Actinomycins biosynthesis

Little is known concerning the mechanism of biogenesis of the often occurring Y-methylamino acids. There is evidence that glycine and l-valine are the direct precursors of sarcosine > and Y-methyl-L-valine in actinomycin biosynthesis and that the methyl group is provided by methionine . 

Actinomydn.—The phenoxazinone skeleton of the actinomycins (181) has been shown to derive from two molecules of tryptophan via 3-hydroxy-4-methylanthranilic acid (185),methionine serving as the source of the aromatic methyl groups.Depression of the incorporation of radioactive tryptophan into actinomycin by kynurenine (182) and 3-hydroxy-4-methylkynurenine (184) indicated that (182) and (184) could well be biosynthetic intermediates. In contrast 3-hydroxykynurenine (183) was found to have little or no effect on tryptophan incorporation, thus casting doubt on its participation in actinomycin biosynthesis. However, both [ Hjkynurenine [as (182)] and [ H]-3-hydroxykynurenine [as (183)] have recently been shown to be efficient precursors for actinomycin in Streptomyces antibioticus. 3-Hydroxykynurenine (183) is therefore implicated in actinomycin biosynthesis and further substantive evidence is provided for the pathway tryptophan —> (182) — (183) — (184) —> (185) —> actinomycin (181). 

Aromatic methylation involves transfer of a methyl group from methionine. The mechanism of this transfer in actinomycin biosynthesis was examined by feeding [Me- H3]methionine to S. antibioticus The actinomycin isolated contained tri-and hexa-deuterio-species, from which it follows that all the hydrogens of the methyl... 

Actinomycin.—Further exploration of actinomycin biosynthesis has involved the preparation of protoplasts of Streptomyces species. 

E. A Possible Role for Cuanosine Tetraphosphate (ppCpp) in the Regulation of Actinomycin Biosynthesis... 

This chapter is dedicated to the metnory of Edward Katz, whose pioneering work on the physiolc, biochemtstty. and genetics of actinomycin biosynthesis laid the foundation for many of the studies described herein. 

In most cases the mechanism by which nutrients control secondary metabolism is unknown. However, glucose and other rapidly used carbon sources repress the formation of iV-acetylkanamycin amidohydrolase, thought to be the final enzyme of kanamycin A biosynthesis (D 1.3) and phenoxazinone synthase, an enzyme required in actinomycin biosynthesis (D 8.4.1). 

During inhibition of actinomycin synthesis by D-valine, it was noted that a substance accumulated in the medium which yielded D-valine after mild acid hydrolysis. The compound was isolated, crystallized and identified by NMR spectra as N-succinyl-D-valine by comparison with authentic material (B arch as et al., 1964). The relationship of N-succinyl-D-valine to the inhibition of actinomycin biosynthesis by D-valine is not entirely clear. The compound does not appear to inhibit actinomycin formation. The possibility exists that N-succinyl-D-valine is a normal metabolite in the biosynthesis of antibiotic D-valine from free L-valine. d-Valine, in high concentrations, might inhibit antibiotic formation by competition with L-valine for the succinylation reaction. 

Katz, E., and W. A. Goss Influence of amino acids on actinomycin biosynthesis. Nature 182, 1668 (1958). 

Katz, E., M. Wise, and H. Weissbach Actinomycin biosynthesis. Differential effect of chloramphenicol on protein and peptide antibiotic synthesis. J. Biol. Chem. 240, 3071 (1965). 

Weissbach, H., B. Redfield, V. Beavan, and E. Katz 4-Methyl-3-hydroxy-anthranilic acid, an intermediate in actinomycin biosynthesis. Biochem. Biophys. Research Commun. 19, 524 (1965). 

Yoshida, T., A. Mauger, B. Witkop, and E. Katz Influence of methylproline isomers upon actinomycin biosynthesis. Biochem. Biophys. Research. Commun. 25, 66 (1966). 

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