Roles of type II thioesterases and their application for secondary metabolite yield improvement.

Magdalena Kotowska,Krzysztof Pawlik

doi:10.1007/s00253-014-5952-8

Abstract

A large number of antibiotics and other industrially important microbial secondary metabolites are synthesized by polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). These multienzymatic complexes provide an enormous flexibility in formation of diverse chemical structures from simple substrates, such as carboxylic acids and amino acids. Modular PKSs and NRPSs, often referred to as megasynthases, have brought about a special interest due to the colinearity between enzymatic domains in the proteins working as an “assembly line” and the chain elongation and modification steps. Extensive efforts toward modified compound biosynthesis by changing organization of PKS and NRPS domains in a combinatorial manner laid good grounds for rational design of new structures and their controllable biosynthesis as proposed by the synthetic biology approach. Despite undeniable progress made in this field, the yield of such “unnatural” natural products is often not satisfactory. Here, we focus on type II thioesterases (TEIIs)—discrete hydrolytic enzymes often encoded within PKS and NRPS gene clusters which can be used to enhance product yield. We review diverse roles of TEIIs (removal of aberrant residues blocking the megasynthase, participation in substrate selection, intermediate, and product release) and discuss their application in new biosynthetic systems utilizing PKS and NRPS parts.

Highlights

Microorganisms have been long exploited for their ability to produce antibiotics and a variety of other compounds of medical and industrial importance
NAC is a structural analog of phosphopantetheine. Another group of substrates more closely resembling the natural systems are isolated acyl carrier protein (ACP) (PCP) domains or even entire polyketide synthases (PKSs) (NRPS) modules with different polyketide/peptide chains and short residues attached to 4′PP (Table 1)
TEIIs from surfactin and bacitracin synthetases hydrolyzed peptidyl carrier protein (PCP)-bound intermediates which could not be further processed by the nonribosomal peptide synthetases (NRPSs), much more slowly than the acetyl group (Table 1) (Schwarzer et al 2002)

Summary

Introduction

Microorganisms have been long exploited for their ability to produce antibiotics and a variety of other compounds of medical and industrial importance. Another group of substrates more closely resembling the natural systems are isolated ACP (PCP) domains or even entire PKS (NRPS) modules with different polyketide/peptide chains and short residues attached to 4′PP (Table 1).

Results

Conclusion