Translational Medicine
Open Access
ISSN: 2161-1025
ISSN: 2161-1025
Genbin Shi
Scientific Tracks Abstracts: Transl Med
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. We have characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer, synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups, and developed a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8-dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their Kd and IC50 values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7- dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl- 7,8-dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure.
Genbin Shi obtained his Ph.D. in 1995 from Chinese Academy of Sciences Shanghai Institute of Materia Medica in Organic Chemistry and Medicinal Chemistry, and received postdoctoral trainings at Michigan State University in Protein Biochemistry and at Vanderbilt University in Cell Biology. He became a Research Assistant Professor at Vanderbilt University before joining the National Cancer Institute as a Research Fellow in 2008.