From Peptide Precursors to Oxazole and Thiazole-Containing Peptide Antibiotics: Microcin B17 Synthase

Abstract

Esherichia coli microcin B17 is a posttranslationally modified peptide that inhibits bacterial DNA gyrase. It contains four oxazole and four thiazole rings and is representative of a broad class of pharmaceutically important natural products with five-membered heterocycles derived from peptide precursors. An in vitro assay was developed to detect heterocycle formation, and an enzyme complex, microcin B17 synthase, was purified and found to contain three proteins, McbB, McbC, and McbD, that convert 14 residues into the eight mono- and bisheterocyclic moieties in vitro that confer antibiotic activity on mature microcin B17. These enzymatic reactions alter the peptide backbone connectivity. The propeptide region of premicrocin is the major recognition determinant for binding and downstream heterocycle formation by microcin B17 synthase. A general pathway for the enzymatic biosynthesis of these heterocycles is formulated.

Cyclic peptide marine metabolites and CuII

“…CO 2 hydration (carbonic anhydrase activity), 23,34,43,56,57,90,93,94 and phosphoester hydrolysis ( phosphatase activity) 88 have recently been proposed as possible biological functions, and this will be discussed in detail below. Due to the known cytotoxic, antibacterial, antineoplastic and antiviral activities of the metal-free cyclic pseudo-peptides, medicinal and pharmaceutical applications have been studied extensively 13,17,18,44,95,96 and still are a driving force for cyclic peptide chemistry. The cyclic pseudo-peptides' use as macrocyclic ligands in transition metal coordination chemistry has been another focus of Lissoclinum-derived cyclic peptides, and small side-chain (iso-propyl); right: bulky side-chain (tert-butyl).…”

Patellamide A and C biosynthesis by a microcin-like pathway inProchloron didemni, the cyanobacterial symbiont ofLissoclinum patella

“…Trunkamide and related molecules often contain proline, thiazolines, and prenylated serine and threonine derivatives. These features could easily result from either a ribosomal or nonribosomal peptide biosynthetic pathway, because precedents exist for heterocyclization and cyclization in both cases (18)(19)(20)(21). We initially chose to investigate the nonribosomal hypothesis of patellamide biosynthesis using a homology-based approach (22).…”

A global assembly line for cyanobactins

“…The patellamides (3)(4)(5)(6)(7)(8) are biosynthesized through a unique ribosomal route 2 with some similarity to microcin pathways ( Fig. 1) 8 .…”