Functional and structural characterization of the proteins from early steps of calicheamicin biosynthesis

Abstract

Polyketides are structurally diverse secondary metabolites produced by bacteria, fungi and plants with a vast variety of biological activities and pharmaceutical properties. Among the polyketide products, naturally-occurring enediynes are some of the most potent antitumor natural products ever discovered. There are two different types of enediyne cores known to date, namely the bicyclo[7.3.0]-dodecadienediyne and bicyclo[7.3.1]-tridecadiynene. Despite some variations in structure, all enediynes consist of three important functional moieties that account for their unprecedented antibiotic and antitumor activities. A central aglycone warhead “attacks” DNA by hydrogen abstraction through the free radicals generated by the Bergman or Myers-Saito cyclization mechanism; a delivery system composed of oligosaccharide fragments guides the molecule to the DNA target and a triggering device activates the molecule to generate the highly reactive free radicals. Due to their astonishing capacity in cleaving DNA, some of the enediynes have already been employed in cancer treatment.

Calicheamicin γ1I, which belongs to the 10-membered enediyne family, is one of the earliest enediyne natural products used in the treatment of leukemia. Although the structure and the chemical functionality of Calicheamicin γ1I have been fully deciphered since its discovery, the biosynthetic pathway of the bicyclo[7.3.1]-tridecadiynene is still shrouded in mystery. Studies on the biosynthesis of enediynes have recently been made possible with the identification of gene clusters responsible for enediyne biosynthesis in 2002.