The strong inhibition of triosephosphate isomerase by the natural beta-carbolines may explain their neurotoxic actions.
The natural beta-carbolines (BC) closely resemble the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in structure. The N-methylated beta-carbolinium ions (BC+) are potent inhibitors of mitochondrial respiration and are nigrostriatal neurotoxins. Utilizing [3H]BC, we have identified several proteins to which BC binds with high affinity (e.g. the chaperone member glucose regulated protein 78, the enzyme carboxylesterase, the cytochrome P450 2E1, the enzyme monoamine oxidase B and a small G-protein of the Rho subfamily). In the present study we isolated a protein from bovine brain to which [3H]BC binds with high affinity and identified it being the enzyme triosephosphate isomerase (TPI; EC 5.3.1.1.). 2,9-Dimethyl-BC+ was the most potent inhibitor of TPI, clearly more potent than the known inhibitors. TPI deficiency is a rare disorder in humans characterized by a severe progressive extrapyramidal course. Thus, TPI inhibition could contribute to neurodegeneration observed after injection of BCs into substantia nigra. Furthermore, the findings fit into the hypothesis of BCs as endogenous toxins responsible for neurodegeneration.
Bonnet
R
R
Section of Clinical Neurobiology, Clinic of Psychiatry and Psychotherapy, Charité, Campus Benjamin Franklin, Free University, Eschenallee 3, 14050 Berlin, Germany.
Pavlovic
S
S
Lehmann
J
J
Rommelspacher
H
H
D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D001923:Brain Chemistry; D002243:Carbolines / Q000633:toxicity*; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005260:Female; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D020267:MPTP Poisoning / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D011869:Radioligand Assay; D013347:Subcellular Fractions / Q000737:chemistry / Q000201:enzymology; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D014316:Tritium
D002243:Carbolines; D009498:Neurotoxins; D014316:Tritium; D014305:Triose-Phosphate Isomerase