Branched-chain amino acid catabolism provides precursors for the Type II polyketide antibiotic, actinorhodin, via pathways that are nutrient dependent

Abstract

Polyketide antibiotics are among the most important therapeutics used in human and animal health care. Type II polyketides are composed primarily of acetate-derived thioesters, and the subunits for the PKS are contained in a single module that includes a ketosynthase, acyl carrier protein, chain-length factor and sometimes a keto-reductase, aromatase, cyclase and modifying enzymes, such as glycosylases or hydroxylases. While the enzyme complexes that make up the PKS have been the focus of intense study (Khosla in Chem Rev 7:2577-2590, 1997), the pathways for precursor synthesis have not been established and predictions are complicated by the fact that acetate may be derived from a number of metabolic pathways. Here we show that 50% of the acetate for synthesis of the Type II polyketide, actinorhodin, in Streptomyces coelicolor, is derived from the catabolism of the branched amino acids by pathways that are nutrient dependent. The streptomycetes are apparently unique in that they contain two BCDH gene clusters, each of which is potentially capable of converting leucine, valine and isoleucine to the corresponding thioesters, and contain at least three different pathways for valine catabolism that are differentially used in response to nutrient availability.

Multicopy <i>proC </i>in <i>Streptomyces coelicolor </i> A3(2) Elicits a Transient Production of Prodiginines, while <i>proC</i> Deletion Does Not Yield a Proline Auxotroph

“…Interaction of Biosyntheses of Proline and Prodiginine in S. coelicolor A3(2) J Mol Microbiol Biotechnol 2010;19:152-158 153 na et al, 2008;Stirrett et al, 2009]. Analogous to our report on the Put -mutants, these studies show how precursors may be generated from catabolic pathways, and then specifically shunted into polyketide biosynthesis.…”

The ROK Family Regulator Rok7B7 Pleiotropically Affects Xylose Utilization, Carbon Catabolite Repression, and Antibiotic Production in Streptomyces coelicolor

“…All data point to control of antibiotic production by Rok7B7, with activation of Act and repression of Red and CDA. The proteomics experiments also showed upregulation of the degradation pathway for branched-chain amino acids (leucine, isoleucine, and valine), which are precursors for biosynthesis of polyketides such as actinorhodin (64), suggesting that besides antibiotic production, Rok7B7 also controls precursor supply.…”

Spatial and temporal control of fungal natural product synthesis

“…isovaleryl-CoA, isobutyryl-CoA, etc.) of various polyketide antibiotics 19, 20 . The utilization of common substrates for primary and secondary metabolism suggests that the cell must control the flux of substrates between primary and secondary metabolic pathways in some fashion.…”