Dramatic Species Differences in the Susceptibility of Monoamine Oxidase B to a Group of Powerful Inhibitors

Krueger, Matthew J.; Mazouz, Fathi; Ramsay, Rona R.; Milcent, René; Singer, Thomas P.

doi:10.1006/bbrc.1995.1079

Cited by 50 publications

(26 citation statements)

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“…There can be dramatic differences among species in the susceptibility of their mitochondrial enzymes to inhibition (Krueger et al 1995). If these differences also occur as variations among geographically separated congeners or conspecifics, then this would be an important topic for future study, for it would provide a biochemical test of Thompson's (2005) geographic mosaic of selection hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Papyriferic Acid, An Antifeedant Triterpene From Birch Trees, Inhibits Succinate Dehydrogenase From Liver Mitochondria

et al. 2009

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Papyriferic acid (PA) is a triterpene that is secreted by glands on twigs of the juvenile ontogenetic phase of resin producing tree birches (e.g., Betula neoalaskana, B. pendula) and that deters browsing by mammals such as the snowshoe hare (Lepus americanus). We investigated the pharmacology of PA as a first step in understanding its antifeedant effect. After oral administration to rats, PA and several metabolites were found in feces but not urine, indicating that little was absorbed systemically. Metabolism involved various combinations of hydrolysis of its acetyl and malonyl ester groups, and hydroxylation of the terpene moiety. The presence of a malonyl group suggested a possible interaction with succinate dehydrogenase (SDH), a mitochondrial enzyme known to be competitively inhibited by malonic acid. The effect of PA on the oxidation of succinate by SDH was examined in mitochondrial preparations from livers of ox, rabbit, and rat. In all three species, PA was a potent inhibitor of SDH. Kinetic analysis indicated that, unlike malonate, PA acted by an uncompetitive mechanism, meaning that it binds to the enzyme-substrate complex. The hydrolysis product of PA, betulafolienetriol oxide, was inactive on SDH. Overall, the evidence suggests that PA acts as the intact molecule and interacts at a site other than the succinate binding site, possibly binding to the ubiquinone sites on complex II. Papyriferic acid was potent (K(iEIS) ranged from 25 to 45 microM in the three species) and selective, as malate dehydrogenase was unaffected. Although rigorous proof will require further experiments, we have a plausible mechanism for the antifeedant effect of PA: inhibition of SDH in gastrointestinal cells decreases mitochondrial energy production resulting in a noxious stimulus, 5-HT release, and sensations of nausea and discomfort. There is evidence that the co-evolution of birches and hares over a large and geographically-diverse area in Northern Europe and America has produced marked differences in the formation of PA by birches, and the tolerance of hares to dietary PA. The present findings on the metabolic fate and biochemical effects of PA provide a rational basis for investigating the mechanisms underlying differences among populations of hares in their tolerance of a PA-rich diet.

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Section: Discussionmentioning

confidence: 99%

Papyriferic Acid, An Antifeedant Triterpene From Birch Trees, Inhibits Succinate Dehydrogenase From Liver Mitochondria

et al. 2009

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“…In fact, we have previously found that the same amino acid substitutions made on human MAO, A-F208I and B-I199F, did not result in a change in specificities (21), as was observed in rats. Several reports indicate the existence of large differences in specificities among MAOs of the same subtype but from different mam- malian species (27)(28)(29)(30). Some oxadiazolone compounds have inhibitory potencies that vary four orders of magnitude between rat and bovine MAO B (28), whereas some antidepressant drugs show a B over A specificity in mouse and rat MAOs and the reverse specificity in rat and monkey MAOs (29).…”

Section: Discussionmentioning

confidence: 99%

Substrate and Inhibitor Specificities for Human Monoamine Oxidase A and B Are Influenced by a Single Amino Acid

Geha

Rebrin

Chen

et al. 2001

Journal of Biological Chemistry

156

106

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Monoamine oxidase (MAO) is responsible for the oxidation of biogenic and dietary amines. It exists as two isoforms, A and B, which have a 70% amino acid identity and different substrate and inhibitor specificities. This study reports the identification of residues responsible for conferring this specificity in human MAO A and B. Using site-directed mutagenesis we reciprocally interchanged three pairs of corresponding nonconserved amino acids within the central portion of human MAO. Mutant MAO A-I335Y became like MAO B, which exhibits a higher preference for ␤-phenylethylamine than for the MAO A preferred substrate serotonin (5-hydroxytryptamine), and became more sensitive to deprenyl (MAO B-specific inhibitor) than to clorgyline (MAO A-specific inhibitor). The reciprocal mutant MAO B-Y326I exhibited an increased preference for 5-hydroxytryptamine, a decreased preference for ␤-phenylethylamine, and, similar to MAO A, was more sensitive to clorgyline than to deprenyl. These mutants also Monoamine oxidase (MAO 1 ; amine:oxygen oxidoreductase (deaminating) (flavin-containing), EC 1.4.3.4) catalyzes the oxidative deamination of biogenic and xenobiotic amines and plays an important role in regulating their levels. MAO is a flavin-adenine dinucleotide-containing enzyme located on the mitochondrial outer membrane (1-3). It exists in two forms, A and B. MAO A preferentially oxidizes serotonin (5-hydroxytryptamine, 5-HT) and is inhibited by low concentrations of clorgyline (4) and Ro 41-1049 (5), whereas MAO B preferentially oxidizes ␤-phenylethylamine (PEA) and is inhibited by low concentrations of (Ϫ)-deprenyl (6) and Ro 16 -6491 (7). Dopamine is a common substrate (8). MAO A and B are composed of 527 and 520 amino acids, respectively, and have a 70% amino acid identity (9). They are closely linked on the X-chromosome (10) and have an identical intron-exon organization, indicating that they are derived from a common ancestral gene (11). Higher 5-HT and norepinephrine levels and a phenotype characterized by increased aggressive behavior is observed when the MAO A gene is deficient in humans (12) and in mice (13). Disruption of the MAO B gene in mice results in increased PEA but not 5-HT, norepinephrine, or dopmanie and confers a resistance to the Parkinsonism-inducing toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (14). Because MAO is an integral membrane protein, it is difficult to crystallize, and its three-dimensional structure has not been reported.To determine the region(s) responsible for the substrate and inhibitor specificities of the two isoenzymes, we and other groups have made point mutations and chimeric MAO A/B enzymes (15-21). It has been shown that reciprocally interchanging amino acids Phe-208 in MAO A and its corresponding residue in MAO B, Ile-199, was sufficient to partially reverse the substrate and inhibitor specificities of rat MAOs (22) but not human MAOs (21). This indicated that different amino acid residues may determine specificity in human and rat MAOs. We also found that the residues that...

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“…Fig. 3 shows that CSC potently and competitively inhibits MAO-B activity in a mitochondrial preparation from mouse brain with a K i value of ϳ100 nM, a value comparable with that of the most potent known competitive MAO-B inhibitors (20). In contrast to MAO-B, MAO-A (from human placenta) was not significantly inhibited by CSC.…”

Section: Mppmentioning

confidence: 73%

8-(3-Chlorostyryl)caffeine May Attenuate MPTP Neurotoxicity through Dual Actions of Monoamine Oxidase Inhibition and A2A Receptor Antagonism

Chen

Steyn²,

Staal³

et al. 2002

Journal of Biological Chemistry

108

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The neurodegeneration of Parkinson's disease (PD) 1 targets dopaminergic neurons that project to the striatum (1). In PD the progressive loss of striatal dopamine leads to a progressive deterioration in motor function. Despite the availability of dopamine-replacement strategies that generally offer considerable symptomatic relief early in the disease, as yet no therapy has been shown to slow the underlying neurodegenerative process.Adenosine A 2A receptor antagonists recently have attracted attention as potential neuroprotective agents because of a remarkable convergence of epidemiological and laboratory data that link the A 2A receptor to the development of PD (2). Prospective studies of several large populations have shown that caffeine consumption is associated with a reduced risk of developing PD (3,4). The risk of PD decreased with increasing prior intake of coffee or of caffeine from other sources and was independent of smoking status or other potential confounding factors. Notably, consumption of decaffeinated coffee was not related to PD risk (4).The possibility that the reduced risk of PD among caffeine consumers is due to a neuroprotective effect of caffeine has been supported by our finding that caffeine can reduce dopaminergic neuron toxicity in a mouse model of PD (5). Low doses of caffeine can attenuate the loss of striatal dopamine and of dopamine transporter (DAT) binding sites induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The neuroprotection by caffeine, a nonspecific adenosine receptor antagonist (6), could be mimicked by relatively specific adenosine A 2A receptor antagonists but not an A 1 antagonist (5, 7). A 2A receptor knockout mice also were resistant to MPTP-induced depletion of striatal dopamine. Together these laboratory data have suggested a potential neurobiological basis for the inverse association between caffeine use and PD.Here we examine the neuroprotective properties of 8-(3-chlorostyryl)caffeine (CSC), a selective and potent A 2A antagonist closely related to caffeine (8) in the MPTP model of PD (9). Because the neurotoxicity of MPTP requires its oxidation to the active toxin, the 1-methyl-4-phenylpyridinium (MPP ϩ ) species, by monoamine oxidase B (MAO-B), we investigated the effects of CSC on MPTP metabolism in vivo and on MAO activity in vitro. The results of these studies offer new insight into structure-activity relationships for MAO-B inhibitors and suggest a

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Dramatic Species Differences in the Susceptibility of Monoamine Oxidase B to a Group of Powerful Inhibitors

Cited by 50 publications

References 0 publications

Papyriferic Acid, An Antifeedant Triterpene From Birch Trees, Inhibits Succinate Dehydrogenase From Liver Mitochondria

Papyriferic Acid, An Antifeedant Triterpene From Birch Trees, Inhibits Succinate Dehydrogenase From Liver Mitochondria

Substrate and Inhibitor Specificities for Human Monoamine Oxidase A and B Are Influenced by a Single Amino Acid

8-(3-Chlorostyryl)caffeine May Attenuate MPTP Neurotoxicity through Dual Actions of Monoamine Oxidase Inhibition and A2A Receptor Antagonism

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