Seven Amino Acids Are Degraded to Acetyl-CoA 1Dr. Nikhat Siddiqi

All the amino acids that form pyruvate can also form acetyl CoA via pyruvate dehydrogenase. In addition portions of the carbon skeletons of seven amino acids—tryptophan, lysine, phenylalanine, tyrosine, leucine, isoleucine, and threonine—yield acetyl-CoA and/or acetoacetyl-CoA, the latter being converted to acetyl-CoA. 2Dr. Nikhat Siddiqi

Catabolic pathways for tryptophan, lysine, phenylalanine, tyrosine, leucine, and isoleucine 3Dr. Nikhat Siddiqi

Phenylalanine Phenylalanine and its oxidation product tyrosine (both with nine carbons) are degraded into two fragments, both of which can enter the citric acid cycle: four of the nine carbon atoms yield free acetoacetate, which is converted to acetoacetyl-CoA and thus acetyl-CoA, and a second four-carbon fragment is recovered as fumarate. Eight of the nine carbons of these two amino acids thus enter the citric acid cycle; the remaining carbon is lost as CO2. Phenylalanine, after its hydroxylation to tyrosine, is also the precursor of dopamine, a neurotransmitter, and of norepinephrine and epinephrine, hormones secreted by the adrenal medulla. Melanin, the black pigment of skin and hair, is also derived from tyrosine. 4Dr. Nikhat Siddiqi

Phenylalanine 5Dr. Nikhat Siddiqi

Phenylalanine is hydroxylated to tyrosine by phenylalanine hydroxylase. Phenylalanine hydroxylase (also called phenylalanine-4- monooxygenase) is one of a general class of enzymes called mixed-function oxidases, all of which catalyze simultaneous hydroxylation of a substrate by an oxygen atom of O2 and reduction of the other oxygen atom to H2O. Phenylalanine hydroxylase requires the cofactor tetrahydrobiopterin, which carries electrons from NADH to O2 and becomes oxidized to dihydrobiopterin in the process. It is subsequently reduced by the enzyme dihydrobiopterin reductase in a reaction that requires NADH. 6Dr. Nikhat Siddiqi

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Phenylketonuria A genetic defect in phenylalanine hydroxylase, the first enzyme in the catabolic pathway for phenylalanine, is responsible for the disease phenylketonuria (PKU), the most common cause of elevated levels of phenylalanine (hyperphenylalaninemia). 8Dr. Nikhat Siddiqi

Phenylketonuria In individuals with PKU, a secondary, normally little-used pathway of phenylalanine metabolism comes into play. In this pathway phenylalanine undergoes transamination with pyruvate to yield phenylpyruvate. Phenylalanine and phenylpyruvate accumulate in the blood and tissues and are excreted in the urine—hence the name “phenylketonuria.” Much of the phenylpyruvate, rather than being excreted as such, is either decarboxylated to phenylacetate or reduced to phenyllactate. Phenylacetate imparts a characteristic odor to the urine, which nurses have traditionally used to detect PKU in infants. The accumulation of phenylalanine or its metabolites in early life impairs normal development of the brain, causing severe mental retardation. 9Dr. Nikhat Siddiqi

Alternative pathways for catabolism of phenylalanine in phenylketonuria 10Dr. Nikhat Siddiqi

Phenylketonuria Phenylketonuria can also be caused by a defect in the enzyme that catalyzes the regeneration of tetrahydrobiopterin. 11Dr. Nikhat Siddiqi

Alkaptonuria Another inheritable disease of phenylalanine catabolism is alkaptonuria, in which the defective enzyme is homogentisate dioxygenase. Less serious than PKU, this condition produces few ill effects, although large amounts of homogentisate are excreted and its oxidation turns the urine black. 12Dr. Nikhat Siddiqi

Alkaptonuria Alkaptonuria is of considerable historical interest. Archibald Garrod discovered in the early 1900s that this condition is inherited, and he traced the cause to the absence of a single enzyme. Garrod was the first to make a connection between an inheritable trait and an enzyme, a great advance on the path that ultimately led to our current understanding of genes and the information pathways. 13Dr. Nikhat Siddiqi

Tyrosine Transamination of tyrosine to p- hydroxyphenylpyruvate is catalyzed by tyrosine α-ketoglutarate transaminase (tyrosine aminotransferase). P-hydroxyphenylpyruvate forms homogentisate catalysed by p- hydroxyphenylpyruvate dioxygenase where ascorbic acid is the reductant. 14Dr. Nikhat Siddiqi

Homogentisate oxidase opens the aromatic ring to form maleylacetoacetate. Isomerization of maleylacetoacetate-cis, trans isomerase resulting in the formation of fumarylacetoacetate. Hydrolysis of fumarylacetoacetate forms fumarate and acetoacetate catalysed by fumarylacetoacetate hydrolase. The acetoacetate forms acetyl CoA plus acetate catalyzed by β-ketothiolase. 15Dr. Nikhat Siddiqi

Tyrosine 16Dr. Nikhat Siddiqi

Metabolic defects Refer to the enzymes in the figure. 17Dr. Nikhat Siddiqi

Tryptophan Tryptophan breakdown is the most complex of all the pathways of aminoacid catabolism in animal tissues; portions of tryptophan (four of its carbons) yield acetyl-CoA via acetoacetyl- CoA. Some of the intermediates in tryptophan catabolism are precursors for the synthesis of other biomolecules, including nicotinate, a precursor of NADand NADP in animals; serotonin, a neurotransmitter in vertebrates; and indoleacetate, a growth factor in plants. 18Dr. Nikhat Siddiqi

Catabolic pathways for tryptophan, lysine, phenylalanine, tyrosine, leucine, and isoleucine 19Dr. Nikhat Siddiqi

Tryptophan Tryptophan oxygenase catalyzes cleavage ofindole ring with incorporation of two atoms of molecular oxygen forming N-formylkynurenine. Hydrolytic removal of formyl group of N- formylkynurenine catalyzed by kynurenine formylase of mammalian liver produces kynurenine. Further metabolism yields α-keto adipate which is converted to acetoacetyl CoA. 20Dr. Nikhat Siddiqi

Tryptophan 21Dr. Nikhat Siddiqi

Kynurenine and hydroxykynurenine are converted to hydroxyanthranilate by kynureninase, a pyridoxal phosphate enzyme. Hartnup disease, an autosomal recessive trait results in defective intestinal and renal transport of neutral amino acids including tryptophan 22Dr. Nikhat Siddiqi

Tryptophan as precursor 23Dr. Nikhat Siddiqi

Lysine Lysine is an entirely ketogenic amino acid. There is an initial transamination of the ε- amino group which requires α-ketoglutarate as the acceptor and cosubstrate. The resulting compound is α-ketoadipate which forms acetoacetyl CoA. Dr. Nikhat Siddiqi24

Leucine Leucine and isoleucine also give acetyl CoA. More details will be explained in branched chain amino acid catabolism. 25Dr. Nikhat Siddiqi

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