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Deciphering the Function of NTF2‐like Proteins Associated with Polyketide Biosynthesis in Actinomycetes
Author(s) -
Vuksanovic Nemanja,
Zhu Xuechen,
Silvaggi Nicholas R.,
Melançon Charles E.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.766.8
Subject(s) - actinorhodin , streptomyces coelicolor , polyketide , gene cluster , natural product , biology , streptomyces , polyketide synthase , gene , mutant , biochemistry , enzyme , bacteria , biosynthesis , microbiology and biotechnology , genetics
Bioactive natural products are the active components in many therapeutic drugs, and as antibiotic resistance emerges as a global threat, a quest for novel natural products with antibiotic activity becomes increasingly important. Actinomycetes are known to produce many bioactive secondary metabolites, such as polyketides, some of which are powerful antibacterial agents. The gene cluster involved in production of actinorhodin, a benzoisochromanequinone antibiotic found in Streptomyces coelicolor A3(2), has been extensively studied. However, the role of the ActVI‐ORFA gene has remained controversial. Strains where the gene has been disrupted still produce actinorhodin, only at much‐reduced levels compared to the wild‐type strain. A number of studies have suggested a regulatory role for ActVI‐ORFA. Our in vivo kinetic studies of S. Coelicolor mutants show that strains without functional ActVI‐ORFA accumulate at least one off‐pathway intermediate. We also report the structures of ActVI‐ORFA and a homologue, CA‐Cyc3, from Catenulispora acidiphila . Both proteins exhibit the α‐and‐β barrel fold characteristic of NTF2‐like superfamily proteins and possess a His/Asp diad, a motif found in a variety of enzymes that perform acid/base catalysis. Taken together, our functional and structural data suggest that ActVI‐ORFA may have an enzymatic role, directing the pathway away from the shunt product and toward the synthesis of actinorhodin.