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Dietary protein is digested in the intestine, producing amino acids that are transported throughout the body. Cellular proteins are degraded at widely variable rates, ranging from minutes to the life of the organism.
The turnover of cellular proteins is a regulated process requiring complex enzyme systems. Proteins to be degraded are conjugated with ubi-quitin, a small conserved protein, in a reaction driven by ATP hydrolysis. The ubiquitin conjugating system is composed of three distinct enzymes. A large, barrel-shaped complex called the proteasome digests the ubiquitinated proteins. The proteasome also requires ATP hydrolysis to function. The resulting amino acids provide a source of precursors for protein, nucleotide bases, and other nitrogenous compounds.
Surplus amino acids are used as metabolic fuel. The first step in their degradation is the removal of their α-amino groups by transamination to an α-ketoacid. Pyridoxal phosphate is the coenzyme in all aminotransferases and in many other enzymes catalyzing amino acids transformations. The α-amino group funnels into α-ketoglutarate to form glutamate, which is then oxidatively deaminated by glutamate dehydrogenase to give NH4+and α-ketoglutarate. NAD+ or NADP+ is the electron acceptor in this reaction.
The first step in the synthesis of urea is the formation of carbamoyl phosphate, which is synthesized from CO2, NH4+, and two molecules of ATP by carbamoyl phosphate synthetase. Ornithine is then carbamoylated to citrulline by orthinine transcarbamoylase. These two reactions take place in mitochondria. Citrulline leaves the mitochondrion and condenses with aspartate to form argininosuccinate, which is cleaved into arginine and fumarate. The other nitrogen atom of urea comes from aspartate. Urea is formed by the hydrolysis of arginine, which also regenerates ornithine. Some enzymatic deficiencies of the urea cycle can be bypassed by supplementing the diet with arginine or compounds that form conjugates with glycine and glutamine.
The carbon atoms of degraded amino acids are converted into pyruvate, acetyl CoA, acetoacetate, or an intermediate of the citric acid cycle. Most amino acids are solely glucogenic, two are solely ketogenic, and a few are both ketogenic and glucogenic. Alanine, serine, cysteine, glycine, threonine, and tryptophan are degraded to pyruvate. Asparagine and aspartate are converted into oxaloacetate. α-Ketoglutarate is the point of entry for glutamate and four amino acids (glutamine, histidine, proline, and arginine) that can be converted into glutamate. Succinyl CoA is the point of entry for some of the carbon atoms of three amino acids (methionine, isoleucine, and valine) that are degraded through the intermediate methylmalonyl CoA. Leucine is degraded to acetoacetyl CoA and acetyl CoA. The breakdown of valine and isoleucine is like that of leucine. Their α-ketoacid derivatives are oxidatively decarboxylated by the branched-chain α-ketoacid dehydrogenase.
The rings of aromatic amino acids are degraded by oxygenases. Phenylalanine hydroxylase, a monooxygenase, uses tetrahydrobiopterin as the reductant. One of the oxygen atoms of O2 emerges in tyrosine and the other in water. Subsequent steps in the degradation of these aromatic amino acids are catalyzed by dioxygenases, which catalyze the insertion of both atoms of O2 into organic products. Four of the carbon atoms of phenylalanine and tyrosine are converted into fumarate, and four emerge in acetoacetate.
Errors in amino acid metabolism served as sources of some of the first insights into the correlation between pathology and biochemistry. Although there are many hereditary errors of amino acid metabolism, phenylketonuria is the best known. This condition is the result of the accumulation of high levels of phenylalanine in the body fluids. By unknown mechanisms, this accumulation results in mental retardation unless the afflicted are placed on low phenylalanine diets immediately after birth.
ubiquitin
proteasome
aminotransferase (transaminase)
glutamate dehydrogenase
pyridoxal phosphate (PLP)
pyridoxamine phosphate (PMP)
alanine cycle
urea cycle
carbamoyl phosphate synthetase
N-acetylglutamate
ketogenic amino acid
glucogenic amino acid
biopterin
phenylketonuria