Characterization of the Nocardiopsin Biosynthetic Gene Cluster Reveals Similarities to and Differences from the Rapamycin and FK‐506 Pathways. Issue 6 (5th March 2015)

• Record Type: Journal Article
• Authors: Bis, Dana M.; Ban, Yang H.; James, Elle D.; Alqahtani, Norah; Viswanathan, Rajesh; Lane, Amy L.
• Is Part Of: Chembiochem. Volume 16:Issue 6(2015)
• Page Start: 990
• Page End: 997
• Publication Date: 2015-03-05
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201500007
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Macrolide‐pipecolate natural products, such as rapamycin (<bold>1</bold>) and FK‐506 (<bold>2</bold>), are renowned modulators of FK506‐binding proteins (FKBPs). The nocardiopsins, from <italic>Nocardiopsis</italic> sp. CMB‐M0232, are the newest members of this structural class. Here, the biosynthetic pathway for nocardiopsins A–D (<bold>4</bold>–<bold>7</bold>) is revealed by cloning, sequencing, and bioinformatic analyses of the <italic>nsn</italic> gene cluster. In vitro evaluation of recombinant NsnL revealed that this lysine cyclodeaminase catalyzes the conversion of <sc>L</sc>‐lysine into the <sc>L</sc>‐pipecolic acid incorporated into <bold>4</bold> and <bold>5</bold>. 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 <italic>nsn</italic> 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.</p> </abstract>