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

N-Methylated beta-carbolinium compounds (N-Me-BCs), including 2-N-methyl and 2,9-N,N-dimethyl analogs, structural analogs of 1-methyl-4-phenylpyridinium (MPP+), may be endogenously bioactivated, MPP(+)-like toxins, capable of inducing parkinsonism. Both MPP+ and selected N-Me-BCs inhibit NADH-linked mitochondrial respiration (Complex I). We now show that both also inhibit succinate-supported (Complex II) respiration, the greatest inhibition (80%) being seen for 2,9-dimethylharmanium. Complex I inhibition occurs at MPP+ concentrations (IC50 = 0.17 mM) about one order of magnitude lower than Complex II inhibition (greater than 1.2 mM). In contrast, Complex I and Complex II inhibition by the N-Me-BCs tested occurred at similar concentrations (I, 0.1 mM; II, 0.25 mM) and concentrations similar to Complex I inhibition by MPP+. 2,9-N,N-Dimethyl-BCs, which are the permanently charged BC analogs of MPP+, show inhibitory characteristics similar to MPP+: slow onset of inhibition, potentiation by TPB, and reversal by DNP. The fact that succinate oxidation cannot bypass the Complex II inhibition by N-Me-BCs could enhance any chronic neurotoxicity of N-Me-BCs.
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PMID:Inhibition of mitochondrial succinate oxidation--similarities and differences between N-methylated beta-carbolines and MPP+. 131 43

N-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, kills dopaminergic neurons after its accumulation in mitochondria where it inhibits Complex I of the respiratory chain. MPP+ inhibits respiration by binding to both a hydrophobic and a hydrophilic site on Complex I and this inhibition is increased by the lipophilic tetraphenylboron anion (TPB-) which facilitates movement of MPP+ through membranes and its penetration to the hydrophobic binding site on Complex I. To investigate the inhibition of respiration by MPP(+)-like compounds, we have measured simultaneously NADH-linked mitochondrial respiration and the uptake and accumulation of the N-benzyl-4-styrylpyridinium and N-ethyl-4-styrylpyridinium cations in mitochondria using ion-selective electrodes. The data provide direct evidence that TPB- increases the inhibition not by increasing matrix concentration but by facilitating access to the inhibitory sites on Complex I. We have also compared the rates of uptake of MPP+ analogues of varied lipophilicity by the inner membrane and the development of inhibition of NADH oxidation, using an inverted mitochondrial inner membrane preparation and appropriate ion-selective electrodes. These experiments demonstrated that the amount of MPP+ analogue bound to the inner membrane greatly exceeded the quantity required for complete inhibition of NADH oxidation. Moreover, binding to the membrane occurred much more rapidly than the development of inhibition with all MPP+ analogues tested. This suggests that the attainment of a correct orientation of these compounds within the membrane and the binding site may be a rate-limiting step in the development of inhibition.
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PMID:Inhibition of complex I by hydrophobic analogues of N-methyl-4-phenylpyridinium (MPP+) and the use of an ion-selective electrode to measure their accumulation by mitochondria and electron-transport particles. 788 89

The effect of tetraphenylboron (TPB(?)), an activator of a membrane transport of lipophilic cations, on the inhibition of mouse liver mitochondrial respiration induced by a neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)), and by some structurally related compounds was studied. Of the compounds tested, MPP(+) and 4-phenylpyridine (4-PP) significantly inhibited the respiration in an ADP-activated oxidation of substrates (state 3). TPB(?), dose-dependently, shortened the lag time of MPP(+)-induced inhibition and thus lowered the concentrations of MPP(+) for the inhibition. However, TPB(?), even at the high concentration (10 ?M), did not significantly affect 4-PP-induced inhibition. Carbonyl-cyanide-m-chlorophenylhydrazone (CCCP) blocked the respiratory inhibition by MPP(+), independent of K(+) concentration in the medium, and valinomycin blocked the inhibition only in the medium containing high K(+) concentration. Determination of the intramitochondrial MPP(+) concentration revealed about 1000-fold concentrated MPP(+) from that in the medium during the incubation with TPB(?), indicative of potentiation of MPP(+) transport into mitochondria by TPB(?). This might account for the enhancement of respiratory inhibition by MPP(+). In the case of 4-PP, it will penetrate the mitochondrial membrane and intrinsically inhibit the respiration, but cannot accumulate in mitochondria. The present results indicate that, although the inhibitory potency of MPP(+)per se is similar to 4-PP, MPP(+) will be highly concentrated within mitochondria by the membrane potential, as the drive force for its transport.
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PMID:Enhancement by tetraphenylboron of inhibition of mitochondrial respiration induced by 1-methyl-4-phenylpyridinium ion (MPP(+)). 2050 Dec 61

The effects of the 1-methyl-4-phenylpyridinium ion (MPP(+)) and some structurally related compounds on mitochondrial respiration and lactate production in mouse brain synaptosomes were studied with and without tetraphenylboron (TPB(?)), an activator of membrane transport of lipophilic cations. Without TPB(?), both MPP(+) and 4-phenylpyridine (4-PP), at concentrations of 1 mM, weakly inhibited synaptosomal respiration, but paraquat and 4-phenyl-1,2,3,6-tetrahydropyridine (PTP) did not. In the presence of 10 ?M TPB(?), MPP(+), at lower concentrations, significantly inhibited respiration and increased lactate production, but these two effects with 4-PP were not as great as those with MPP(+). Regardless of TPB(?), paraquat did not affect respiration or lactate production, but PTP, with TPB(?), somewhat accelerated both systems. In these experiments, except PTP, the degree of increase in lactate production caused was in close parallel with that of the inhibition of synaptosomal respiration. The present results conclusively indicate that, without TPB(?), MPP(+) scarcely permeates synaptosomal membranes of mouse whole brain. The present results confirm previous findings that nigrostriatal dopamine neurons, which selectively take up MPP(+) by the DA transport system, may be more selectively damaged by concentrated MPP(+) than other neurons that essentially lack a transport system with poor permeability for MPP(+) through their neuronal membranes.
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PMID:Effect of the tetraphenylboron ion on the inhibition of mitochondrial respiration in synaptosomes by the 1-methyl-4-phenylpyridinium ion (MPP(+)). 2050 3