BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART III. BIOSYNTHESIS OF MACROMOLECULAR PRECURSORS

CHAPTER 21. BIOSYNTHESIS OF AMINO ACIDS AND HEME

21.7. S-Adenosylmethionine is the principal methyl donor

Tetrahydrofolate can carry a methyl group at N⁵, but its group transfer potential is not sufficiently high. In most biosyntheses, the donor of the activated methyl group is S-adenosylmethionine, which we have already encountered in discussing The conversion of phosphatidylethanolamine into phosphatidylcholine (Section 20.3). S-Adenosylmethionine is synthesized by The transfer of the adenosyl group of ATP to the sulfur atom of Methionine. The methyl group of methionine is activated by the positive charge of the adjacent sulfur atom, making its reactivity much higher than that of N⁵-methyltetrahydrofolate.

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The synthesis of S-adenosylmethionine is unusual in that the triphosphate group of ATP is cleaved to pyrophosphate and orthophosphate. The pyrophosphate is then hydrolyzed. Thus, in this activation reaction, all phosphorus-oxygen bonds in ATP are cleaved, which significantly increases the reactivity of the methyl group.

S-Adenosylhomocysteine is formed by the transfer of the methyl group of S-adenosylmethionine to an acceptor, such as phosphatidylethanolamine. S-Adenosylhomocysteine is then hydrolyzed to homocysteine and adenosine.

Methionine can be regenerated by the transfer of the methyl group of N⁵-methyltetrahydrofolate. This reaction is catalyzed by homocysteine methyltransferase.

Methylcobalamin_, the coenzyme of homocysteine methyltransferase, serves as an intermediate in this Methyl group transfer. In mammals, only one other reaction is known to require vitamin B₁₂: the rearrangement of L-methylmalonyl-CoA to succinyl-CoA (Section 18.11). Other Donors, such as betaine, an oxidation product of Choline, can also participate in the methylation of homocysteine to form methionine.

These reactions constitute the activated methyl cycle (Fig. 21.7). Methyl groups enter the cycle in the conversion of homocysteine to methionine and are made highly reactive by the Cleavage of three high-energy bonds (~ P). The high methyl transfer potential of S-adenosylmethionine enables its transfer to A wide variety of acceptors, such as the amino group of the neurotransmitter norepinephrine (Section 37.11) and a glutamic acid residue of one of the chemotaxis regulatory Proteins (Section 37.23).

Fig. 21.7. The activated methyl cycle

21.8. Cysteine is synthesized from serine and homocysteine

In addition to being a precursor of methionine in the activated methyl cycle, homocysteine is also an intermediate in the synthesis of Cysteine. Serine and homocysteine condense to form cystathionine (Fig. 21.8). This reaction is catalyzed by cystathionine synthase, a pyridoxal enzyme. Cystathionine is then deaminated and cleaved to cysteine and α-ketobutyrate by cystathionase, another pyridoxal enzyme. The net equation for these two reactions is:

Homocysteine + Serine → Cysteine + α-Ketobutyrate.

Fig. 21.8. Synthesis of cysteine

Note that the sulfur atom of cysteine comes from homocysteine, whereas its carbon Skeleton comes from serine.

This concludes our Structure/133.html">Discussion of the Biosynthesis of nonessential Amino Acids. The formation of Tyrosine by the hydroxylation of phenylalanine was discussed earlier (Section 18.16).

21.9. Shikimate and chorismate are intermediates in the biosynthesis of aromatic amino acids

We now turn to the Biosynthesis of Essential amino acids, the pathways of which are much more complex than those of nonessential amino acids. For the discussion

... we chose two syntheses: those of aromatic Amino Acids and Histidine.

The synthesis of phenylalanine, tyrosine, and Tryptophan in E. coli proceeds via a common pathway (Fig. 21.9). The first step is the Condensation of phosphoenolpyruvate (an intermediate of Glycolysis) with erythrose 4-phosphate (an intermediate of the Pentose Phosphate Pathway). The resulting seven-carbon sugar loses its phosphoryl group and cyclizes to form 5-dehydroquinic acid. Dehydration yields 5-dehydroshikimate, which is reduced by NADPH to shikimate. Then, another molecule of phosphoenolpyruvate condenses with 5-phosphoshikimate; the resulting product loses its phosphate group and is converted to chorismate.

Fig. 21.9. Biosynthetic pathway of aromatic amino acids in E. coli

After the formation of chorismate, the biosynthetic pathway branches. Let us first follow the branch leading to the synthesis of prephenate (Fig. 21.11).

Fig. 21.11. Synthesis of tyrosine and phenylalanine from chorismate

In the reaction catalyzed by mutase, chorismate is converted to prephenate, the immediate precursor of the aromatic ring of Phenylalanine and Tyrosine. Dehydration and decarboxylation reactions of prephenate yield phenylpyruvate. In addition, Oxidative Decarboxylation of prephenate yields p-hydroxyphenylpyruvate. These α-keto acids undergo Transamination to form phenylalanine and tyrosine, respectively.

The branch starting with the synthesis of anthranilate leads to the synthesis of tryptophan. The amino group from the glutamine side chain is transferred to chorismate, forming anthranilate. In general, glutamine serves as an amino group donor in many biosynthetic reactions. Then anthranilate condenses with phosphoribosyl pyrophosphate (PRPP), an activated form of ribose phosphate. In addition, PRPP is a key intermediate in the synthesis of histidine, as well as purine and pyrimidine NUCLEOTIDES (Section 22.3). The C-1 atom of ribose 5-phosphate binds to the nitrogen atom of anthranilate. The driving force of this reaction is the Hydrolysis of pyrophosphate.

The ribose moiety of phosphoribosylanthranilate undergoes rearrangement (Fig. 21.12) to form 1-(o-carboxyphenylamino)-1-deoxyribulose 5-phosphate. This intermediate is cleaved and decarboxylated to yield indole-3-glycerol phosphate. Finally, indole-3-glycerol phosphate reacts with serine to form tryptophan. The glycerophosphate side chain of indole-3-glycerol phosphate is replaced by the carbon skeleton and amino group of serine. This reaction is catalyzed by tryptophan synthase.

Fig. 21.12. Synthesis of tryptophan from chorismate

Tryptophan synthase of E. coli has an α₂β₂ subunit structure. The enzyme can be dissociated into two α subunits and a β₂ complex. Individually, they catalyze partial reactions that lead to the synthesis of tryptophan:

Each Active Site of β₂ contains Pyridoxal phosphate as a prosthetic group. Upon Formation of the α₂β₂ complex, the catalytic properties of its α and β₂ components change markedly. The rates of the partial Reactions Catalyzed by the α₂β₂ complex are more than 10-fold higher than the rates of the reactions catalyzed by the individual subunits. Moreover, the synthesis of tryptophan by α₂β₂ proceeds via a coordinated mechanism. Indole formed in the first partial reaction immediately reacts with serine without being released from the α₂β₂ complex. Thus, interactions between the subunits of a multisubunit enzyme can alter its catalytic properties.