Candicidin biosynthesis

Martin JF, Aparicio JF (2009) Enzymology of the polyenes pimaricin and candicidin biosynthesis. Methods Enzymol 459 215-242... 

Zhou Y, Meng Q, You D, Li J, Chen S, Ding D, Zhou X, Zhou H, Deng Z (2008) Selective Removal of Aberrant Extender Units by a Type II Thioesterase for Efficient FR-008/ Candicidin Biosynthesis in Streptomyces sp. Strain FR-008. Appl Environ Microbiol 23 7235... 

The inhibitory effect of inorganic phosphate on biosynthetic pathways of secondary metabolites including non--phosphorylated intermediates is explained less readily. The action usually involves the derepression of synthesis of enzymes which carry out the formation of secondary products after the inorganic phosphate has been exhausted (4). The study by Martin et al. (23) of the effect of orthophosphate on candicidin biosynthesis in Streptomyces griseus suggested that inorganic phosphate either inhibits the activity of candicidin synthases or represses their synthesis (24). Inorganic phosphate also represses the synthesis of anhydrotetracycline hydratase in Streptomyces aureofaciens while benzyl thiocyanate abolishes its inhibitory effect (4). 

Citrate is a positive effector of aceiyl-CoA carboxylase (92), the crayme involved in the biosynthesis of the malonyl-CoA needed for polyketide biosynthesis. However, high levels of citrate were clearly inhibitory for candicidin biosynthesis, apparently due to its metahchelating properties (91 )-... 

Martm JF. McDaniel LE. Specific inhibition of candicidin biosynthesis by the lipogenic inhibitor cerulenin. Biochim Biophys Acta 1975 411 186-194. 

Criado LM, Martin JF, Gil J A. The pab gene from Streptomjces gn sf us, encoding p-aminoben-zoic acid synthase, is located between genes possibly involved in candicidin biosynthesis. Gene 1993 126 135-139. 

Asturias JA. Liras P, Martfn JF. Phosphate control of pobS gene transcription during candicidin biosynthesis. Gene 1990 93 79-84. 

The biogenesis of the polyene MACROLIDE candicidin (a heptaene) is mostly from acetate and propionate with the additional presence in the structure of p-am1noacetophenone and mycosamine (3-ami no-3,6-dideoxy D-mannopyranose) 43. The biosynthesis of the candidin and candihexin complexes (heptaene and hexaene, respectively) seems to be via sugar-free aglycones which are within the producing mycelium. Glycosylation may take place during secretion of the final products. 

Candicidin production by Streptomyces griseus was inhibited by inorganic phosphate, which suppressed the biosynthesis of p-aminobenzoate, the starter unit for the synthesis of this 38-membered heptaene macrolide antibiotic [95]. P-aminobenzoic acid synthase (PABA synthase) catalyses the conversion of chorismic acid to PABA, which is a precursor to candicidin. 

The shikimate pathway is the major route to aromatic compounds in actinomycetales. Biosynthesis of the aromatic side chains of candicidin [95] and peri-mycin [100] has been shown to arise directly from glucose via shikimate andp-aminobenzoate. 

One year later, the sequencing of a complete FR-008/candicidin gene cluster spanning 137.2 kb was reported. Computer-assisted analysis of the sequence revealed 21 potential orfs putatively responsible for FR-008 biosynthesis, as shown in Figure 7.52. 

Asturias JA, Martin JF, Liras P. Biosynthesis and phosphate control of candicidin by Strepto-myces acrimyeini JI2236 Effect of amplification of the pabAB gene. ] Ind Microbiol 13 1994 183-169. 

The three different moieties of polyene macrolides (i.e., the macrolide ring, the aromatic moiety, and the aminosugar moiety) are synthesized by three separate pathways (7). Initial results obtained in the case of candicidin indicated that, at least, the genes involved in the biosynthesis of the aromatic moiety and the macrolide ring are clustered. 

Early studies demonstrated that oils and fatty acids stimulated the production of the polyene macrolide antibiotics fungichromin and filipin, but not amphotericin B or candicidin (89). The stimulation polyene antibiotic biosynthesis by oils might be a simple precursor effect. Catabolism of fatty acids results in a increased pool of acetyh QiA. which is subsequently used for polyene biosynthesis. 

Z. Gil J A, Liras P, Naharro G, Villanueva JR, Martin JF. Regulation by aromatic amino acids of the biosynthesis of candicidin by Streptomyces griseus. J Gen Microbiol 1980 118 189-195. 

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