Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopamine (100 microM, 10-30 min) inhibits/inactivates the MgATP-dependent generation of a transmembrane proton electrochemical gradient in chromaffin granule ghosts. The dopamine dependent inhibition was enhanced by adding soluble dopamine beta-monooxygenase (DBM, 0.2 U/ml) and completely prevented by ascorbate (1 mM), dithiothreitol (2 mM) and approximately 80% by the DBM inhibitor fusaric acid (10 microM). This indicates that the inhibition is caused by the dopamine semiquinone free radical generated during DBM-dependent dopamine oxidation. Catalase, superoxide dismutase or both did not prevent the inhibition, and DBM-catalysed dopamine oxidation did not change the basal level of lipid peroxidation, excluding the involvement of reactive oxygen species as being responsible for the inhibition. N-ethylmaleimide-sensitive ATPase activity (i.e. the proton translocating ATPase) in the vesicle membranes was inhibited during dopamine incubation, indicating that the toxic metabolite (dopamine semiquinone) inhibits proton pumping by inhibiting the endogenous vacuolar H(+)-ATPase. As this proton pump represents the driving force for the vesicular uptake and storage of catecholamines, the dopamine dependent inhibition, if taking place in vivo, may inhibit dopamine uptake in storage vesicles in sympathetic neurons, e.g. as observed in the myopathic hamster heart.
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PMID:Dopamine oxidation generates an oxidative stress mediated by dopamine semiquinone and unrelated to reactive oxygen species. 922 Mar 58

A new compound, 1-(2-methyl-4-methoxyphenyl)-4-[(3-hydroxypropyl)amino]-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (DBM-819), inhibited gastric H(+)/K(+) ATPase in the rabbit (EC 3.6.1.3) with an IC(50) value of 5 microM. However, DBM-819 was a weak inhibitor of kidney Na(+)/K(+) ATPase in the dog, indicating that it has selectivity for the gastric H(+)/K(+) ATPase. The inhibition was reversible and non-competitive with respect to the activating cation K(+). The presence of dithiothreitol did not protect the H(+)/K(+) ATPase from inactivation. The inhibition by DBM-819 was potentiated by acid pretreatment of the compound, suggesting that DBM-819 is converted into a more active intermediate under acidic conditions. The results suggest that DBM-819 is a potent, selective and reversible inhibitor of gastric H(+)/K(+) ATPase, and that the essential cysteine residue may not be involved in the DBM-819-mediated inactivation of gastric H(+)/K(+) ATPase.
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PMID:Biochemical properties of a newly synthesized H(+)/K(+) ATPase inhibitor, 1-(2-methyl-4-methoxyphenyl)-4-. 1113 74

The metabolism of 1-(2-methyl-4-methoxyphenyl)-4-[(3-hydroxypropyl)amino]-6-methyl-2,3-dihydropyrrolo[3,2c]quinoline (DBM-819), a new H(+)/K(+) ATPase inhibitor, has been studied by HPLC with spectrometric detection and on-line LC-electrospray mass spectrometry. In vitro incubation of DBM-819 with rat liver microsomes in the presence of NADPH resulted in the production of four metabolites (M1-4), whereas DBM-819 was oxidized to two metabolites, M2 and M4, by human liver microsomes. M2, M3 and M4 were identified as O-demethyl-DBM-819, 8-hydroxy-DBM-819 and N-dehydroxypropyl-DBM-819, respectively, based on LC/MS/MS analysis with authentic standards. M1 was tentatively identified as 1-(hydroxy-2-methyl-4-methoxyphenyl)-4-[(3-hydroxypropyl)amino]-6-methyl-2,3-dihydropyrrolo[3,2c]quinoline. Rat liver CYP1A1/2 catalyzed the oxidation of DBM-819 to 8-hydroxy-DBM-819 and N-dehydroxypropyl-DBM-819. Human CYP3A4 was a major isozyme for the formation of O-demethyl-DBM-819 as well as N-dehydroxypropyl-DBM-819.
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PMID:In vitro metabolism of a new H(+)/K(+) ATPase inhibitor DBM-819 in liver microsomes using HPLC and electrospray mass spectrometry. 1174 83

Cuproproteins such as PHM and DBM mature in late endosomal vesicles of the mammalian secretory pathway where changes in vesicle pH are employed for sorting and post-translational processing. Colocation with the P1B-type ATPase ATP7A suggests that the latter is the source of copper and supports a mechanism where selectivity in metal transfer is achieved by spatial colocation of partner proteins in their specific organelles or vesicles. In previous work we have suggested that a lumenal loop sequence located between trans-membrane helices TM1 and TM2 of the ATPase, and containing five histidines and four methionines, acts as an organelle-specific chaperone for metallation of the cuproproteins. The hypothesis posits that the pH of the vesicle regulates copper ligation and loop conformation via a mechanism which involves His to Met ligand switching induced by histidine protonation. Here we report the effect of pH on the HM loop copper coordination using X-ray absorption spectroscopy (XAS), and show via selenium substitution of the Met residues that the HM loop undergoes similar conformational switching to that found earlier for its partner PHM. We hypothesize that in the absence of specific chaperones, HM motifs provide a template for building a flexible, pH-sensitive transfer site whose structure and function can be regulated to accommodate the different active site structural elements and pH environments of its partner proteins.
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PMID:pH-regulated metal-ligand switching in the HM loop of ATP7A: a new paradigm for metal transfer chemistry. 2724 96