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

Geha, Rani Maurice; Rebrin, Igor; Chen, Kevin; Shih, Jean C.

doi:10.1074/jbc.m006972200

Cited by 156 publications

(113 citation statements)

References 26 publications

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“…Thus, Ile-335 in MAOA and Tyr-326 in MAOB play a crucial role in substrate/inhibitor selectivity. These results are consistent with our previous structural analysis of rat MAOA and site-directed mutagenesis studies (7,12). The structure of 1,4-diphenyl-2-butene in MAOB would collide with Phe-208 of MAOA, which corresponds to Ile-199 of MAOB.…”

Section: Structure Of the Substrate/inhibitor Cavity With A Specific supporting

confidence: 82%

Structure of human monoamine oxidase A at 2.2-Å resolution: The control of opening the entry for substrates/inhibitors

Son

Ma²,

Kondou³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

529

461

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The mitochondrial outer membrane-anchored monoamine oxidase (MAO) is a biochemically important flavoenzyme that catalyzes the deamination of biogenic and xenobiotic amines. Its two subtypes, MAOA and MAOB, are linked to several psychiatric disorders and therefore are interesting targets for drug design. To understand the relationship between structure and function of this enzyme, we extended our previous low-resolution rat MAOA structure to the high-resolution wild-type and G110A mutant human MAOA structures at 2.2 and 2.17 Å, respectively. The high-resolution MAOA structures are similar to those of rat MAOA and human MAOB, but different from the known structure of human MAOA [De Colibus L, et al. (2005) Proc Natl Acad Sci USA 102:12684 -12689], specifically regarding residues 108 -118 and 210 -216, which surround the substrate/inhibitor cavity. The results confirm that the inhibitor selectivity of MAOA and MAOB is caused by the structural differences arising from Ile-335 in MAOA vs. Tyr-326 in MAOB. The structures exhibit a C-terminal transmembrane helix with clear electron density, as is also seen in rat MAOA. Mutations on one residue of loop 108 -118, G110, which is far from the active center but close to the membrane surface, cause the solubilized enzyme to undergo a dramatic drop in activity, but have less effect when the enzyme is anchored in the membrane. These results suggest that the flexibility of loop 108 -118, facilitated by anchoring the enzyme into the membrane, is essential for controlling substrate access to the active site. We report on the observation of the structure-function relationship between a transmembrane helical anchor and an extra-membrane domain.single transmembrane helix ͉ transmembrane helical anchor ͉ harmine ͉ x-ray structure M onoamine oxidase (MAO) is an enzyme localized to the mitochondrial outer membrane and catalyzes the deamination of biogenic and xenobiotic amines, such as neuroactive serotonin, norepinephrine, and dopamine. MAO contains a flavin adenine dinucleotide (FAD) covalently bound to a cysteine residue by an 8␣-(S-cysteinyl)-riboflavin linkage (1). MAO plays a decisive role in some psychiatric and neurological disorders, including depression and Parkinson's disease. Because inhibition of MAO increases the level of neurotransmitters in the central nervous system, searching for the effective inhibitors represents one important approach to developing novel drugs to treat such illnesses. MAO has two subtypes, MAOA and MAOB, whose amino acid sequences are up to 70% identical, although each enzyme has unique substrate and inhibitor specificities (2): MAOA oxidizes serotonin, whereas MAOB does not; MAOA is selectively inhibited by clorgyline, whereas MAOB is highly inhibited by deprenyl. In addition, the oxidative deamination produces harmful hydrogen peroxide that may further generate free radicals (3). Development of selective and reversible MAO inhibitors is important not only from the standpoint of treating symptoms (i.e., by increasing the biological half-life of mo...

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Section: Structure Of the Substrate/inhibitor Cavity With A Specific supporting

confidence: 82%

Structure of human monoamine oxidase A at 2.2-Å resolution: The control of opening the entry for substrates/inhibitors

Son

Ma²,

Kondou³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

529

461

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“…A total of 200 g of total protein from cells was incubated with 100 M [ 14 C]serotonin in the assay buffer. The reaction products were extracted and its radioactivity was measured as described (26).…”

Section: Withdrawal Of Growth Factors (Serum Starvation) and Treatmentsmentioning

confidence: 99%

Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway

Ou¹,

Chen²,

Shih

2006

Proc. Natl. Acad. Sci. U.S.A.

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147

145

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Monoamine oxidase A (MAO A) degrades serotonin, norepinephrine, and dopamine and produces reactive oxygen that may cause neuronal cell death. We have previously reported that a novel transcription factor R1 (RAM2͞CDCA7L͞JPO2) inhibits the MAO A promoter and enzymatic activities. This study reports the roles of MAO A and R1 in apoptosis and proliferation. We have found that in serum starvation-induced apoptosis, p38 kinase, MAO A, and caspase-3 were increased, whereas Bcl-2 and R1 were reduced. Using a p38 kinase inhibitor, R1 overexpression, and MAO A inhibitor, we have shown that MAO A and R1 are downstream of p38 kinase and Bcl-2, but upstream of caspase-3. Inhibition of MAO A prevents cell apoptosis. This notion was further supported by the finding that serum starvation-induced apoptosis is reduced in cortical brain cells from MAO A-deficient mice compared with WT. In addition, we found that MAO A and R1 are involved in the c-Myc-induced proliferative signaling pathway in the presence of serum. Immunoprecipitation and immunohistochemistry experiments indicate that the oncogene c-Myc colocalizes with R1 and induces R1 gene expression. Using R1 overexpression, R1 small interfering RNA, and a MAO A inhibitor, we found that R1 and MAO A act upstream of cyclin D1 and E2F1. In summary, this study demonstrates the functions of MAO A and its repressor R1 in apoptotic signaling pathways.c-Myc ͉ caspase-3 ͉ p38 kinase ͉ proliferation ͉ transcription factor M onoamine oxidases (MAOs) A and B, located on the outer mitochondria membrane with a 70% amino acid sequence identity (1, 2), catalyze the oxidative deamination of biogenic and dietary amines including monoamine neurotransmitters serotonin, norepinephrine, dopamine, and phenylethylamine. MAO plays important roles in several psychiatric and neurological disorders (3). MAO exists in two forms, MAO A and MAO B. Their catalytic activity generates H 2 O 2 and nitrogen species, which are toxic products and may cause oxidative damage to mtDNA and have potential implications for apoptosis, aging, and neurodegenerative processes (4).The in vivo function of MAO A and MAO B has been studied extensively in MAO A and MAO B knockout (KO) mice (5-7). The regulation of MAO A and MAO B gene expression by extracellular stimulation, phorbol 12-myristate 13-acetate (PMA), has also been examined. PMA selectively increases MAO B but not MAO A gene expression by activation of protein kinase C and mitogen-activated protein kinase (MAPK) signaling pathways (8).Ample evidence has indicated an important role for MAO A in apoptosis. MAO A expression has been shown to increase after the depletion of neurotrophic factor mediated by p38 kinase in PC12 cells (9). A MAO A inhibitor, clorgyline, was able to protect cells from apoptosis induced by serum starvation in human melanoma m14 cells (10). More recently, MAO A has been found to be a target of a dopaminergic neurotoxin, N-methyl-(R)-salsolinol, which leads to apoptosis in a human neuroblastoma SH-SY5Y cell line (11). This apoptotic activity co...

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“…The reaction products were then extracted with ethyl acetate/toluene (1:1) and centrifuged at 4°C for 10 min. The organic phase containing the reaction product was extracted, and its radioactivity was obtained by liquid scintillation spectroscopy (22).…”

Section: Figmentioning

confidence: 99%

Dual Functions of Transcription Factors, Transforming Growth Factor-β-inducible Early Gene (TIEG)2 and Sp3, Are Mediated by CACCC Element and Sp1 Sites of Human Monoamine Oxidase (MAO) B Gene

Chen

Shih

2004

Journal of Biological Chemistry

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Monoamine oxidases (MAO)A and B catalyze the oxidative deamination of many biogenic and dietary amines. Abnormal expression of MAO has been implicated in several psychiatric and neurodegenerative disorders. Human MAO B core promoter (؊246 to ؊99 region) consists of CACCC element flanked by two clusters of overlapping Sp1 sites. Here, we show that cotransfection with transforming growth factor (TGF)-␤-inducible early gene (TIEG)2 increased MAO B gene expression at promoter, mRNA, protein, and catalytic activity levels in both SH-SY5Y and HepG2 cells. Mutation of the CACCC element increased the MAO B promoter activity, and cotransfection with TIEG2 further increased the promoter activity, suggesting that CACCC was a repressor element. This increase was reduced when the proximal Sp1 overlapping sites was mutated. Similar interactions were found with Sp3. These results showed that TIEG2 and Sp3 were repressors at the CACCC element but were activators at proximal Sp1 overlapping sites of MAO B. Gel-shift and chromatin immunoprecipitation assays showed that TIEG2 and Sp3 bound directly to CACCC element and the proximal Sp1 sites in both synthetic oligonucleotides and natural MAO B core promoter. TIEG2 had a higher affinity to Sp1 sites than CACCC element, whereas Sp3 had an equal affinity to both elements. Thus, TIEG2 was an activator, but Sp3 had no effect on MAO B gene expression. This study provides new insights into MAO B gene expression and illustrates the complexity of gene regulation.Monoamine oxidase (MAO) 1 plays an important role in the metabolism of biogenic amines, including serotonin (5-hydroxytryptamine), norepinephrine, dopamine, tyramine, and phenylethylamine (PEA). There are two isoenzymes of MAO (MAO A and MAO B) that exhibit distinct substrate and inhibitor specificity (1, 2; for review, see Ref.3). Although both forms of MAO are expressed throughout the body, they differ in celland tissue-specific expressions. Placenta and fibroblasts predominantly express MAO A (4, 5), and platelets and lymphocytes express only MAO B (6). In the brain, even though MAO A prefers 5-hydroxytryptamine and MAO B prefers PEA as substrate, MAO B but not MAO A was found in serotonergic neurons (7,8). MAO A was expressed in catecholaminergic neurons, whereas MAO B is rich in astrocytes. Moreover, MAO B but not MAO A activity increases progressively in the brain throughout adult life (7, 9).MAO A and MAO B are coded by different genes (10) and are closely linked on X chromosome, Xp11.2-11.4 (11). Both consist of 15 exons with identical exon-intron organization (12). The promoter of MAO A has bi-directional activity (13) and consists of a functional polymorphism in a 30-bp repeat sequence (14). The 5Ј-flanking sequence of MAO B gene has been characterized. The maximal promoter activity for MAO B gene was found to be in the Ϫ246 to Ϫ99 region. This region consists of two clusters of overlapping Sp1 sites separated by a CACCC element (15). Previously, we have shown that Sp1 and Sp3 can bind to both proximal and distal clusters...

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

Cited by 156 publications

References 26 publications

Structure of human monoamine oxidase A at 2.2-Å resolution: The control of opening the entry for substrates/inhibitors

Structure of human monoamine oxidase A at 2.2-Å resolution: The control of opening the entry for substrates/inhibitors

Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway

Dual Functions of Transcription Factors, Transforming Growth Factor-β-inducible Early Gene (TIEG)2 and Sp3, Are Mediated by CACCC Element and Sp1 Sites of Human Monoamine Oxidase (MAO) B Gene

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