3- Amino-5-hydroxybenzoic

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). 

Figure 11.5 3-Amino-5-hydroxybenzoic acid as a precursor to the porfiromycin C quinone. 

Figure 11.6 The aminoshikimate pathway to 3-amino-5-hydroxybenzoic acid.

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... 

Dankwardt SM, Phan TM, Krstenansky JL, Combinatorial synthesis of small-molecule libraries using 3-amino-5-hydroxybenzoic acid, Mol. Diversity, 1 113-20, 1996. 

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). 

The specific and proximate precursor of the mCyN unit in ansamycin polyketides is 3-amino-5-hydroxybenzoic acid 59 (AHBA) [94]. The biosynthesis of AHBA has recently been described by Floss and co-workers from the initial branch point of the shikimic acid pathway prior to 3-deoxy-D-flra/jzno-heptulo-sonic acid 7-phosphate (DAHP) [95]. The pathway shown in Scheme 25 was delineated by feedings of the proposed AHBA precursors, in labelled forms, to cell-free extracts of both the rifamycin B producer A. mediterranei S699 and the ansatrienin A producer S. collinus Tul892. In these experiments each of the compounds 61-64 was converted into AHBA with generally increasing efficiency. Most importantly the shikimate pathway compound DAHP cannot replace phosphoenolpyruvate 61 and erythrose 4-phosphate 60, or aminoDAHP 62 as the precursor of AHBA 59. 

Biosynthetic studies on these compounds have been carried out by Floss et al. and they have established that 3-amino-5-hydroxybenzoic acid is the precursor of the mC7N unit, the quinone moiety, by a new variant of the shikimate pathway [183]. 

Geldanomycin, Rif.amycin, and Antibiotic A23187. — It is now clear that 3-amino-5-hydroxybenzoic acid (103) is the long-sought, key CyN intermediate involved in the biosynthesis of rifamycins and mitomycins. On the other hand, the C N intermediate involved in the biosynthesis of the 3-aminoacetophenone residue in pactamycin (101) is 3-aminobenzoic acid (100) (cf. Vol. 12, p.21). 

Rifamycin B, produced by Amycolatopsis mediterranei, is one of the most notable members of the ansamycin family [36, 37, 64, 65] (Fig. 14). It has been used clinically in a synthetically modified form called rifampicin and it is still one of the first-line therapies effective in the treatment of tuberculosis and other mycobacterial infections. The starter unit for rifamycin polyketide assembly is part of the chromophore and is derived from 3-amino-5-hydroxybenzoic acid. Five polyketide synthases are involved in the formation of rifamycin chromophore and the first polyketide synthase contains at the N terminus the loading domain for 3-amino-5-hydroxybenzoic acid, which consists of an acyl-CoA ligase linked to ACP, and module 1-3. The rifamycin polyketide synthase lacks a TE domain at the C terminus. The release of polyketide chain from polyketide synthase and the formation of amide to generate the macrocyclic lactam will be catalyzed by RifF, which is very similar to arylamine A-acetyltransferase. 

As for the precursor(s) of the W-C7N unit, it was reported that 3-amino-5-hydroxybenzoic acid (AHBA) (118) was incorporated into the ansa(myco)trienins (95 and 96). On the other hand, shikimic acid (119) was not incorporated into the n-C7N unit of this compound, even though 118 was definitely derived via the shikimate pathway [184,185]. 

General name for antitumor antibiotics with benzo-quinone and aziridine structural units from cultures of streptomycetes (e. g., Streptomyces lavendulae, S. ver-ticillatus, S. caespitosus). There are more than 15 natural variants containing a pyrrolo) 1,2-a)indole system and differing in R and R, with OH in place of OCHj at C-9a, and different stereochemistries at C-9. The violet to blue-violet, optically active M. crystallize readily and are soluble in water, methanol, and acetone. A cluster of 47 bacterial genes that control biosynthesis of M. C has been characterised. The biosynthetic building block of the benzoquinone (C7N) unit is 3-amino-5-hydroxybenzoic acid, several total syntheses have been repotted. 

The biosynthesis of R. is stimulated by B-factor and starts from 3-amino-5-hydroxybenzoic acid (C7N-unit), from which the skeleton of the naphthohydro-quinone bridged by a macrolactam is formed via the polyketide pathway. Insertion of oxygen into the ansa-bridge and further functionalization occur later in the biosynthetic sequence. Syntheses of R. have been reported. 

The m-CyN unit is derived from the shikimate pathway and possesses a Cj group and an amino group meta-disposed on a benzene ring. For example, some of the alkaloids described in this chapter are established to be derived from 3-amino-5-hydroxybenzoic acid, and other isomers are also involved in the biosynthesis of various alkaloids. 

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