期刊
METABOLIC ENGINEERING
卷 48, 期 -, 页码 254-268出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymben.2018.06.008
关键词
Actinomycetes; Pirin; Beta-oxidation of fatty acids; Secondary metabolism; Antibiotics
资金
- Advanced Technologies Network (ATeN) Center at the University of Palermo in the frame of Mediterranean Center for Human Health Advanced Biotechnologies (Med-CHHAB) project [PONa3_00273 - Avviso MIUR D.D. n. 254/Ric]
- Italian Ministry for Education, Universities and Research [PON01_02093]
Pirins are evolutionarily conserved iron-containing proteins that are found in all kingdoms of life, and have been implicated in diverse molecular processes, mostly associated with cellular stress. In the present study, we started from the evidence that the insertional inactivation of pirin-like gene SAM23877_RS18305 (pirA) by Phi C31 Att/Int system-based vectors in spiramycin-producing strain Streptomyces ambofaciens ATCC 23877 resulted in marked effects on central carbon and energy metabolism gene expression, high sensitivity to oxidative injury and repression of polyketide antibiotic production. By using integrated transcriptomic, proteomic and metabolite profiling, together with genetic complementation, we here show that most of these effects could be traced to the inability of the pirA-defective strain to modulate beta-oxidation pathway, leading to an unbalanced supply of precursor monomers for polyketide biosynthesis. Indeed, in silico protein-protein interaction modeling and in vitro experimental validation allowed us to demonstrate that PirA is a novel redox-sensitive negative modulator of very long-chain acyl-CoA dehydrogenase, which catalyzes the first committed step of the beta-oxidation pathway.
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