Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+), the active product of MPTP, caused Parkinson's disease-like symptoms. The mechanism of action of MPP+ is unknown, but analogues of MPTP lacking an N-methyl group were found to be essentially devoid of toxicity, which means that the methyl group of the pyridine ring plays a role in the toxicity. This is of interest because S-adenosylmethionine (SAM), which is the biologic methyl donor and requires a methyl group for its action, also caused MPP(+)-like motor deficits in rodents. Therefore, the requirement of a methyl group by MPTP and MPP+ for their actions suggests that, like SAM, MPP+ and MPTP may serve as methyl donors. This hypothesis was tested by reacting SAM, MPP+, or MPTP with dopamine in the presence of catechol-O-methyltransferase and measuring the methylated product of dopamine produced. Like SAM, MPP+, but not MPTP, methylated dopamine. The methylated product coeluted from chromatographic columns with standard 3-methoxytyramine. Concentrations of 15.6, 62.5, 250, and 1000 nmoles/tube increased the 3-methoxytyramine recovered above controls by 0.0, 6.88, 44.55, 129.47 and 5.8, 13.9, 50.58, 121.31 nmoles for SAM and MPP+, respectively. The dopamine that remained unreacted was dose-dependently decreased. MPTP had no significant effect. The ability of MPP+ to serve as a methyl donor may represent a mechanism for the toxicity of MPP+.
 ...
PMID:1-Methyl-4-phenylpyridinium (MPP+) but not 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) serves as methyl donor for dopamine: a possible mechanism of action. 159 Sep 12

Orally administered Madopar (levodopa/benserazide 4:1) dose-dependently antagonized haloperidol-induced (1 mg/kg s.c.) catalepsy in MPP(+)-lesioned mice. Pretreatment with a new selective catechol-O-methyltransferase (COMT) inhibitor, tolcapone (30 mg/kg p.o.), slightly potentiated the antagonistic effect of Madopar (15 mg/kg p.o.) on haloperidol-induced catalepsy. The ability of tolcapone to increase the Madopar effect was significantly attenuated by high doses of 3-O-methyldopa (3-OMD) (800 mg/kg i.p.). This might suggest a competitive blockade of the active transport of levodopa through the blood-brain barrier. In conclusion, the inhibitory effect of tolcapone on the O-methylation of levodopa to 3-OMD by COMT is largely due to improved levodopa and dopamine availability in the brain, and to the reduced formation of 3-OMD.
 ...
PMID:The COMT inhibitor tolcapone potentiates the anticataleptic effect of Madopar in MPP(+)-lesioned mice. 795 69