Studies towards biosynthesis and combinatorial biosynthesis of ionophoric polyether salinomycin

• Grant number: 11/17510-6
• Support Opportunities: Scholarships abroad - New Frontiers
• Start date: March 01, 2012
• End date: February 24, 2013
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Luciana Gonzaga de Oliveira
• Grantee: Luciana Gonzaga de Oliveira
• Host Investigator: Peter Frances Leadlay
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Cambridge, England
• Associated research grant: 08/00605-1 - Exploring Brazilian biodiversity to obtain 'non-natural' natural products, AP.JP

Abstract

A substantial number of valuable drugs available these days are based upon or inspired in natural products. Among the most useful natural products, polyketides and non-ribosomal peptides share high molecular complexity and therapeutic activity. Though the production of such metabolites is being observed from several organisms as bacteria, fungi, insects, dinoflagellates, mollusks and sponges, culturable actinobacteria are certainly the most prolific and versatile producers.In the case of actinobacteria, the assembly-line enzimology of modular polyketide synthetases (PKSs) and nonribosomal peptides synthetases (NRPSs) are finely established. The genes are arranged in the order in which the encoded multienzymes function in the assembly-line, a feature known as co-linearity. Such characteristic enhances the evolvability of the system, which means that careful modification of the parental gene could result in modifications of the multienzyme function and consequently of the resulting metabolite. The present application intend to understand the molecular mechanisms involved in the biosynthesis of salinomycin a polyketide from ionophoric polyether family that is currently attracting considerable interest due to an unexpected effect on cancer stem cells. Combining the understanding of the biosynthetic mechanisms and the knowledge of the organization of the salinomycin gene cluster allow engineering some pathways in order to get small but significant alterations in the structure affording structural analogues. Therefore, understanding the mechanisms of catalysis and stereochemical control involved in the epoxide formation and opening during the process of salinomycin biosynthesis could underpin and encourage the understanding of the structure-function associated with such interesting target. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LUHAVAYA, HANNA; WILLIAMS, SIMON R.; HONG, HUI; DE OLIVEIRA, LUCIANA GONZAGA; LEADLAY, PETER F.. Site-Specific Modification of the Anticancer and Antituberculosis Polyether Salinomycin by Biosynthetic Engineering. CHEMBIOCHEM, v. 15, n. 14, p. 2081-2085, SEP 22 2014. (11/17510-6)

LUHAVAYA, HANNA; DIAS, MARCIO V. B.; WILLIAMS, SIMON R.; HONG, HUI; DE OLIVEIRA, LUCIANA G.; LEADLAY, PETER F.. Enzymology of Pyran RingA Formation in Salinomycin Biosynthesis. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, v. 54, n. 46, p. 13622-13625, NOV 9 2015. (10/15971-3, 11/17510-6)