Isatin interaction with glyceraldehyde-3-phosphate dehydrogenase, a putative target of neuroprotective drugs: partial agonism with deprenyl.
There is evidence that the binding of deprenyl, a monoamine oxidase (MAO) B inhibitor, and other propargylamines to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is primarily responsible for their neuroprotective and antiapoptotic effects. Thus, GAPDH may be a target for other neuroprotective drugs. Using two independent approaches, radioligand analysis and an optical biosensor technique, we demonstrate here that GAPDH also interacts with the endogenous, reversible MAO B inhibitor, isatin. Deprenyl inhibited both [3H]isatin binding to GAPDH, and the binding of this enzyme to an isatin analogue, 5-aminoisatin, immobilized on to an optical biosensor cell. Another MAO inhibitor, tranylcypromine, was ineffective. Both deprenyl and isatin inhibited GAPDH-mediated cleavage of E. coli tRNA, and their effects were not additive. We suggest that isatin may be an endogenous partial functional agonist of deprenyl in its effect on GAPDH and GAPDH-mediated RNA cleavage. Changes in level of endogenous isatin may influence the neuroprotective effect of deprenyl in vivo.
Medvedev
A
A
Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia. Alexei.Medvedev@ibmc.msk.ru
Buneeva
O
O
Gnedenko
O
O
Fedchenko
V
V
Medvedeva
M
M
Ivanov
Y
Y
Glover
V
V
Sandler
M
M
D000818:Animals; D015374:Biosensing Techniques / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D007510:Isatin / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009132:Muscles / Q000737:chemistry; D009243:NAD / Q000493:pharmacokinetics; D040081:Protein Array Analysis / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D012642:Selegiline / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
D008996:Monoamine Oxidase Inhibitors; D009243:NAD; D014316:Tritium; D012642:Selegiline; D007510:Isatin; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases