Neurotoxin-induced impairment of biopterin synthesis and function: Initial stage of a Parkinson-like dopamine deficiency syndrome.

摘要: Disorders of the function tyrosine hydroxylase play an important role in occurrence Parkinson syndrome. The enzyme that catalyses first, rate-limiting step biosynthesis to dopamine requires cofactor tetrahydrobiopterin. This compound supplies reduction equivalent for activation molecular oxygen. Binding is affected by phosphorylation or dephosphorylation protein and, thereby, influences activity. Nerve and chromaffin cells synthesize dopamine, noradrenaline serotonin are able tetrahydrobiopterin de novo from guanosine-triphosphate as a precursor. In patients suffering Parkinson's disease remarkable decrease biopterin content was found brain. dopaminergic system studied with experimental model. antimetabolite 6-aminonicotinamide induces deficit striatum significant slowdown utilization this transmitter. abolition 6-aminonicotinamide-induced muscular rigidity l-DOPA agonists implies produces Parkinson-like syndrome rats. There reports on basis effect which also understanding possible disturbances synthesis biopterins. effector 6-aminonicotinamide-adenine-dinucleotide-phosphate (6-ANADP), blocks pentose phosphate pathway, formed enzymatic neurotoxic synthesis. clonal cell line PC-12 used study occurring system. These contain all enzymes catecholamine synthesis, including those Addition culture medium resulted agent, 6-ANADP, glycohydrolase localized endoplasmic reticulum. depressed after application 6-aminonicotinamide. intracellular total reduced DOPA production. decreased compensated addition precursor sepiapterin, indicating NADPH-dependent reductases were not inhibited antimetabolic nucleotide 6-ANADP. production fully normalized sepiapterin. NADH further increase production, probably recycling pathway. first GTP 7,8-neopterin-triphosphate seems be particularly sensitive action exogenous neurotoxins. A site BH(4) concerns dihydropteridin-reductase, recycles qBH(2) BH(4). Neurotoxin-induced impairment pathogenetically disorder at initial stage disease.