title: Crystal structures of human pyridoxal kinase in complex with the neurotoxins, ginkgotoxin and theophylline: insights into pyridoxal kinase inhibition.
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.
authors.affiliation: Department of Medicinal Chemistry, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Gandhi
authors.forename: Jigar V
authors.initials: JV
authors.lastname: Desai
authors.forename: Mohini S
authors.initials: MS
authors.lastname: Ghatge
authors.forename: Martino L
authors.initials: ML
authors.lastname: di Salvo
authors.forename: Stefano
authors.initials: S
authors.lastname: Di Biase
authors.forename: Richmond
authors.initials: R
authors.lastname: Danso-Danquah
authors.forename: Faik N
authors.initials: FN
authors.lastname: Musayev
authors.forename: Roberto
authors.initials: R
authors.lastname: Contestabile
authors.forename: Verne
authors.initials: V
authors.lastname: Schirch
authors.forename: Martin K
authors.initials: MK
authors.lastname: Safo
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009498:Neurotoxins / Q000737:chemistry* / Q000494:pharmacology; D011731:Pyridoxal Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011736:Pyridoxine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013806:Theophylline / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C406624:4'-O-methylpyridoxine; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D013806:Theophylline; D011731:Pyridoxal Kinase; D011736:Pyridoxine