Ansamycin biosynthesis

The evidence then is that, for rifamycin and other ansamycins, biosynthesis diverts at a so-far unidentified (but early) compound in the shikimic acid pathway to give 3-amino-5-hydroxybenzoic acid (91) (as its CoA ester). This compound then yields, on the one hand, the mitomycins [e.g. porfiromycin (88)1 and, on the other, the CoA ester of P8/1-OG (92), which then affords diverse metabolites such as rifamycin B (87) and actamycin (86) (cf. ref. 83 for a detailed scheme). 

Streptovaridns and Mitomycins.—Consideration of the structures deduced for metabolites with the streptovaricin skeleton which lack in particular the extensive oxygenation of say streptovaricin D, has allowed a reasonable sequence of events for streptovaricin biosynthesis to be proposed. (The streptovaridns belong to the class of ansamydns. For earlier reviews on ansamycin biosynthesis see ref. 5, p. 52, and ref. 6, p. 45.)... 

The ansa-chain of the ansamycins streptovaricins (4), rifamycins (263), geldanamycin (4), and herbimycin (32) has been shown to be polyketide in origin, being made up of propionate and acetate units with the 0-methyl groups coming from methionine. The remaining aromatic C N portion of the ansamacroHdes is derived from 3-amino-5-hydroxybenzoic acid (264—266) which is formed via shikimate precursors. Based on the precursors of the rifamycins and streptovaricins isolated from mutant bacteria strains, a detailed scheme for the biosynthesis of most of the ansamacroHdes has been proposed (95,263). 

Wehrli, W. Ansamycins Chemistry, Biosynthesis and Biological Activity. 72, 21-49 (1977). 

Wehrli, W. Ansamycins Chemistry, Biosynthesis and Biological Activity. 72, 21-49 (1977). Weiss, A. Crystal Field Effects in Nuclear Quadrupole Resonance. 30, 1-76 (1972). 

Kim C-G, Kirschning A, Bergon P, Zhou P, Su E, Sauerbrei B, Ning S, Ahn Y, Breuer M, Leistner E, Floss HG (1996) Biosynthesis of 3 -Amino-5 -hydroxybenzoic Acid, the Precursor of mCyN Units in Ansamycin Antibiotics. J Am Chem Soc 118 7486... 

Ghisalba O (1985) Biosynthesis of Rifamycins (Ansamycins) and Microbial Production of Shikimate Pathway Precursors, Intermediates, and Metabolites. Chimia 39 79... 

Investigations of the biosynthesis of the rifamycins, streptovaricins and geldanamycin proved that the ansa chain of the ansamycins is synthesized as proposed by Woodward. The isolation of the precursors rifamycin W, damavaricin C and D and the protostreptovaricins, together with the fact that rifamycin B and tolypomycin Y are cosynthesized by Streptomyces tolypophorus26 make it probable that the rifamycins, streptovaricins and tolypomycin Y have a common progenitor. 

Studies using 14C-labelled precursors and C-l3 carbon magnetic resonance have suggested that the biosynthesis of the benzenic ansamycin geldanamycin follows essentially the same pathway as that of the rifamycins and streptovaricins50. Geldanamycin is composed of 3 acetate and four propionate units which are attached to a C7N unit in the same direction of growth as is found in rifamycins and streptovaricins. The incorporation of three acetate units into the ansa chain, as opposed to two in the naphthalenic ansamycins, excludes the existance of a common precursor. 

Nothing is known about the biosynthesis of the maytansine group, the only ansamycins so far identified as being of plant origin. Their similarity to the bacterial metabolite geldanamycin has led to the hypothesis that despite their occurrence in plants, microorganisms might be involved in their production. 

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