The bkdR Gene of Streptomyces coelicolor Is Required for Morphogenesis and Antibiotic Production and Encodes a Transcriptional Regulator of a Branched-Chain Amino Acid Dehydrogenase Complex

Abstract

ABSTRACT Products from the degradation of the branched-chain amino acids valine, leucine, and isoleucine contribute to the production of a number of important cellular metabolites, including branched-chain fatty acids, ATP and other energy production, cell-cell signaling for morphological development, and the synthesis of precursors for polyketide antibiotics. The first nonreversible reactions in the degradation of all three amino acids are catalyzed by the same branched-chain α-keto acid dehydrogenase (BCDH) complex. Actinomycetes are apparently unique among bacteria in that they contain two separate gene clusters, each of which encodes a BCDH enzyme complex. Here, we show that one of these clusters in Streptomyces coelicolor is regulated, at least in part, at the level of transcription by the product of the bkdR gene. The predicted product of this gene is a protein with similarity to a family of proteins that respond to leucine and serve to activate transcription of amino acid utilization operons. Unlike most other members of this class, however, the S. coelicolor bkdR gene product serves to repress transcription, suggesting that the branched-chain amino acids act as inducers rather than coactivators of transcription. BkdR likely responds to the presence of branched-chain amino acids. Its role in transcriptional regulation may be rationalized by the fact that transition from vegetative growth to aerial mycelium production, the first stage of morphological development in these complex bacteria, is coincident with extensive cellular lysis generating abundant amounts of protein that likely serve as the predominant source of carbon and nitrogen for metabolism. We suggest that bkdR plays a key role in the ability of Streptomyces species to sense nutrient availability and redirect metabolism for the utilization of branched-chain amino acids for energy, carbon, and perhaps even morphogen synthesis. A null mutant of bkdR is itself defective in morphogenesis and antibiotic production, suggesting that the role of the bkdR gene product may be more global than specific nutrient utilization.