title: Neurotoxin-induced impairment of biopterin synthesis and function: Initial stage of a Parkinson-like dopamine deficiency syndrome.
abstract: Disorders of the function of the tyrosine hydroxylase play an important role in the occurrence of the Parkinson syndrome. The enzyme that catalyses the first, rate-limiting step in the biosynthesis to dopamine requires the cofactor tetrahydrobiopterin. This compound supplies the reduction equivalent for activation of molecular oxygen. Binding of the cofactor to the enzyme is affected by phosphorylation or dephosphorylation of the enzyme protein and, thereby, influences the activity. Nerve and chromaffin cells that synthesize dopamine, noradrenaline and serotonin are able to synthesize the cofactor tetrahydrobiopterin de novo from guanosine-triphosphate as a precursor. In patients suffering from Parkinson's disease a remarkable decrease in biopterin content was found in the brain. The function of the dopaminergic system was studied with an experimental Parkinson model. The antimetabolite 6-aminonicotinamide induces a dopamine deficit in the striatum with a significant slowdown in the utilization of this transmitter. The abolition of the 6-aminonicotinamide-induced muscular rigidity by l-DOPA and dopamine agonists implies that the antimetabolite produces a Parkinson-like syndrome in rats. There are reports on the molecular basis of this effect which are also important for understanding possible disturbances of the synthesis of biopterins. The effector 6-aminonicotinamide-adenine-dinucleotide-phosphate (6-ANADP), which blocks the pentose phosphate pathway, is formed by an enzymatic neurotoxic synthesis. The clonal cell line PC-12 was used to study the molecular basis of the disturbances occurring in the dopaminergic system. These cells contain all the enzymes for catecholamine synthesis, including those for the synthesis of the cofactor tetrahydrobiopterin. Addition of 6-aminonicotinamide to the culture medium resulted in the synthesis of the neurotoxic agent, 6-ANADP, by a glycohydrolase localized in the endoplasmic reticulum. The synthesis of biopterin was depressed after application of 6-aminonicotinamide. The decrease of intracellular tetrahydrobiopterin and total biopterin resulted in reduced DOPA production. The decreased content of biopterin cofactor synthesis was compensated for by the addition of the precursor sepiapterin, indicating that the NADPH-dependent reductases in biopterin synthesis were not inhibited by the antimetabolic nucleotide 6-ANADP. DOPA production was not fully normalized by sepiapterin. Addition of NADH to the medium resulted in a further increase of DOPA production, probably by activation of the recycling pathway. The first step in the synthesis of biopterin from GTP to 7,8-neopterin-triphosphate seems to be particularly sensitive to the action of exogenous neurotoxins. A further sensitive site of action in synthesis to the cofactor BH(4) concerns the function of the dihydropteridin-reductase, which recycles qBH(2) to BH(4). Neurotoxin-induced impairment of biopterin synthesis is probably a pathogenetically important disorder at the initial stage of Parkinson's disease.
authors.affiliation: Institut für Pharmakologie, Freie Universität Berlin, Thielallee 69/73, D-1000 Berlin 33, F.R.G.
authors.forename: H
authors.initials: H
authors.lastname: Herken