Crystal Structures of Human Pyridoxal Kinase in Complex with the Neurotoxins, Ginkgotoxin and Theophylline: Insights into Pyridoxal Kinase Inhibition

Authors

Amit Gandhi, Virginia Commonwealth University
Jigar V. Desai, Virginia Commonwealth University
Mohini S. Ghatge, Virginia Commonwealth University
Martino L. di Salvo, Sapienza Università di Roma
Stefano Di Biase, Sapienza Università di Roma
Richmond Danso-Danquah, Virginia Commonwealth University
Faik N. Musayev, Virginia Commonwealth University
Roberto Contestabile, Sapienza Università di Roma
Verne Schirch, Virginia Commonwealth University
Martin A. Safo, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2012

Journal/Book/Conference Title

PLOS ONE

Volume

7

DOI of Original Publication

10.1371/journal.pone.0040954

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pone.0040954

Date of Submission

November 2014

Abstract

Several drugs and natural compounds are known to be highly neurotoxic, triggering epileptic convulsions or seizures, and causing headaches, agitations, as well as other neuronal symptoms. The neurotoxic effects of some of these compounds, including theophylline and ginkgotoxin, have been traced to their inhibitory activity against human pyridoxal kinase (hPL kinase), resulting in deficiency of the active cofactor form of vitamin B6, pyridoxal 5′-phosphate (PLP). Pyridoxal (PL), an inactive form of vitamin B6 is converted to PLP by PL kinase. PLP is the B6 vitamer required as a cofactor for over 160 enzymatic activities essential in primary and secondary metabolism. We have performed structural and kinetic studies on hPL kinase with several potential inhibitors, including ginkgotoxin and theophylline. The structural studies show ginkgotoxin and theophylline bound at the substrate site, and are involved in similar protein interactions as the natural substrate, PL. Interestingly, the phosphorylated product of ginkgotoxin is also observed bound at the active site. This work provides insights into the molecular basis of hPL kinase inhibition and may provide a working hypothesis to quickly screen or identify neurotoxic drugs as potential hPL kinase inhibitors. Such adverse effects may be prevented by administration of an appropriate form of vitamin B6, or provide clues of how to modify these drugs to help reduce their hPL kinase inhibitory effects.

Rights

Copyright: © 2012 Gandhi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Medicinal Chemistry Publications