Biosynthesis of the streptovaricins: 3-Amino-5-hydroxybenzoic acid as a precursor to the meta-C7N unit.

Abstract

[Ctfr&0xj;-14C]-3-ammo-5-hydroxybenzoic acid (AHBA) has been shown to be incorporated by Streptomyces spectabilis to the extent of greater than 0. 1 %(35 : 1 dilution) in the ansamycin antibiotic streptovaricin C, the major componentof the streptovaricin complex. When[carboxy-i3C]AHBA was similarly administered, C-21 (quinone methide carbonyl at 188.3ppm) of streptovaricin C was specifically labeled (at twenty one times natural abundance). In preparation for the 13C incorporation study the 13C NMR spectrum of streptovaricin C was investigated, making extensive use of short-and long-range HETCOR. These assignments revise some of those proposed earlier for streptovaricin C.The meta-C7N units in the aromatic chromophores of several ansamycin antibiotics have been shown to be biosynthetically derived from 3-amino-5-hydroxybenzoic acid (AHBA) as a discrete biological intermediate. Rifamycin,1) actamycin,2) geldanamycin,3) the ansamitocins,4) and the mitomycins5) have all been shown to incorporate AHBA as a precursor. Although the biosynthesis of AHBA from primary metabolic precursors has not yet been completely determined, there is evidence that the compoundcomes from a branch of the shikimic acid pathway.6) Wereport here the biosynthetic incorporation of 13C-and 14C-labeled AHBAinto the naphthoquinoid chromophore of streptovaricin C (1), thus providing additional evidence that AHBA is a commonprogenitor of the ansamycinantibiotics. In addition, we have revised some of the previously reported 13C NMRassignments of 1 based on new 2D heteronuclear correlation experiments.7) Our continued interest in the biosvnthesis of the streotovaricins is based in Dart on reports of their derivatives' antiviral activities,8) most recently against the HIV virus.9) Streptovaricin analogues with modified biological activities could conceivably be produced through mutasynthetic modifications based on a knowledge of the biosynthetic origin of these compounds. 10)

The biosynthesis of 3-amino-5-hydroxybenzoic acid (AHBA), the precursor of mC7N units in ansamycin and mitomycin antibiotics: a review

“…Later work has repeatedly confirmed the specific role of AHBA as precursor of the mC 7 N unit of various other compounds. [34][35][36][37][38][39] The biosynthetic question then raised was how AHBA was formed by a route that is related to the shikimate pathway. An important issue was whether the nitrogen of AHBA was attached to the carbon corresponding to C-3 or C-5 of shikimate.…”

Ansavaricins A–E: five new streptovaricin derivatives from Streptomyces sp. S012

“…S65 †). [22][23][24] The ROESY cross-peak observed from H-26 to H-24 proposed the relative conguration at the C-26 position, but the relative conguration of C-27 remained unknown for lack of related experimental data. Thus, 1 was deduced to be a new seco-streptovaricin, namely ansavaricin A (Fig.…”

Ansavaricins F–I, new DNA topoisomerase inhibitors produced by Streptomyces sp. S012

“…The structure and absolute conguration of the known compound streptovaricin C had been determined by X-ray analysis of a heavy atom derivative. 19,20 Although the structure of 1 was different from that of streptovaricin C, the ROESY correlations described in Fig. 2 suggested that both of them had the same relative congura-tions at C-18, C-19, C-22, C-23, C-24 and C-25.…”

“…S29 †). 5,20 On the basis of the above analyses, the gross structure of 1 was deduced as a new ansamycin type polyketide, for which we proposed the name ansavaricin F.…”