Regulation of the Streptomyces coelicolor Calcium-Dependent Antibiotic by absA , Encoding a Cluster-Linked Two-Component System

Abstract

The Streptomyces coelicolor absA two-component system was initially identified through analysis of mutations in the sensor kinase absA1 that caused inhibition of all four antibiotics synthesized by this strain. Previous genetic analysis had suggested that the phosphorylated form of AbsA2 acted as a negative regulator of antibiotic biosynthesis in S. coelicolor (T. B. Anderson, P. Brian, and W. C. Champness, Mol. Microbiol. 39:553-566, 2001). Genomic sequence data subsequently provided by the Sanger Centre (Cambridge, United Kingdom) revealed that absA was located within the gene cluster for production of one of the four antibiotics, calcium-dependent antibiotic (CDA). In this paper we have identified numerous transcriptional start sites within the CDA cluster and have shown that the original antibiotic-negative mutants used to identify absA exhibit a stronger negative regulation of promoters upstream of the proposed CDA biosynthetic genes than of promoters in the clusters responsible for production of actinorhodin and undecylprodigiosin. The same antibiotic-negative mutants also showed an increase in transcription from a promoter divergent to that of absA, upstream of a putative ABC transporter, in addition to an increase in transcription of absA itself. Interestingly, the negative regulation of the biosynthetic transcripts did not appear to be mediated by transcriptional regulation of cdaR (a gene encoding a homolog of the pathway-specific regulators of the act and red clusters) or by any other recognizable transcriptional regulator associated with the cluster. The role of absA in regulating the expression of the diverse antibiotic biosynthesis clusters in the genome is discussed in light of its location in the cda cluster.

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

“…These ActII-ORF4-like SARPs are referred to here as "small SARPs." Members of a second class of SARP CSRs ("medium SARPs") resemble CdaR in being around 600 aa long, and these all show end-to-end similarity to each other (229). Still other SARP CSRs are much larger, containing about 1,000 residues ("large SARPs").…”

Cohesion Group Approach for Evolutionary Analysis of TyrA, a Protein Family with Wide-Ranging Substrate Specificities

“…As discussed above, S. coelicolor PapC is widely divergent from all other PapC proteins, the latter of which collect together within a single TyrA ␤ cohesion group (not shown in the figures and tables of this review). S. coelicolor PapC is assumed to play a role in the synthesis of calcium-dependent antibiotic because of the position of its encoding gene in the middle of the large CDA (calcium-dependent antibiotic) gene cluster (65). PapC proteins are generally assumed to utilize 4-amino-prephenate as a substrate, thereby producing 4-amino-phenylpyruvate as product.…”

“…Streptomyces coelicolor possesses two paralogs (TyrA a and PapC) that occupy the same cohesion group (TyrCG-17). The PapC paralog is encoded by a gene within the calcium-dependent antibiotic cluster (65) and possesses an alanine residue at position 154. The TyrA and PapC homologs in S. coelicolor are closely related intra-cohesion-group paralogs, of which PapC presumably arose recently by gene duplication, followed by a novel specialization of substrate specificity.…”

Role of nsdA in negative regulation of antibiotic production and morphological differentiation in Streptomyces bingchengensis

“…3 Global regulators, such as bldA, 4 bldB, 5 bldD 6 and bldG, 7 perform the highest level regulation and affect both morphological and physiological differentiation. 8,9 At intermediate levels in the regulatory cascades, many regulatory genes, such as afsB, 10 abaA, 11 absB, 12 afsK-afsR 13,14 and tcrA, 15 and two-component systems, such as afsQ1-afsQ2, 16 absA1-absA2, 17,18 cutS-cutR 19 and phoR-phoP, 20 have been identified, which regulate the synthesis of two or more antibiotics. absA1-absA2, cutScutR, phoR-phoP, tcrA and some pathway-specific repressors regulate antibiotic production in a negative manner, as mutations in these genes resulted in the overproduction of the corresponding antibiotic(s).…”