title: Avenolide, a Streptomyces hormone controlling antibiotic production in Streptomyces avermitilis.
abstract: Gram-positive bacteria of the genus Streptomyces are industrially important microorganisms, producing >70% of commercially important antibiotics. The production of these compounds is often regulated by low-molecular-weight bacterial hormones called autoregulators. Although 60% of Streptomyces strains may use γ-butyrolactone-type molecules as autoregulators and some use furan-type molecules, little is known about the signaling molecules used to regulate antibiotic production in many other members of this genus. Here, we purified a signaling molecule (avenolide) from Streptomyces avermitilis--the producer of the important anthelmintic agent avermectin with annual world sales of $850 million--and determined its structure, including stereochemistry, by spectroscopic analysis and chemical synthesis as (4S,10R)-10-hydroxy-10-methyl-9-oxo-dodec-2-en-1,4-olide, a class of Streptomyces autoregulator. Avenolide is essential for eliciting avermectin production and is effective at nanomolar concentrations with a minimum effective concentration of 4 nM. The aco gene of S. avermitilis, which encodes an acyl-CoA oxidase, is required for avenolide biosynthesis, and homologs are also present in Streptomyces fradiae, Streptomyces ghanaensis, and Streptomyces griseoauranticus, suggesting that butenolide-type autoregulators may represent a widespread and another class of Streptomyces autoregulator involved in regulating antibiotic production.
authors.affiliation: International Center for Biotechnology,  Osaka University, Suita, Osaka 565-0871,  Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kitani
authors.forename: Kiyoko T
authors.initials: KT
authors.lastname: Miyamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takamatsu
authors.forename: Elisa
authors.initials: E
authors.lastname: Herawati
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Iguchi
authors.forename: Kouhei
authors.initials: K
authors.lastname: Nishitomi
authors.forename: Miho
authors.initials: M
authors.lastname: Uchida
authors.forename: Tohru
authors.initials: T
authors.lastname: Nagamitsu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.forename: Haruo
authors.initials: H
authors.lastname: Ikeda
authors.forename: Takuya
authors.initials: T
authors.lastname: Nihira
mesh_terms: D000871:Anthelmintics / Q000378:metabolism*; D003470:Culture Media; D006728:Hormones / Q000737:chemistry / Q000378:metabolism*; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000378:metabolism; D008024:Ligands; D013058:Mass Spectrometry; D019906:Nuclear Magnetic Resonance, Biomolecular; D012997:Solvents; D013302:Streptomyces / Q000378:metabolism*
chemical_list: D000871:Anthelmintics; D003470:Culture Media; D006728:Hormones; D008024:Ligands; D012997:Solvents; D007559:Ivermectin; C019264:avermectin