The genetic basis of precursor supply for the biosynthesis of macrolide and polyether antibiotics

Macrolide and polyether biosynthesis in actinomycetes is regulated at the level of precursor supply by effects of nutrients on the sources of the low-molecular-weight fatty acids used to build the carbon framework of these antibiotics. Ammonium ion appears to suppress the first enzymes of valine and threonine catabolism and also inhibits their activity. Disruption of the valine dehydrogenase (vdh) gene of Streptomyces coelicolor destroys its ability to grow on branched-chain amino acids as the sole nitrogen source in a minimal medium but has no effect on the biosynthesis of the acetate-derived antibiotic, actinorhodin. Expression of the vdh gene is repressed by > 25 mM ammonium ion or glucose but not by valine, glycerol, or maltose. Vdh enzyme activity is stimulated by valine induction. These results suggest that the inhibition of valine catabolism by ammonium and/or glucose could explain why macrolide production is inhibited by ammonium ion.