Posttranslational tyrosine geranylation in cyanobactin biosynthesis

• Published in: Journal of the American Chemical Society Vol. 140; no. 19; pp. 6044 - 6048
• Main Authors: Morita, Maho, Hao, Yue, Jokela, Jouni K., Sardar, Debosmita, Lin, Zhenjian, Sivonen, Kaarina, Nair, Satish K., Schmidt, Eric W.
• Format: Journal Article
• Language: English
• Published: 01-05-2018
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.8b03137

Prenylation is a widespread modification widely that improves the biological activities of secondary metabolites. This reaction also represents a key modification step in biosyntheses of cyanobactins, a family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) produced by cyanobacteria. In cyanobactins, amino acids are commonly isoprenylated by ABBA prenyltransferases that use C5 donors. A potential exception was the discovery of piricyclamides, from a fresh-water cyanobacterium were proposed to have a C10 geranyl group. Here we characterize a novel geranyltransferase involved in piricyclamide biosynthesis. Using the purified enzyme, we show that the enzyme PirF catalyzes Tyr
O
-geranylation, which is an unprecedented posttranslational modification. In addition, the combination of enzymology and analytical chemistry revealed the structure of the final natural product, piricyclamide 7005E1, and the regioselectivity of PirF, which has potential as a synthetic biological tool providing drug-like properties to diverse small molecules.