Bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: Transition state analogs for high affinity binding

Author:

Shi,Genbin

Shaw,Gary

Zhu, Fengxia

Tarasov,Sergey

Ji,Xinhua
Author Address

Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, MD, USA., Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, MD, USA; School of Chemistry and Chemical Engineering, Huaiyin Normal University, Huaiyin, Jiangsu Province, China(1)., Structural Biophysics Laboratory, National Cancer Institute, Frederick, MD, USA., Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, MD, USA. Electronic address: jix@mail.nih.gov.,

Abstract:

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthesis pathway. It catalyzes pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). HPPK is essential for microorganisms but absent in mammals; therefore, it is an attractive target for developing novel antimicrobial agents. Previously, based on our studies of the structure and mechanism of HPPK, we created first-generation bisubstrate inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed second-generation inhibitors by replacing the phosphate bridge with a linkage that contains a piperidine moiety. Here, we report third-generation inhibitors designed based on the piperidine-containing inhibitor, mimicking the transition state. We synthesized two such inhibitors, characterized their protein-binding and enzyme inhibition properties, and determined their crystal structures in complex with HPPK, advancing the development of such bisubstrate analog inhibitors. Published by Elsevier Ltd.

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