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.
Highlights
Some well known drugs that are directed at different targets have been shown to inhibit human pyridoxal kinase activity with a concomitant deficiency in pyridoxal 59-phosphate (PLP) causing unwanted neurotoxic side effects, such as peripheral neuropathy, unconsciousness, convulsions or seizures, sleeplessness, headache, restlessness, agitation, tremors, and hallucination [1,2,3,4,5,6,7]
Several medicinal compounds are known to exhibit neurotoxic effects, which have been traced to their inhibitory activity against human PL kinase with concomitant PLP deficiency [1,2,3,4,5,6,7]
To gain insight into how these compounds affect vitamin B6 metabolism and the concomitant PLP deficiency, we performed structural studies of hPL kinase cocrystallized with these compounds
Summary
Some well known drugs that are directed at different targets have been shown to inhibit human pyridoxal kinase (hPL kinase) activity with a concomitant deficiency in pyridoxal 59-phosphate (PLP) causing unwanted neurotoxic side effects, such as peripheral neuropathy, unconsciousness, convulsions or seizures, sleeplessness, headache, restlessness, agitation, tremors, and hallucination [1,2,3,4,5,6,7]. A decrease in GABA level, induced by antivitamin B6 agents, is known to be accompanied by epileptic seizures [9]. Several of these agents, such as progabide, theophylline, and ginkgotoxin are potent hPL kinase inhibitors [1,2,3,4,5,10,11,12,13,14,15,16,17,18,19,20,21], resulting in PLP deficiency with a concomitant reduction in PLPdependent enzyme activities, such as that of glutamate decarboxylase, which catalyzes formation of GABA from L-glutamate. It has long been recognized that co-administration of pyridoxine, the primary dietary form of vitamin B6 together with these hPL kinase inhibitors reduce or prevent their associated neurotoxic side effects [5,17,22,23]
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