Biosynthesis-driven structure-activity relationship study of premonensin-derivatives.

A Ismail-Ali,M Pflieger,A Wittinghofer,N Pryk,F Schulz,E K Fansa,S Kushnir,S Yahiaoui

doi:10.1039/c6ob01201a

Abstract

The controlled derivatization of natural products is of great importance for their use in drug discovery. The ideally rapid generation of compound libraries for structure-activity relationship studies is of particular concern. We here use modified biosynthesis for the generation of such a library of reduced polyketides to interfere with the oncogenic KRas pathway. The polyketide is derivatized via side chain alteration, and variations in its redox pattern and in its backbone chain length through manipulation in the corresponding polyketide synthase. Structural and biophysical analyses revealed the nature of the interaction between the polyketides and KRas-interacting protein PDE6δ. Non-natural polyketides with low nanomolar affinity to PDE6δ were identified.

Highlights

Reduced polyketides form a well-known group of natural products with a multitude of bioactivities and high structural diversity
We set up crystallization trials using different premonensin derivatives to gain structural insights into the mode of interaction between premonensin and PDE6δ
Superimposition of the PDE6δ–premonensin A complex structure with the structure of the PDE6δ–Rheb complex (PDB code: 3T5G) (Fig. 1A; left) shows that premonensin A inserts into the hydrophobic cavity of PDE6δ, forming a similar hydrophobic interaction pattern as that mediated by the farnesyl moiety of Rheb (Fig. 1A; right)

Summary

Introduction

Reduced polyketides form a well-known group of natural products with a multitude of bioactivities and high structural diversity. This was enabled by either site-directed mutagenesis or by the innate promiscuity of acyltransferase domains.[4] In this context, we described the precursor-directed biosynthesis of the nonnatural shunt product premonensin.[5] In that study, the intrinsic substrate promiscuity of the monensin polyketide synthase (PKS) acyltransferase in module 5 was exploited by supplying small-scale cultures of S. cinnamonensis A495 6 with several malonic acid derivatives bearing different substituents at position 2. We set up crystallization trials using different premonensin derivatives to gain structural insights into the mode of interaction between premonensin and PDE6δ.

Results

Conclusion