Disease relevance of MAOB

• Monoamine oxidase (MAO), which exists in two forms (MAOA and MAOB), plays an important role in the oxidative metabolism of neurotransmitters such as dopamine, and has been implicated in the etiology of Parkinson's disease (PD) [1].
• Increased activities of MAOA and MAOB in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy [2].
• When considered together, the 'at risk genotype'--low activity genotypes at both the MAOA and MAOB loci--shows a relative risk for obesity of 5.01 [3].
• Additionally, estrogen-related receptor alpha (ERRalpha) up-regulates MAO-B gene expression in breast cancer cells [4].
• A deleterious role played by MAO B is the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a proneurotoxin that can cause a parkinsonian syndrome in mammals [5].

Psychiatry related information on MAOB

• This study was conducted to detect a possible association of MAOA and/or MAOB genes with pathological gambling (PG) [6].
• The association between (GT)n dinucleotide repeats in monoamine oxidase gene loci, monoamine oxidase A (MAOA) and B (MAOB), and Parkinson's disease (PD), Alzheimer's disease (AD), and Lewy body variant (LBV) of AD were determined [7].
• Therefore, our results did not support the involvement of the alleles at MAOA and MAOB in the etiology of mood disorder [8].
• As for association studies, significant association between bipolar disorder and MAOB gene was detected [9].
• Platelet MAO-B activity increased after smoking cessation but without a significant difference [10].

High impact information on MAOB

• Here we show that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role for MAOB in the metabolism of PEA [11].
• Increased stress response and beta-phenylethylamine in MAOB-deficient mice [11].
• By subcloning a YAC with a 640 kilobases (kb) insert which spans the DXS7-MAOB interval we have generated a cosmid contig which extends 250 kb beyond the MAOB gene [12].
• We propose that reduction of MAO B activity may synergize with nicotine to produce the diverse behavioural and epidemiological effects of smoking [13].
• Mechanisms of bioactivation by MAO-B of MPTP to MPP+, concentration of MPP+ in neurons with a catecholamine uptake system, and vulnerability to cellular toxic effects of MPP+ are the basis for the specificity of MPTP targeting of nigrostriatal dopaminergic neurons [14].

Chemical compound and disease context of MAOB

• Monoamine oxidase B (MAO-B) is implicated in the cause of Parkinson's disease (PD) because of its role in metabolizing the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and forming H2O2 during dopamine metabolism [15].
• Simultaneous MAO-B and COMT inhibition in L-Dopa-treated patients with Parkinson's disease [16].
• Thus, the lower but equally MAO-B inhibitory dose of selegiline in Zydis Selegiline 1.25 mg, which is associated with lower concentrations of potentially harmful metabolites, could offer a safer and more predictable treatment in the management of patients with Parkinson's disease [17].
• Selegiline (L-deprenyl), a selective inhibitor of MAO-B, ameliorates the "wearing off" akinesia and delays the need for levodopa in mild, previously untreated Parkinson's disease [18].
• As the first MAO-B inhibitor approved for the treatment of Parkinson's disease, concerns were raised about the safety of the drug based on the adverse effect profiles of older, nonselective MAO inhibitors [19].

Biological context of MAOB

• The implications of fast acetylation, selective MAO inhibitors, types MAOA and MAOB, and measures of platelet MAO inhibition are discussed in this article [20].
• Human MAOA and MAOB genes isolated from X chromosome-specific libraries span at least 60 kilobases, consist of 15 exons, and exhibit identical exon-intron organization [21].
• Our results map the gene responsible for the disorder between the MAOB and DXS426, m27 beta and p58-1 loci, on the short arm of the X chromosome at Xp11.3, which suggest the possibility that the same gene is responsible for both primary retinal dysplasia and Norrie disease [22].
• We have performed linkage analysis of the family using the L1.28, p58-1 and m27 beta probes, and DXS426 and MAOB associated microsatellites [22].
• It has been shown from pulsed-field gel electrophoresis (PFGE) that the monoamine oxidase genes A and B (MAOA & MAOB) and DXS7 loci are physically very close [23].

Anatomical context of MAOB

• Activities of both MAOA and MAOB were significantly increased in frontal cortex and caudate nucleus, two brain regions shown previously to be the site of functional and morphological alterations of astrocytes and increased concentrations of the acid metabolites of dopamine and serotonin [2].
• In Northern blot analyses MAOA mRNA was expressed broadly in various parts of the canine brain, whereas MAOB mRNA was found only in specific brain regions, such as the hypothalamus, hippocampus, brain stem and olfactory bulb [24].
• A monoclonal antibody was used to prepare immunoaffinity columns that efficiently bind monoamine oxidase B activity but not monoamine oxidase A activity from detergent extracts of human liver mitochondria [25].
• Normal levels of MAO-A activities, as well as normal amounts and size of the MAO-A mRNA, were observed in cultured skin fibroblasts from these patients, and MAO-B activity in their platelets was normal [26].
• However, the imidazoline binding domain was not detected in platelet membrane preparations containing amounts of MAO-B equivalent to those in the photolabeled liver membranes indicating that recognition of this domain is tissue-restricted [27].

Associations of MAOB with chemical compounds

• Monoamine oxidases A and B [MAOA and MAOB; amine:oxygen oxidoreductase (deaminating) (flavin-containing), EC 1.4.3.4] play important roles in the metabolism of neuroactive, vasoactive amines and the Parkinsonism-producing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [21].
• Exon 12 codes for the covalent FAD-binding-site and is the most conserved exon; the MAOA and MAOB exon 12 products share 93.9% peptide identity [21].
• This 4.96 Mb region contains, among others, the genes for monoamine oxidase A (MAOA) and B (MAOB), which are involved in the oxidative deamination of several neurotransmitters, including dopamine and serotonin [28].
• Exon 12 (bearing the codon for cysteine, which carries the covalently bound FAD cofactor) and exon 13 are highly conserved between human MAOA and MAOB genes (92% at the amino acid level) [29].
• To understand the mechanisms of specific substrate and inhibitor recognitions of MAOA and MAOB, we have determined the crystal structure of rat MAOA complexed with the specific inhibitor, clorgyline, at 3.2A resolution [30].

Physical interactions of MAOB

• 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 [31].
• Transcription factor binding to the core promoter of the human monoamine oxidase B gene in the cerebral cortex and in blood cells [32].

Enzymatic interactions of MAOB

• Additional studies revealed that MMPP was a poor substrate of only MAO B (Km,app = 9.5 mM) and that acid treatment of MMPP led to the formation of a product that could be readily oxidized by both MAO A and B. Similar acid pretreatment of TMMP yielded a product that was a much poorer substrate for MAO B than the parent compound [33].

Regulatory relationships of MAOB

• Cys5 and Cys266 were identified as the only residues modified by biotin-derivatized NEM in clorgyline-inactivated MAO A and pargyline-inactivated MAO B, respectively [34].
• Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2 [35].
• Reduction in glial fibrillary acidic protein mRNA abundance induced by (-)-deprenyl and other monoamine oxidase B inhibitors in C6 glioma cells [36].
• Platelet monoamine oxidase B (MAO-B) activity and its relationship to DL-fenfluramine-induced prolactin response in healthy men [37].

Other interactions of MAOB

• Interestingly, ERalpha or ERbeta alone have no effect on MAO-B promoter activity but can down-regulate the activation function of ERRs, whereas glucocorticoid receptor does not [4].
• The ability of ERRs to stimulate MAO-B promoter activity was reduced in ER-positive MCF-7 and T47D cells [4].
• The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese [38].
• CONCLUSION: Significant associations with PD were found in polymorphisms of NAT2, MAOB, GSTT1, and tRNAGlu [39].
• We investigated whether genetic variants of MAO-B intron 13 and DRD2 TaqIB polymorphism could be associated with smoking status among control subjects [40].

Analytical, diagnostic and therapeutic context of MAOB

• Restriction mapping of the YAC indicates that it contains both MAOA and MAOB genes in addition to the DXS7 locus [23].
• To understand the ethnicity-specific effects of genetic polymorphism, we performed a case-control study of the association between PD susceptibility and polymorphism of MAOB and COMT, both separately and in combination, in Taiwanese [38].
• Molecular cloning of canine monoamine oxidase subtypes A (MAOA) and B (MAOB) cDNAs and their expression in the brain [24].
• A single-stranded conformational polymorphism was identified in an MAO-B polymerase chain reaction product after Hae III digestion [15].
• By using chromatin immunoprecipitation assay, we demonstrate that ERs compete with ERRs for binding to the MAO-B promoter at selective AGGTCA motifs, thereby changing the chromatin status and cofactor recruitment to a repressed state [4].

References