Crystallization and preliminary crystallographic analysis of rat monoamine oxidase A complexed with clorgyline

Ma, Jiangfeng; Kubota, Fumie; Yoshimura, Masato; Yamashita, Eiki; Nakagawa, Atsushi; Ito, Akio; Tsukihara, Tomitake

doi:10.1107/s0907444903025770

Cited by 11 publications

(11 citation statements)

References 5 publications

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“…The application of recent technological developments in polynucleotide technology and the availability of the crystal structure for MAO-B [173], with the promise that the structure for MAO-A should soon be available from at least one source [174], have allowed some major advances, but there remain several grey areas about the regulation and functions of the enzymes. There will be a lot of fun, and probably some startling new discoveries, in the MAO field for many years to come.…”

Section: Resultsmentioning

confidence: 99%

Monoamine Oxidases: Certainties and Uncertainties

Tipton

Boyce²,

O'Sullivan³

et al. 2004

Current Medicinal Chemistry

179

117

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A great deal has been learned about the behaviour of monoamine oxidase in the 75 years since it was first discovered, but there is still a great deal left to understand. This review concentrates on the dynamic aspects of our knowledge of the interactions of MAO with substrates and inhibitors and how it may collaborate with other enzymes, with particular emphasis on aspects that remain to be clarified.

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Section: Resultsmentioning

confidence: 99%

Monoamine Oxidases: Certainties and Uncertainties

Tipton

Boyce²,

O'Sullivan³

et al. 2004

Current Medicinal Chemistry

179

117

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“…This behavior is consistent with available structural data showing the monopartite active site cavities of the two enzymes being quite similar. 8,26 …”

Section: Discussionmentioning

confidence: 99%

²H Kinetic Isotope Effects and pH Dependence of Catalysis as Mechanistic Probes of Rat Monoamine Oxidase A: Comparisons with the Human Enzyme

Wang

Edmondson

2011

Biochemistry

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Monoamine oxidase A (MAO A) is a mitochondrial outer membrane-bound flavoenzyme important in the regulation of serotonin and dopamine levels. Since the rat is extensively used as an animal model in drug studies, it is important to understand how rat MAO A behaves in comparison with the more extensively studied human enzyme. For many reversible inhibitors, rat MAO A exhibits Ki values similar to those of human MAO A. The pH profile of kcat for rat MAO A shows a pKa of 8.2±0.1 for the benzylamine ES complex and pKa values of 7.5±0.1 and 7.6±0.1 for the respective ES complexes with p-CF3-1H and p-CF3-2H-benzylamine. In contrast to the human enzyme, the rat enzyme exhibits a single pKa value (8.3±0.1) with kcat/Km benzylamine vs. pH and pKa values of 7.8±0.1 and 8.1±0.2 are found for the ascending limbs, respectively, of kcat/Km vs. pH profiles for p-CF3-1H and p-CF3-2H-benzylamine and 9.3±0.1 and 9.1±0.2 for their respective descending limbs. The oxidation of para-substituted benzylamine substrate analogues by rat MAO A exhibit large deuterium kinetic isotope effects on kcat and on kcat/Km. These effects are pH-independent, and range from 7 to 14, demonstrating a rate-limiting α-C-H bond cleavage step in catalysis. Quantitative structure-activity correlations of log kcat with the electronic substituent parameter (σ) at pH 7.5 and at 9.0 show a dominant contribution with positive ρ values (+1.2 – 1.3) and a pH-independent negative contribution from the steric term. Quantitative structure-activity relationship analysis of the binding affinities of the para-substituted benzylamine analogues to rat MAO A show an increased van der Waals volumes (Vw) increases the affinity of the deprotonated amine for the enzyme. These results demonstrate that rat MAO A exhibits similar but not identical functional properties with the human enzyme and provide additional support for C-H bond cleavage via a polar nucleophilic mechanism.

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“…Although MAO‐A and its isoform MAO‐B have 70% amino acid identity, MAO‐A has a 500‐fold lower IC 50 for clorgyline than MAO‐B (Geha et al, 2001). In addition, both site‐directed mutagenesis and comparison of the crystal structures of MAO‐A and MAO‐B complexed with their inhibitors showed that a single amino acid in these two isoforms determines their substrate and inhibitor specificities (Geha et al, 2001; Ma et al, 2004). However, clorgyline also has other activities unrelated to inhibition of MAO‐A.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells

et al. 2008

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Monoamine oxidase A (MAO-A) expression is associated with high-grade prostate cancer. Immunohistochemistry showed that MAO-A is also expressed in the basal epithelial cells of normal prostate glands. Using cultured primary prostatic epithelial cells as a model, we showed that MAO-A prevents basal epithelial cells from differentiating into secretory cells. Under differentiationpromoting conditions, clorgyline, an irreversible MAO-A inhibitor, induced secretory cell-like morphology and repressed expression of cytokeratin 14, a basal cell marker. More importantly, clorgyline induced mRNA and protein expression of androgen receptor (AR), a hallmark of secretory epithelial cells. In clorgyline-treated cells, androgen induced luciferase activity controlled by the promoter of prostate-specific antigen, an AR target gene, in a dose-dependent manner. This activity was blocked by the AR antagonist Casodex, showing that AR is functional. In turn, androgen decreased MAO-A expression in clorgyline-treated, secretory-like cells. Our results demonstrated that cultured basal epithelial cells have the potential to differentiate into secretory cells, and that inhibition of MAO-A is a key factor in promoting this process. Increased expression of MAO-A in high-grade prostate cancer may be an important contributor to its de-differentiated phenotype, raising the possibility that MAO-A inhibition may restore differentiation and reverse the aggressive behavior of high-grade cancer.

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Crystallization and preliminary crystallographic analysis of rat monoamine oxidase A complexed with clorgyline

Cited by 11 publications

References 5 publications

Monoamine Oxidases: Certainties and Uncertainties

Monoamine Oxidases: Certainties and Uncertainties

²H Kinetic Isotope Effects and pH Dependence of Catalysis as Mechanistic Probes of Rat Monoamine Oxidase A: Comparisons with the Human Enzyme

Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells

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Crystallization and preliminary crystallographic analysis of rat monoamine oxidase A complexed with clorgyline

Cited by 11 publications

References 5 publications

Monoamine Oxidases: Certainties and Uncertainties

Monoamine Oxidases: Certainties and Uncertainties

2H Kinetic Isotope Effects and pH Dependence of Catalysis as Mechanistic Probes of Rat Monoamine Oxidase A: Comparisons with the Human Enzyme

Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells

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²H Kinetic Isotope Effects and pH Dependence of Catalysis as Mechanistic Probes of Rat Monoamine Oxidase A: Comparisons with the Human Enzyme