Biosynthesis of Nonessential Amino Acids

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Chapter: Biochemistry : Amino Acid Degradation and Synthesis

Nonessential amino acids are synthesized from intermediates of metabolism or, as in the case of tyrosine and cysteine, from the essential amino acids phenylalanine and methionine, respectively.


BIOSYNTHESIS OF NONESSENTIAL AMINO ACIDS

Nonessential amino acids are synthesized from intermediates of metabolism or, as in the case of tyrosine and cysteine, from the essential amino acids phenylalanine and methionine, respectively. The synthetic reactions for the nonessential amino acids are described below and are summarized later in Figure 20.14. [Note: Some amino acids found in proteins, such as hydroxyproline and hydroxylysine, are modified after their incorporation into the protein.]


Figure 20.14 Summary of the metabolism of amino acids in humans. Genetically determined enzyme deficiencies are summarized in white boxes. Nitrogen-containing compounds derived from amino acids are shown in small, yellow boxes. Classification of amino acids is color coded: Red = glucogenic; brown = glucogenic and ketogenic; green ketogenic. Compounds in BLUE ALL CAPS are the seven metabolites to which all amino acid metabolism converges. CoA = coenzyme A; NAD(H) = nicotinamide adenine dinucleotide.

 

A. Synthesis from α-keto acids

Alanine, aspartate, and glutamate are synthesized by transfer of an amino group to the α-keto acids pyruvate, oxaloacetate, and α-ketoglutarate, respectively. These transamination reactions (Figure 20.12;) are the most direct of the biosynthetic pathways. Glutamate is unusual in that it can also be synthesized by the reverse of oxidative deamination, catalyzed by glutamate dehydrogenase, when ammonia levels are high.


Figure 20.12 Formation of alanine, aspartate, and glutamate from the corresponding α-keto acids. PLP = pyridoxal phosphate.

 

B. Synthesis by amidation

 

1. Glutamine: This amino acid, which contains an amide linkage with ammonia at the γ-carboxyl, is formed from glutamate by glutamine synthetase (see Figure 19.18). The reaction is driven by the hydrolysis of ATP. In addition to producing glutamine for protein synthesis, the reaction also serves as a major mechanism for the transport of ammonia in a nontoxic form.

 

2. Asparagine: This amino acid, which contains an amide linkage with ammonia at the β-carboxyl, is formed from aspartate by asparagine synthetase, using glutamine as the amide donor. Like the synthesis of glutamine, the reaction requires ATP and has an equilibrium far in the direction of amide synthesis.

 

C. Proline

 Glutamate via glutamate semialdehyde is converted to proline by cyclization and reduction reactions. [Note: The semialdehyde can also be transaminated to ornithine.]

 

D. Serine, glycine, and cysteine

1. Serine: This amino acid arises from 3-phosphoglycerate, an intermediate in glycolysis (see Figure 8.18), which is first oxidized to 3-phosphopyruvate and then transaminated to 3-phosphoserine. Serine is formed by hydrolysis of the phosphate ester. Serine can also be formed from glycine through transfer of a hydroxymethyl group by serine hydroxymethyltransferase using N5,N10-methylene-THF as the one-carbon donor (see Figure 20.6A). [Note: Selenocysteine (Sec), the 21st genetically encoded amino acid, is synthesized from serine and selenium while serine is attached to transfer RNA. Sec is found in several proteins such as glutathione peroxidase.]


Figure 20.6 A. Interconversion of serine and glycine and oxidation of glycine. B. Dehydration of serine to form pyruvate. PLP = pyridoxal phosphate.

 

2. Glycine: This amino acid is synthesized from serine by removal of a hydroxymethyl group, also by serine hydroxymethyltransferase (see Figure 20.6A). THF is the one-carbon acceptor.

 

3. Cysteine: This amino acid is synthesized by two consecutive reactions in which Hcy combines with serine, forming cystathionine, which, in turn, is hydrolyzed to α-ketobutyrate and cysteine (see Figure 20.8). (Hcy is derived from methionine) Because methionine is an essential amino acid, cysteine synthesis can be sustained only if the dietary intake of methionine is adequate.



Figure 20.8 Degradation and resynthesis of methionine. [Note: The resynthesis of methionine from homocysteine is the only reaction in which tetrahydrofolate both carries and donates a methyl (-CH3) group. In all other reactions, SAM is the methyl group carrier and donor.] PPi = pyrophosphate; Pi = inorganic phosphate.

 

E. Tyrosine

Tyrosine is formed from phenylalanine by phenylalanine hydroxylase. The reaction requires molecular oxygen and the coenzyme tetrahydrobiopterin (BH4), which is synthesized from guanosine triphosphate. One atom of molecular oxygen becomes the hydroxyl group of tyrosine, and the other atom is reduced to water. During the reaction, BH4 is oxidized to dihydrobiopterin (BH2). BH4 is regenerated from BH 2 by NADH-requiring dihydropteridine reductase. Tyrosine, like cysteine, is formed from an essential amino acid and is, therefore, nonessential only in the presence of adequate dietary phenylalanine.

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