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Six Amino Acids Are Degraded to Pyruvate

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1 Six Amino Acids Are Degraded to Pyruvate
Dr. Nikhat Siddiqi

2 The carbon skeletons of six amino acids are converted in whole or in part to pyruvate.
The pyruvate can then be converted to either acetyl-CoA (a ketone body precursor) or oxaloacetate (a precursor for gluconeogenesis). Thus amino acids catabolized to pyruvate are both ketogenic and glucogenic. Dr. Nikhat Siddiqi

3 The six are alanine, tryptophan, cysteine, serine, glycine, and threonine.
Dr. Nikhat Siddiqi

4 Dr. Nikhat Siddiqi

5 Alanine & Cysteine Alanine yields pyruvate directly on transamination with-ketoglutarate, and the side chain of tryptophan is cleaved to yield alanine and thus pyruvate. Cysteine is converted to pyruvate in two steps; one removes the sulfur atom, the other is a transamination. Dr. Nikhat Siddiqi

6 Serine Humans and other vertebrates degrade serine to glycine and N5, N10-Methylene tetrahydrofolate. Following the reaction catalyzed by serine hydroxymethyl transferase serine catabolism merges with that of glycine. In rodent liver serine is converted to pyruvate by serine dehydratase. Both the β-hydroxyl and the α-amino groups of serine are removed in this single pyridoxal phosphate–dependent reaction. In this reaction the loss of water is followed by hydrolytic loss of ammonia. Dr. Nikhat Siddiqi

7 Glycine Glycine is degraded via three pathways, only one of which leads to pyruvate. Glycine is converted to serine by enzymatic addition of a hydroxymethyl group. This reaction, catalyzed by serine hydroxymethyl transferase, requires the coenzymes tetrahydrofolate and pyridoxal phosphate. In the second pathway, which predominates in animals, glycine undergoes oxidative cleavage to CO2, NH4 , and a methylene group (-CH2-). This readily reversible reaction, catalyzed by glycine cleavage enzyme (also called glycine synthase), also requires tetrahydrofolate, which accepts the methylene group. Dr. Nikhat Siddiqi

8 In this oxidative cleavage pathway the two carbon atoms of glycine do not enter the citric acid cycle. One carbon is lost as CO2 and the other becomes the methylene group of N5,N10-methylenetetrahydrofolate, a one carbon group donor in certain biosynthetic pathways. Dr. Nikhat Siddiqi

9 This second pathway for glycine degradation appears to be critical in mammals.
Humans with serious defects in glycine cleavage enzyme activity suffer from a condition known as nonketotic hyperglycinemia. The condition is characterized by elevated serum levels of glycine, leading to severe mental deficiencies and death in very early childhood. Dr. Nikhat Siddiqi

10 Glycine In the third and final pathway of glycine degradation, the achiral glycine molecule is a substrate for the enzyme D-amino acid oxidase. The glycine is converted to glyoxylate, an alternative substrate for hepatic lactatedehydrogenase. Glyoxylate is oxidized in an NAD-dependent reaction to oxalate. Dr. Nikhat Siddiqi

11 Glycine Dr. Nikhat Siddiqi

12 The primary function of D-amino acid oxidase, present at high levels in the kidney, is thought to be the detoxification of ingested D-amino acids derived from bacterial cell walls and from cooked foodstuffs (heat causes some spontaneous racemization of the L-amino acids in proteins). Oxalate, whether obtained in foods or produced enzymatically in the kidneys, has medical significance. Crystals of calcium oxalate account for up to 75% of all kidney stones. Dr. Nikhat Siddiqi

13 Threonine There are two significant pathways for threonine degradation. One pathway leads to pyruvate via glycine. The conversion to glycine occurs in two steps, with threonine first converted to 2-amino-3 ketobutyrate by the action of threonine dehydrogenase. This is a relatively minor pathway in humans, accounting for 10% to 30% of threonine catabolism, but is more important in some other mammals. The major pathway in humans leads to succinyl-CoA and is described later. Dr. Nikhat Siddiqi

14 Threonine Threonine is cleaved to acetaldehyde and glycine by threonine aldolase. Acetaldehyde is then oxidized to acetate which is converted to acetyl CoA. Glycine is catabolized as described earlier. Dr. Nikhat Siddiqi

15 Cystine Cystine in mammals is converted to cysteine by cystine reductase. Catabolism of cystine then merges with that of cysteine. (fig from Harper) Dr. Nikhat Siddiqi

16 Cysteine Two pathways of catabolism
The direct oxidative (cysteine sulfinate) pathway. The transamination (3-mercaptopyruvate) pathway. Dr. Nikhat Siddiqi

17 Conversion of cystine to cysteine sulfinate is catalyzed by cysteine dioxygenase an enzyme that requires Fe 2+ and NAD(P)H. Further catabolism of cysteine sulfinate involves transamination to β-sulfinyl pyruvate which is converted to pyruvate and sulfite by desulfinase. Dr. Nikhat Siddiqi

18 Reversible transamination of cysteine to 3-mercaptopyruvate is catalyzed by cysteine transaminase or by glutamate or aspargine transaminase of mammalian liver and kidney. Reduction of 3-mercaptopyruvate by L-lactate dehydrogenase forms 3-mercaptolactate excreted in the urine. Alternately 3-mercaptolactate undergoes desulfuration to form pyruvate. Dr. Nikhat Siddiqi

19 Dr. Nikhat Siddiqi

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