Mechanism-based inactivation of monoamine oxidases A and B by tetrahydropyridines and dihydropyridines

Krueger, Matthew J.; McKeown, Kathleen A.; Ramsay, Rona R.; Youngster, Stephen K.; Singer, Thomas P.

doi:10.1042/bj2680219

Cited by 21 publications

(10 citation statements)

References 17 publications

(45 reference statements)

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“…Similar results were obtained using 4'-alkyl-MPP ÷ analogs to protect NADH dehydrogenase from inhibition by and binding of rotenone [48,49]. A logical extension of these studies, now in progress in our laboratory, will be the identification of the peptide involved in binding these inhibitors, using photoaffinity labeling with 4'-azido-3[H]MPP ÷ .…”

Section: Identification Of the Binding Site On Nadh Dehydrogenasesupporting

confidence: 56%

“…All but the nheptyl and n-decyl analog nevertheless dissociate on dilution, so that they may be completely removed by centrifugation and washing of submitochondrial particles, with resultant recovery of the activity, whereas piericidin A remains firmly (but non-covalently) bound at the specific site during such treatment, and rotenone dissociates only partly during several cycles of centrifugation and resuspension in sucrose-serum albumin. This difference in the dissociation of the enzymeinhibitor complexes permitted the demonstration that MPP ÷ analogs prevent the binding of rotenone and of piericidin A to NADH dehydrogenase and thus protect the enzyme from their powerful inhibitory effect [48,49]. Fig.…”

Section: Identification Of the Binding Site On Nadh Dehydrogenasementioning

confidence: 98%

“…Early studies [8] indicated that the rate of inactivation of MAO B by MPTP and MPDP ÷ were identical, suggesting that processing of the latter compound was responsible for the irreversible loss of activity. Recent studies [26], using a rapid scan spectrophotometer and a multicomponent analysis program, confirmed that the mechanism-based inactivation of MAO B by the dihydropyridinium is faster than inactivation by the tetrahydropyridinium for MPTP and several analogs, whereas the reverse is true of MAO A, which processes MPDP ÷ and its analogs poorly. Ottoboni et al [27] also came to the conclusion that the mechanism-based inactivation of MAO B in the course of MPTP oxidation is primarily due to the second 2-e oxidation.…”

Section: Contributions To the Biochemistry Of Monoamine Oxidasesmentioning

confidence: 99%

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Mechanism of the neurotoxicity of MPTP

1990

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This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1-methyl-4-phenyl-l-l,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP + (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the Z-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP + and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP + and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP ÷, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.Monoamine oxidase; MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine); Neurotoxin; NADH dehydrogenase

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Section: Identification Of the Binding Site On Nadh Dehydrogenasesupporting

confidence: 56%

Section: Identification Of the Binding Site On Nadh Dehydrogenasementioning

confidence: 98%

Section: Contributions To the Biochemistry Of Monoamine Oxidasesmentioning

confidence: 99%

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Mechanism of the neurotoxicity of MPTP

1990

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“…Second, the extracellular levels of MPDP+ remained quite stable throughout the 4 days of incubation of astrocytes in the presence of MPTP. Previous studies have shown that at relatively low concentrations of MPDP+ M) non-enzymic oxidation to MPP+ occurs, while disproportionation of MPDP+ to MPTP and MPP+ is negligible (Krueger et al, 1990;Singer et al, 1986). Extracellular concentrations of MPDP+ in astrocyte cultures exposed to MPTP were in the lop6 M range; therefore, the lack of accumulation of the unstable molecule of MPDP+ in the culture medium is likely to be due to its autoxidation, which forms MPP+.…”

Section: Discussionmentioning

confidence: 99%

Production and disposition of 1‐methyl‐4‐phenylpyridinium in primary cultures of mouse astrocytes

Monte

Irwin

et al. 1992

Glia

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Dopaminergic neurons are a primary target for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. However, the conversion of MPTP to its neurotoxic 1-methyl-4-phenylpyridinium metabolite (MPP+) is likely to occur in astrocytes via the monoamine oxidase (MAO)-dependent formation of the 1-methyl-4-phenyl-2,3-dihydropyridinium intermediate (MPDP+). The main purpose of this study was to characterize the molecular mechanism(s) by which MPP+, once generated by astrocytes, may reach the extracellular space to become available for the active accumulation into dopaminergic neurons. Primary cultures of mouse astrocytes were used as an in vitro model system. After the addition of MPTP, levels of MPP+ were found to increase at constant rates both intracellularly and extracellularly at time points when no sign of cytotoxicity was evident. In contrast, MPDP+ levels remained quite stable during 4 days of incubation in the presence of MPTP. Finally, when astrocytes were allowed to accumulate MPP+ by pretreatment with either MPTP or MPP+ and then were incubated in fresh medium not containing MPTP or MPP+, intracellular levels of MPP+ rapidly declined and corresponding amounts of this compound were found in the incubation medium. Results of this study are compatible with the following conclusions: 1) the MPP+ accumulated in the extracellular compartment during incubations with MPTP is not released from astrocytes as a consequence of its own cytotoxic effects; 2) MPP+ can be formed extracellularly presumably via autoxidation of MPDP+ after this latter compound has been generated within astrocytes and has crossed astrocyte membranes; and 3) despite its charged chemical structure, MPP+ can cross the plasma membrane toward the extracellular space after being formed within astrocytes.

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“…The metabolism of MPTP by MAO also proved interesting at the molecular level. Not only were there two oxidative steps in the process, first to MPDP + and then to MPP + , but the intermediates in the reaction could inactivate the enzyme [99][100][101].…”

Section: Mao Is a Metabolic Enzymementioning

confidence: 99%

Monoamine Oxidases: The Biochemistry of the Proteins As Targets in Medicinal Chemistry and Drug Discovery

Ramsay

2012

Current Topics in Medicinal Chemistry

101

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Monoamine oxidase (MAO, EC.1.4.3.4) has been a drug target for 60 years, with the primary rationale of developing drugs to treat neuropsychiatric disorders. The biological importance of MAO is to regulate amine levels is the brain and to metabolize amines and drugs in the periphery. This review of the biochemistry of MAO A and MAO B describes the functional properties of the two enzymes integrated with knowledge of the structures of the many MAOinhibitor complexes published in the last 10 years. The analysis of activity, and the chemical and kinetic mechanisms are discussed. Inhibition studies on human MAO in vitro are now facilitated by assays using readily available materials but the kinetics of MAO involving alternative oxidative pathways and sensitivity to the oxygen concentration mean that careful analysis of the data is required as well as the good practice of determining mechanism of inhibition and kinetic constants. Kinetic constants can then be compared with thermodynamic calculations. Inhibitors bind to both the oxidized and reduced forms of MAO present during turnover so both forms should be considered when using molecular dynamics to facilitate drug design. Interaction of inhibitors with the active site can be detected as changes in the visible spectrum and these changes can provide clues about the flavin adduct formed for irreversible inhibitors or about the proximity to the flavin for reversible inhibitors. Developing areas (knock-out mice for behavior, the imidazoline binding site, and imaging to monitor the activity and the inhibition of MAO in the patient) are mentioned.

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Mechanism-based inactivation of monoamine oxidases A and B by tetrahydropyridines and dihydropyridines

Cited by 21 publications

References 17 publications

Mechanism of the neurotoxicity of MPTP

Mechanism of the neurotoxicity of MPTP

Production and disposition of 1‐methyl‐4‐phenylpyridinium in primary cultures of mouse astrocytes

Monoamine Oxidases: The Biochemistry of the Proteins As Targets in Medicinal Chemistry and Drug Discovery

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