrosine via the action of phenylalanine hydroxylase as discussed in the Tyrosine Biosynthesis section. Therefore, the phenylalanine and tyrosine catabolic pathways are the same. Tyrosine is ultimately degraded to fumarate and acetoacetate througgh a series of five reactions. HPD: hydroxyphenylpyruvate dioxygenase.

    GSTZ1: glutathione S-transferase zeta 1 which was formerly called 4-maleylacetoacetate isomerase. FAH: fumarylacetoacetate hydrolase. Inherited mutations in the TAT gene lead to hypertyrosinemia type II TYRSN2; also called Richner-Hanhart syndrome which, as the name implies, is associated with elevated tyrosine levels in the blood and, consequently the urine. This form of tyrosinemia is associated with mental retardation, painful corneal eruptions, photophobia, keratitis, and painful palmoplantar hyperkeratosis.

    TYRSN1 is an autosomal recessive disorder characterized by hypertyrosinemia and progressive liver disease. This disorder also leads to a secondary renal tubular dysfunction resulting in hypophosphatemic rickets. The first inborn error in metabolism ever recognized, alkaptonuria , was demonstrated to be the result of a defect in phenylalanine and tyrosine catabolism. Alkaptonuria is caused by defective homogentisic acid oxidase which is the third enzyme in the tyrosine catabolic pathway.

    Homogentisic acid accumulation is relatively innocuous, causing urine to darken on exposure to air, but no life-threatening effects accompany the disease. The only untoward consequence of alkaptonuria is ochronosis bluish-black discoloration of the tissues and arthritis of indeterminant etiology. Like all amino acids, catabolism of lysine can initiate from uptake of dietary lysine or from the breakdown of intracellular protein.

    Intestinal uptake of lysine involves specific transporter proteins. There are actually at least three transporter mechanisms for lysine transport. The common heavy chain of these two different transporters is encoded by the SLC3A2 gene often referred to as 4F2hc for 4F2 cell-surface antigen heavy chain. Once taken up by the intestines, dietary lysine can be incorporated into protein or catabolized. Unlike the majority of transamination reactions, this one does not employ pyridoxal phosphate as a cofactor.

    Because this transamination reaction is not reversible, lysine is an essential amino acid. The N-terminal half of the AASS protein harbors the lysineoxoglutarate reductase activity and the C-terminal half harbors the saccharopine dehydrogenase activity. The ultimate end-product of lysine catabolism, via this saccharopine pathway, is acetoacetyl-CoA. Genetic deficiencies in either of the first two reactions of the saccharopine pathway of lysine catabolism result in familial hyperlysinemia associated with psychomotor retardation.