Enzymology of the polyenes pimaricin and candicidin biosynthesis

Pimaricin and candicidin are prototypical representatives of the "small" and the "aromatic" polyene macrolides, respectively. Pimaricin, produced by Streptomyces natalensis, is an important antifungal agent used in human therapy for the treatment of fungal keratitis, and in the food industry to prevent mould contamination. Five large polyketide synthase subunits are implicated in the formation of the pimaricin macrolactone ring, while P450 mono-oxygenases and a glycosyltransferase are responsible for ring "decoration." Two transcriptional regulators directly modulate transcription of certain genes in the cluster; an extracellular cholesterol oxidase also participates in such control. Two regulatory locus external to the pimaricin gene cluster, encoding the two-component PhoR-PhoP system for phosphate limitation response, and a gamma-butyrolactone receptor, contribute to the control of pimaricin production. A quorum-sensing inducer of pimaricin biosynthesis (PI-factor) has been identified recently. Candicidin (also named FR-008) contains an aromatic para-aminoacetophenone moiety derived from para-aminobenzoic acid (PABA), which acts as a starter unit in the biosynthesis. Two genes in the candicidin cluster, pabAB and pabC, are involved in the biosynthesis of PABA. Six polyketide synthase subunits encoded by fscA to fscF, containing 21 modules, are involved in the synthesis of the candicidin aglycone. At least three genes (fscO, fscP, and fscTE) encode aglycone modification enzymes. Three genes-fscM1, M2, and M3-are involved in mycosamine biosynthesis and its attachment to the aglycone. The candicidin cluster also includes two ABC transporter genes and four putative transcriptional regulators. Expression of the PABA synthase gene (pabAB) is drastically repressed by phosphate.