Indolmycin, biosynthesis

Indolmycin, biosynthesis of, 864 Inductive effect. 37, 562 alcohol acidity and. 604 carboxylic acid strength and. 758 electronegativity and, 37 electrophilic aromatic substitution and, 562... 

It is probable that methyl transferase reactions proceed by nucleophilic attack on S-adenosylmethionine94 and may involve an SN2-like transition state.95 Thus, inversion of configuration as observed in indolmycin biosynthesis indicates that an odd number of nucleophilic displacements occurs and suggests that the methyl group is transferred directly from donor to (112), i.e. without generation of a methylated-enzyme intermediate.92 The combined results are summarized in Scheme 11. 

Figure 22.7 The biosynthesis of indolmycin from indolylpyruvate occurs through a pathway that includes an alkylation reaction of a short-lived enolate ion intermediate.

This type of alkylation also occurs in nature. For example, S-adenosylmethionine (SAM), an important biological methylation reagent, is involved in the biosynthesis of the antibiotic indolmycin and is responsible for the enantioselective C-methylation of an a-oxocarboxylic acid arising from tryptophan3. 

Indolmycin.—It has been shown that the C-methyl group in indolmycin (82) originates from the methyl group of methionine with inversion of configuration (cf. Vol. 8, p. 23). Previously published in preliminary form,71 the results are now available in a full paper.72 In addition, it has been shown that the A-methylation reaction which occurs in the course of the biosynthesis of indolmycin (82) also proceeds with inversion of configuration of the methyl group of methionine. Similar methyl-transfer with inversion has been recorded in the catechol-O-methyl-transferase reaction,73 and in this case it has been concluded that there is a tight SN2 transition state for the methyl-transfer.74... 

Indolmydn.—Previous evidence on the biosynthesis of indolmycin (88) in Strepto-myces griseus cultures accords with the pathway shown in Scheme 4. The first two steps in the pathway have been carried out using cell-free extracts of 5. griseus - and recent work has led to the isolation of two enzymes which can effect these transformations. The first, tryptophan transaminase, catalysed the pyridoxal phosphate-dependent transamination of L-tryptophan, but not D-trptophan, and in common with some other microbial transaminases, a-ketoglutarate was an efficient amino-group acceptor. L-Phenylalanine, tyrosine, and 3-methyltryptophan (this compound inhibited enzyme function) also underwent transamination. 

INDOLMYCIN (20) is formed from pyruvate, and two enzymes active in initial stages of Its biosynthesis have been studied. They are a transaminase and aC-methyltransferase. The hypothetical route to indolmycin is by indole pyruvate, 3-methyl-indolepyruvate, indolmycenic acid (reduced alpha oxo group) and finally indolmycin which probably takes its amidine group from an arginine molecule 79. The closely related [pyrrolo (1,4) benzodiazepines] 80>81,82 antitumor antibiotics, anthramycin, tomaymycin and sibiromycin are formed from tryptophan (via the kynurenine pathway ), tyrosine and methionine-derived methyl groups 80.si.sz. 

Alkylations are rare but not unknown in biological chemistry. One example occurs during biosynthesis of the antibiotic indolmycin from indolylpymvate when a base abstracts an acidic hydrogen from an a position and the resultant... 

Speedie (4S) has obtained a cell-free preparation from S. flocculus which catalyzes the formation of (31) from L-tryptophan and S-adenosyl-L methionine. The crude enzyme has been purified 2-fold by ammonium sulfate fractionation, and preliminary results with this preparation after dialysis indicated that pyridoxal phosphate is not required, but may cause some stimulation of enzyme activity. At this stage of purification tryptophan transaminase activity was also present, and it has not yet been possible to determine whether the true methylase substrate is an activated tryptophan, or indole pyruvic acid (33), as has been demonstrated to be the case in the biosynthesis of indolmycin (34) (46). 

---