Chemistry Seminar

Discovery of glucose transporter specific ligands

Dr. Jun-Yong Choe
Department of Chemistry
East Carolina University

Abstract

In humans, the transport of glucose and related hexoses (essential molecules for living cells) is facilitated by members of the glucose transporter (GLUT) family, comprised of 14 transporters. Among them, GLUT5 is the only fructose-specific transporter in the family. Its substrate-specificity and tissue-specific expression make it a promising target for treatment of diabetes, metabolic syndrome and cancer, but few GLUT5 inhibitors are known. To identify novel GLUT5 ligands, we adopted two complementary approaches for high-throughput ligand screening. One of them screens in silico multimillion chemical libraries for binding to certain GLUT5 conformations; resulting ligand candidates are then validated in vitro. The other approach seeks to establish a GLUT5 assay system for facile high-throughput inhibitor determination. Usually inhibition of GLUT5 transport is screened or characterized in GLUT5 proteoliposomes and/or human cells. As a time- and cost-efficient alternative to these GLUT5 assay systems, we developed a whole-cell system based on a yeast strain deficient in fructose uptake. In this strain GLUT5 transport activity is associated with cell growth in fructose-based media or assayed by fructose uptake in whole cells. The former method is convenient for high-throughput screening of potential GLUT5 inhibitors and activators, while the latter enables detailed kinetic characterization of identified GLUT5 ligands. So far, we identified 7 GLUT5 inhibitors, including MSNBA which is the most potent and specific GLUT5 inhibitor known. In the process we determined GLUT5 residues that modulate substrate and inhibitor specificity. We aim to harness the molecular basis of ligand specificity into developing better GLUT5 probes and GLUT5-targeting drugs.

Biography

Dr. Choe earned his Ph.D. in Biophysics from Iowa State University, where he worked on the structural basis of fructose- 1,6-bisphosphatase activity and inhibition. He did his postdoc at California Institute of Technology. He was a senior crystallographer at the Structural Genomics Consortium, a joint enterprise between Universities of Toronto and Oxford. He was an assistant physiologist at the University of California, Los Angeles. He moved back to Midwest as faculty at the Chicago Medical School and determined the first 3D crystal structure of a true glucose transporter. His lab research focuses on the structural and functional studies of carbohydrate transporters; their mechanism of transport and inhibition, as well as discovery of new inhibitors that may lead to new drugs for diabetes, cancer and other metabolic diseases. This fall he moved to East Carolina University as joint member of the Department of Chemistry and East Carolina Diabetes & Obesity Institute

Friday, October 19, 2018 at 3:00 pm

Chemical Sciences and Engineering Building, Room 101
1400 Townsend Drive, Houghton, MI 49931

Event Type

Academics, Lectures/Seminars

Target Audience

Students, Faculty/Staff, Alumni/Friends

Department
Chemistry
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