期刊
CHEMBIOCHEM
卷 16, 期 6, 页码 990-997出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201500007
关键词
biosynthesis; macrolides; natural products; pipecolic acid; polyketides
资金
- Research Corporation Cottrell College Science Award
- University of North Florida (UNF) Transformational Learning Opportunity Awards
- UNF Academic Affairs Grants
- UNF Faculty Fellowship Award
- UNF SMART grant
- Case Western Reserve University Case Western Reserve University
Macrolide-pipecolate natural products, such as rapamycin (1) and FK-506 (2), are renowned modulators of FK506-binding proteins (FKBPs). The nocardiopsins, from Nocardiopsis sp. CMB-M0232, are the newest members of this structural class. Here, the biosynthetic pathway for nocardiopsins A-D (4-7) is revealed by cloning, sequencing, and bioinformatic analyses of the nsn gene cluster. In vitro evaluation of recombinant NsnL revealed that this lysine cyclodeaminase catalyzes the conversion of L-lysine into the L-pipecolic acid incorporated into 4 and 5. Bioinformatic analyses supported the conjecture that a linear nocardiopsin precursor is equipped with the hydroxy group required for macrolide closure in a previously unobserved manner by employing a P450 epoxidase (NsnF) and limonene epoxide hydrolase homologue (NsnG). The nsn cluster also encodes candidates for tetrahydrofuran group biosynthesis. The nocardiopsin pathway provides opportunities for engineering of FKBP-binding metabolites and for probing new enzymology in nature's polyketide tailoring arsenal.
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