Manipulation of regulatory genes reveals complexity and fidelity in hormaomycin biosynthesis

Xiaofeng Cai, Roberta Teta, Christoph Kohlhaas, Max Crüsemann, Reiko Ueoka, Alfonso Mangoni, Michael F. Freeman, Jörn Piel

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Hormaomycin (HRM) is a structurally remarkable peptide produced by Streptomyces griseoflavus W-384 that acts as a Streptomyces signaling metabolite and exhibits potent antibiotic activity against coryneform actinomycetes. HRM biosynthetic studies have been hampered by inconsistent and low production. To enhance fermentation titers, the role of its cluster-encoded regulatory genes was investigated. Extra copies of the putative regulators hrmA and hrmB were introduced into the wild-type strain, resulting in an increase of HRM production and its analogs up to 135-fold. For the HrmB overproducer, six bioactive analogs were isolated and characterized. This study demonstrates that HrmA and HrmB are positive regulators in HRM biosynthesis. A third gene, hrmH, was identified as encoding a protein capable of shifting the metabolic profile of HRM and its derivatives. Its manipulation resulted in the generation of an additional HRM analog.

Original languageEnglish (US)
Pages (from-to)839-846
Number of pages8
JournalChemistry and Biology
Volume20
Issue number6
DOIs
StatePublished - Jun 20 2013

Bibliographical note

Funding Information:
This work was supported by a grant from the Deutsche Forschungsgemeinschaft (FOR 854) to J.P. and a Human Frontier Science Program fellowship to M.F.F. We kindly thank Prof. Dr. Zeeck for the hormaomycin WT strain Streptomyces griseoflavus W-384, A. Schneider for optimization of HPLC conditions and preliminary isolation of hormaomycin analogs, and M. Engeser for MS measurements.

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