Analysis of Conserved Active Site Residues in Monoamine Oxidase A and B and Their Three-dimensional Molecular Modeling

Geha, Rani Maurice; Chen, Kevin; Wouters, Johan; Ooms, Frédéric; Shih, Jean C.

doi:10.1074/jbc.m110920200

Cited by 82 publications

(80 citation statements)

References 43 publications

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“…As shown in Table I, an analysis of mSMO FAD binding pocket reveals a high degree of conservation of the residues involved in the stabilization of this prosthetic group among PAO and human monoamine oxidase enzymes (31). This result is not surprising, although it can be used as an internal check for the correctness of the sequence alignment used for mSMO model construction.…”

Section: Structural Analysis and Active Site Modeling Of Msmo-mentioning

confidence: 88%

Heterologous Expression and Characterization of Mouse Spermine Oxidase

Cervelli

Polticelli

Federico

et al. 2003

Journal of Biological Chemistry

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Polyamine oxidases are key enzymes responsible of the polyamine interconversion metabolism in animal cells. Recently, a novel enzyme belonging to this class of enzymes has been characterized for its capability to oxidize preferentially spermine and designated as spermine oxidase. This is a flavin adenine dinucleotidecontaining enzyme, and it has been expressed both in vitro and in vivo systems. The primary structure of mouse spermine oxidase (mSMO) was deduced from a cDNA clone (Image Clone 264769) recovered by a data base search utilizing the human counterpart of polyamine oxidases, PAOh1. The open reading frame predicts a 555-amino acid protein with a calculated M r of 61,852.30, which shows a 95.1% identity with PAOh1. To understand the biochemical properties of mSMO and its structure/function relationship, the mSMO cDNA has been subcloned and expressed in secreted and secreted-tagged forms into Escherichia coli BL21 DE3 cells. The recombinant enzyme shows an optimal pH value of 8.0 and is able to oxidize rapidly spermine to spermidine and 3-aminopropanal and fails to act upon spermidine and N 1 -acetylpolyamines. The purified recombinant-tagged form enzyme (M r ϳ68,000) has K m and k cat values of 90 M and 4.5 s ؊1, respectively, using spermine as substrate at pH 8.0. Molecular modeling of mSMO protein based on maize polyamine oxidase three-dimensional structure suggests that the general features of maize polyamine oxidase active site are conserved in mSMO.Polyamine oxidase (PAO), 1 a flavin adenine dinucleotide (FAD)-containing enzyme, catalyzes the oxidation of polyamines at the secondary amino group, giving different products according to the organism considered. In particular, vertebrate PAOs (EC 1.5.3.11) participate in the interconversion metabolism of polyamines, converting N 1 -acetyl derivatives of spermine (N 1 -acetylSpm) and spermidine (N 1 -acetylSpd) into Spd and putrescine, respectively, plus 3-aminopropanal and H 2 O 2 , (1-3). PAOs with similar characteristics occur in methylotrophic yeasts (4, 5) and amoebae (6). On the contrary, plant (1), bacterial (7), and protozoan (8) PAOs oxidize spermidine and spermine to 4-aminobutanol or N-(3-aminopropyl)-4-aminobutanol, respectively, plus 1,3-diaminopropane and H 2 O 2 . As these compounds cannot be converted directly to other polyamines, this class of PAOs generally is considered to be involved in the terminal catabolism of polyamines. Since PAOs play a crucial role in polyamine catabolism, these enzymes are important drug targets, and in fact, it has been shown that a number of polyamine analogues have an antitumor effect in different cell lines (9 -12).As compared with large and detailed investigations on plant PAOs (1, 13-22), only little attention has been devoted to the animal counterpart (2,(23)(24)(25)(26)(27)(28). Recently, Wang et al. (29) and Vujcic et al. (30) have reported the cloning and characterization of novel mammalian PAO enzymes capable of oxidizing preferentially Spm and for this reason named spermine oxidase (SMO) (30). In ...

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Section: Structural Analysis and Active Site Modeling Of Msmo-mentioning

confidence: 88%

Heterologous Expression and Characterization of Mouse Spermine Oxidase

Cervelli

Polticelli

Federico

et al. 2003

Journal of Biological Chemistry

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“…The most extensively studied catalytic residue is a specific lysine. In all crystal structures examined, this lysine positions the lone water molecule in the active site into a bridging position with the flavin N-5 atom of the FAD cofactor (2,4,9,45). This lysine is absolutely conserved in all Lsd1 orthologues, all PAOs, and all MAOs and is the only residue in the catalytic pocket that is absolutely conserved in the distantly related sarcosine oxidases.…”

Section: Saphire Binds Nucleosomesmentioning

confidence: 99%

Genome-Wide Dynamics of SAPHIRE, an Essential Complex for Gene Activation and Chromatin Boundaries

Gordon

Holt

Panigrahi

et al. 2007

Molecular and Cellular Biology

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In this study, we characterize a four-protein nucleosome-binding complex from Schizosaccharomyces pombe, termed SAPHIRE, that includes two orthologs of human Lsd1, a histone demethylase. The SAPHIRE complex is essential for cell viability, whereas saphire mutants lacking key conserved catalytic residues are viable but thermosensitive, suggesting that SAPHIRE has both an important enzymatic function and an essential nonenzymatic function. SAPHIRE is present in (or adjacent to) particular heterochromatic loci and also in the transcription start site regions of many highly active polymerase II genes. However, ribosomal protein genes are notably SAPHIRE deficient. SAPHIRE promotes activation, as target genes are selectively attenuated in saphire mutants. Interestingly, saphire mutants display increased histone H3 lysine 4 dimethylation, a modification typically associated with euchromatin. SAPHIRE localization is dynamic, as activated genes rapidly acquire SAPHIRE. Furthermore, saphire mutants dramatically shift a heterochromatin-euchromatin boundary in Chr1, suggesting a novel role in boundary regulation.Chromatin is a dynamic material that partitions chromosomes into functional domains (telomeres, centromeres, and rRNA gene arrays) and also partitions individual genes into segments, each with a distinct role in transcriptional regulation. All chromatin regions contain arrays of nucleosomes, which consist of 147 base pairs of DNA wrapped around an octameric disk of histone proteins (24, 34). However, different chromatin regions have distinctive characteristics, including (i) differences in chromatin composition, including histone variants, linker histones, and associated nonhistone chromatin architectural proteins; (ii) structural diversity (nucleosome positioning or compaction); and (iii) variation in covalent modifications of the DNA and histones (34).Covalent histone modifications serve as docking sites for protein domains present in specific factors, which in turn endow the region with unique characteristics (46). Methylation of lysines in the unstructured termini (tails) of histones regulates a wide array of DNA-templated processes, including transcription (12, 47). Methylation of lysines in histone tails is mediated by two families of enzymes, namely, the DOT family and the SET family (30,40). These enzymes can mono-, di-, or trimethylate lysines, and even the subtle difference between di-and trimethylation of the same lysine residue can be discriminated by recognition domains and, therefore, used to recruit distinct factors (21,33,52).Dimethylation of histone H3 lysine 4 (H3K4me2) is generally thought to make chromatin permissive to transcription,

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“…They are coded by different genes, with 70% amino acid identity (5) and with identical intron-exon organization next to each other on the X chromosome (6). The overall three-dimensional structure of MAO A and B are similar (7), but the mitochondria targeting is different (8). The crystal structure of MAO B is now available (9).…”

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confidence: 99%

A Spontaneous Point Mutation Produces Monoamine Oxidase A/B Knock-out Mice with Greatly Elevated Monoamines and Anxiety-like Behavior

Chen

Holschneider

et al. 2004

Journal of Biological Chemistry

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A spontaneous monoamine oxidase A (MAO A) mutation (A863T) in exon 8 introduced a premature stop codon, which produced MAO A/B double knock-out (KO) mice in a MAO B KO mouse colony. This mutation caused a nonsense-mediated mRNA decay and resulted in the absence of MAO A transcript, protein, and catalytic activity and abrogates a DraI restriction site. The MAO A/B KO mice showed reduced body weight compared with wild type mice. Brain levels of serotonin, norepinephrine, dopamine, and phenylethylamine increased, and serotonin metabolite 5-hydroxyindoleacetic acid levels decreased, to a much greater degree than in either MAO A or B single KO mice. Observed chase/ escape and anxiety-like behavior in the MAO A/B KO mice, different from MAO A or B single KO mice, suggest that varying monoamine levels result in both a unique biochemical and behavioral phenotype. These mice will be useful models for studying the molecular basis of disorders associated with abnormal monoamine neurotransmitters. (21), indicating that the increase in 5-HT, a preferred substrate for MAO A, and concomitant decrease in 5-HIAA may form the basis for increased aggression, consistent with the association of low 5-HIAA levels in the cerebrospinal fluid of men who exhibit aggressive behavior (22,23). Although increased aggressive behavior has not been observed in MAO B KO mice (21), low platelet MAO B activity in humans is associated with, and considered a marker for, criminal or impulsive behavior (24), although whether this is accompanied in human subjects by a concomitant decrease in MAO A activity or other related genetic or biochemical aberration is not known.MAO A/B KO mice cannot be generated through the breeding of MAO A KO and MAO B KO mice, due to the close proximity of the isoenzyme genes on the X chromosomes, where the two genes are next to each other at their 3Ј tails, organized in opposite orientations with their last exons being less than 24 kb apart (determined by blat analysis of human and mouse MAO A and B

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Analysis of Conserved Active Site Residues in Monoamine Oxidase A and B and Their Three-dimensional Molecular Modeling

Cited by 82 publications

References 43 publications

Heterologous Expression and Characterization of Mouse Spermine Oxidase

Heterologous Expression and Characterization of Mouse Spermine Oxidase

Genome-Wide Dynamics of SAPHIRE, an Essential Complex for Gene Activation and Chromatin Boundaries

A Spontaneous Point Mutation Produces Monoamine Oxidase A/B Knock-out Mice with Greatly Elevated Monoamines and Anxiety-like Behavior

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