Hydroxybenzoic acid, biosynthesis

An mCyN unit is also present in the core of the polyketide antibiotic asukamycin from Streptomyces nodosas subsp. asukaensis [96]. This has been shown to arise not from a variant of the shikimate pathway, but from the condensation of a C4 unit from the TCA cycle, closely related to succinate, with a C3 unit, possibly dihydroxyacetone phosphate, from the triose pool. Related studies concerning 3-amino-4-hydroxybenzoic acid biosynthesis in Streptomyces murayamaensis mutants MC2 and MC3 support this hypothesis [97]. 

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). 

The shikimate pathway was identified through the study of ultraviolet light-induced mutants of E. coli, Aerobacter aerogenes, and Neurospora. In 1950, using the penicillin enrichment technique (Chapter 26), Davis obtained a series of mutants of E. coli that would not grow without the addition of aromatic substances.4 5 A number of the mutants required five compounds tyrosine, phenylalanine, tryptophan, p-aminobenzoic acid, and a trace of p-hydroxybenzoic acid. It was a surprise to find that the requirements for all five compounds could be met by the addition of shikimic acid, an aliphatic compound that was then regarded as a rare plant acid. Thus, shikimate was implicated as an intermediate in the biosynthesis of the three aromatic amino acids and of other essential aromatic substances.6 7... 

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... 

Biosynthesis of 7,8-didemethyl-8-hydroxy-5-deazaflavin starts from guanosine-5 -triphosphate (GTP), which leads through several steps to 5-amino(6-ribitylamino)-2,4( 1 //,3//)-pyrimidinedione 5 -phosphate, whose addition to 4-hydroxybenzoic acid which comes from shikimate gave the target compound <85JA8300>. The biosynthesis of riboflavin and deazaflavins has been studied in Methanobacterium thermoautotrophicum <91JBC9622>. 

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. 

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). 

Juch, ibid. 26, 839 (1905) Brunner, Ann. 351, 321 (1907) Zeltner, Landau, Ger. pat. 258,887 Frdl. 11, 210 Dyson, Man mo/ of Organic Chemistry vol. 1 (London, 1950) p 614 by oxidstion of salicylic acid with potassium persulfate Ger, pat. 81,297 (to Schering AG) Frdl 4, 127 from p-hydroxyphenol Meyer, U.S. pat. 2,580,336 (1952 to Monsanto) from 5 -bromo -2 -hydroxybenzoic acid Lowen -thal. Pepper, J. Am. Chem. See. 72, 3292 (1950) by Kolbe synthesis Clemens, U.S. pet. 2,816,137 (1957 to Eastman Kodak). Metabolic product of Pertici/fium patulum Tanen -baum, Bassett, Biochim. Biophys. Acta 28, 21 (1958) of Poty-porus tumulosus Cooke Crowden, Ralph, Amt, J. Chem. 14, 475 (1961). Biosynthesis Oaten back, Linnroth, Acta Chem. Scand. 16, 2298 (1962). 

Chorismate is formed from 5-enoylpyruvylshikimic acid 3-phosphate (Figure 21.13). Conversion of chorismate to p-hydroxybenzoic acid leads to synthesis of coenzyme Q. Conversion of chorismate to anthranilate leads to biosynthesis of tryptophan (Figure 21.14). 

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. 

C7H,o05, Mr 174.15. needles, D. 1.6, mp. 178-180°C, [a]g -157° (H2O), pKg4.15 (14.1 °C), soluble in water. S. is a widely distributed component of plants and occurs especially in fruits of the star anise (lllicium anisatum, syn. /. religiosum, Illiciaceae Japanese shi-kimi-no-ki). S. is a key intermediate of the so-called shikimic acid pathway which includes the biosynthesis of the aromatic amino acids phenylalanine, tyrosine, and tryptophan. These, in turn, are precursors of numerous alkaloids, flavonoids, and lignans, as well as 4-amino- and 4-hydroxybenzoic acid, gallic acid, tetrahydrofolic acid, ubiquinones, vitamin K, and nicotinic acid. The synthetic racemate melts at 191-192 °C. 

Biosynthesis From 4-hydroxybenzoic acid and gera-nyl diphosphate. 

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. 

From this result, it was confirmed that 3-amino-5-hydroxybenzoic acid was the direct biosynthetic precursor of the w-CyN unit of porfiromycin. Because of its chemical structure, it might be thought that tryptophan could be involved in the biosynthesis of the mitomycins, like those alkaloids possessing an indole nucleus, whereas in fact the mitomycins were biosynthesized from an m-CyN unit and a D-glucosamine moiety. 

---