“Biosynthesis and Resistance Mechanisms of Capreomycin and Enzyme-Catalyzed Pentacyclic Skeleton Formation in Cyclopiazonic Acid”

Abstract

We employ biochemical and structural biology approaches to investigate the biosynthetic pathways of natural products and the catalytic mechanism of the enzymes involved. Our research focueses on the following two topics:

Capreomycin (CMN) is a nonribosomal peptide (NRP) antituberculosis antibiotic, the structure of which is composed of four nonproteinogenic amino acids, including l-2,3-diaminopropionic acid (l-Dap), β-ureidodehydroalanine, l-capreomycidine (l-Cap), and β-lysine. These nonproteinogenic amino acids play critical roles for the mechanisms of action and resistance of CMN. We combine biochemical characterization and structural determination to elucidate the biosynthesis of these nonproteinogenic amino acids, as well as the operation of an unusual NRPS machinery. Our studies modify the originally proposed biosynthetic pathway and provide insights into nonproteinogenic amino acids formation in CMN and other related natural products.
We investigate enzyme-catalyzed cyclization reactions in cyclopiazonic acid (CPA) biosynthesis. This work resolves a long-standing biosynthetic mystery and expands the known catalytic repertoire of flavoenzymes. Moreover, the identified cyclization enzyme can be repurposed as a biocatalyst for the chemoenzymatic synthesis of structurally diverse indole alkaloid derivatives, highlighting its potential utility in molecular diversification.

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