Monoamine oxidase A

Monoamine oxidase A
Ribbon diagram of an MAO-A monomer, with FAD and clorgiline bound, oriented as if attached to the outer membrane of a mitochondrion.[1]
Available structures PDB 2bxr, 2bxs
Identifiers
Symbols	MAOA;
External IDs	OMIM: 309850 MGI: 96915 HomoloGene: 203 GeneCards: MAOA Gene
EC number	1.4.3.4
Gene Ontology Molecular function • amine oxidase activity • oxidoreductase activity Cellular component • mitochondrion • membrane • integral to membrane Biological process • electron transport • catecholamine metabolic process • behavior • dopamine catabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4128	17161
Ensembl	ENSG00000189221	ENSMUSG00000025037
UniProt	P21397	Q3TPD9
RefSeq (mRNA)	NM_000240	NM_173740
RefSeq (protein)	NP_000231	NP_776101
Location (UCSC)	Chr X: 43.4 – 43.49 Mb	Chr X: 15.78 – 15.84 Mb
PubMed search	[1]	[2]

Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the MAO-A gene.^[2][3] Monoamine oxidase A is an isozyme of monoamine oxidase. It preferentially deaminates norepinephrine (noradrenaline), epinephrine (adrenaline), serotonin, and dopamine (dopamine is equally deaminated by MAO-A and MAO-B). It is inhibited by clorgiline and befloxatone.

Function

Monoamine oxidase A is an enzyme that degrades amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. The protein localizes to the outer mitochondrial membrane. Its encoding gene is adjacent to a related gene (MAO-B) on the opposite strand of chromosome X. Mutation in this gene results in monoamine oxidase deficiency, or Brunner syndrome.^[4]

Clinical significance

In humans, there is a 30-base region repeated different numbers of times in the promoter of the gene, There are 2R (two repeats), 3R, 3.5R, 4R, and 5R copies of the repeat sequence, the 3 and 4 repeats are most common in caucasians. Thus, people may have different versions of the gene. The 3.5R and 4R variants are more highly active than 3R or 5R ^[5].

An association between a rare 2R repeat of the VNTR region of the gene and an increase in the likelihood of committing serious crime or violence has been found.^[6][5]

MAO-A levels in the brain as measured using positron emission tomography are elevated by an average of 34% in patients with major depressive disorder.^[7] Genetic association studies examining the relationship between high-activity MAO-A variants and depression have produced mixed results, with some studies linking the high-activity variants to major depression in females,^[8] depressed suicide in males,^[9] major depression and sleep disturbance in males^[10] and major depressive disorder in both males and females.^[11] Other studies failed to find a significant relationship between high-activity variants of the MAO-A gene and major depressive disorder.^[12][13]

The version of the gene that a person carries may determine or at least significantly influence whether a traumatic childhood experience of violence leads to psychopathy,^[14] but this finding is not universal; it was shown in Caucasian but not non-white Americans.^[15]

In patients with major depressive disorder, those with MAO-A G/T polymorphisms (rs6323) coding for the highest-activity form of the enzyme have a significantly lower magnitude of placebo response than those with other genotypes.^[16]

Warrior gene

A version of the primate monoamine oxidase-A gene has been referred to as the warrior gene. Several different versions of the gene are found in different individuals, although a functional gene is present in most humans (with the exception of a few individuals with Brunner syndrome).^[17] The allele associated with behavioural traits is shorter (30 bases) and may produce less MAO-A enzyme.^[18] This gene variation is in a regulatory promoter region about 1000 bases from the start of the region that encodes the MAO-A enzyme. However, behaviour is dependent on both genes and the environment.^[14]

Statistical frequency of the MAO-A gene varies by ethnicity^[18][19]—as is the case for many genotypes. Due to the sensitive political nature of the findings, and the standard peer review process, the research has been heavily scrutinised. Several objections have been raised,^{[by whom?]} such as the small sample size, and the extrapolation of non-Maori studies to the Maori population. In addition, ideological objections were raised,^{[by whom?]} as well as concerns about announcing such findings in the early stages of research.^{[15][20][21][22]}

In a 2009 criminal trial in the United States, an argument based on a combination of "warrior gene" and history of child abuse was successfully used to avoid a conviction of first-degree murder and the death penalty; however, the convicted murderer was sentenced to 32 years in jail ^[23][24]

Some MAO-A inhibitors

• Synthetic compounds
  • Befloxatone (MD370503)
  • Brofaromine (Consonar)
  • Cimoxatone
  • Clorgiline
  • Methylene Blue
  • Minaprine (Cantor)
  • Moclobemide (Aurox, Manerix)
  • Pirlindole (Pirazidol)
  • Toloxatone (Humoryl)
  • Tyrima (CX 157)
  • Tranylcypromine (non-selective)

• Herbal sources
  • Curcumin (Turmeric)
  • Coptisine (Goldthread)
  • Harmala Alkaloids (Tobacco, Syrian Rue, Passion Flower)
    • Harmine
    • Harmaline
    • Tetrahydroharmaline

References

1. ^ PDB 2BXS; De Colibus L, Li M, Binda C, Lustig A, Edmondson DE, Mattevi A (September 2005). "Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B". Proc. Natl. Acad. Sci. U.S.A. 102 (36): 12684–9. doi:10.1073/pnas.0505975102. PMC 1200291. PMID 16129825. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1200291. 
2. ^ Hotamisligil GS, Breakefield XO (August 1991). "Human monoamine oxidase A gene determines levels of enzyme activity". Am. J. Hum. Genet. 49 (2): 383–92. PMC 1683299. PMID 1678250. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1683299. 
3. ^ Grimsby J, Chen K, Wang LJ, Lan NC, Shih JC (May 1991). "Human monoamine oxidase A and B genes exhibit identical exon-intron organization". Proc. Natl. Acad. Sci. U.S.A. 88 (9): 3637–41. doi:10.1073/pnas.88.9.3637. PMC 51507. PMID 2023912. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=51507. 
4. ^ "Entrez Gene: MAOA monoamine oxidase A". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4128. 
5. ^ ^{a b} Guo G, Ou XM, Roettger M, Shih JC (May 2008). "The VNTR 2 repeat in MAOA and delinquent behavior in adolescence and young adulthood: associations and MAOA promoter activity". Eur. J. Hum. Genet. 16 (5): 626–34. doi:10.1038/sj.ejhg.5201999. PMC 2922855. PMID 18212819. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2922855. 
6. ^ Guo G, Roettger M, Shih JC (August 2008). "The integration of genetic propensities into social-control models of delinquency and violence among male youths". American Sociological Review 73 (4): 543–568. doi:10.1177/000312240807300402. http://www.asanet.org/galleries/default-file/Aug08ASRFeature.pdf. ^{[dead link]}
7. ^ Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S (November 2006). "Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression". Arch. Gen. Psychiatry 63 (11): 1209–16. doi:10.1001/archpsyc.63.11.1209. PMID 17088501. 
8. ^ Schulze TG, Müller DJ, Krauss H, Scherk H, Ohlraun S, Syagailo YV, Windemuth C, Neidt H, Grässle M, Papassotiropoulos A, Heun R, Nöthen MM, Maier W, Lesch KP, Rietschel M (December 2000). "Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder". Am. J. Med. Genet. 96 (6): 801–3. doi:10.1002/1096-8628(20001204)96:6<801::AID-AJMG21>3.0.CO;2-4. PMID 11121185. 
9. ^ Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D, Hrdina PD (July 2002). "High activity-related allele of MAO-A gene associated with depressed suicide in males". Neuroreport 13 (9): 1195–8. doi:10.1097/00001756-200207020-00025. PMID 12151768. 
10. ^ Du L, Bakish D, Ravindran A, Hrdina PD (September 2004). "MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males". Neuroreport 15 (13): 2097–101. doi:10.1097/00001756-200409150-00020. PMID 15486489. 
11. ^ Yu YW, Tsai SJ, Hong CJ, Chen TJ, Chen MC, Yang CW (September 2005). "Association study of a monoamine oxidase a gene promoter polymorphism with major depressive disorder and antidepressant response". Neuropsychopharmacology 30 (9): 1719–23. doi:10.1038/sj.npp.1300785. PMID 15956990. 
12. ^ Serretti A, Cristina S, Lilli R, Cusin C, Lattuada E, Lorenzi C, Corradi B, Grieco G, Costa A, Santorelli F, Barale F, Nappi G, Smeraldi E (May 2002). "Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders". Am. J. Med. Genet. 114 (4): 361–9. doi:10.1002/ajmg.10356. PMID 11992558. 
13. ^ Huang SY, Lin MT, Lin WW, Huang CC, Shy MJ, Lu RB (2009). "Association of monoamine oxidase A (MAOA) polymorphisms and clinical subgroups of major depressive disorders in the Han Chinese population". World J. Biol. Psychiatry 10 (4 Pt 2): 544–51. doi:10.1080/15622970701816506. PMID 19224413. 
14. ^ ^{a b} Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R (August 2002). "Role of genotype in the cycle of violence in maltreated children". Science 297 (5582): 851–4. doi:10.1126/science.1072290. PMID 12161658. Lay summary – eurekalert.org (2002-08-01). 
15. ^ ^{a b} Crampton P, Parkin C (2007). "Warrior genes and risk-taking science". N. Z. Med. J. 120 (1250): U2439. PMID 17339895. http://www.nzma.org.nz/journal/120-1250/2439. 
16. ^ Leuchter AF, McCracken JT, Hunter AM, Cook IA, Alpert JE (August 2009). "Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder". J Clin Psychopharmacol 29 (4): 372–7. doi:10.1097/JCP.0b013e3181ac4aaf. PMID 19593178. 
17. ^ Online 'Mendelian Inheritance in Man' (OMIM) MONOAMINE OXIDASE A; MAOA. -309850
18. ^ ^{a b} Sabol SZ, Hu S, Hamer D (September 1998). "A functional polymorphism in the monoamine oxidase A gene promoter". Hum. Genet. 103 (3): 273–9. doi:10.1007/s004390050816. PMID 9799080. 
19. ^ Lea R, Chambers G (2007). "Monoamine oxidase, addiction, and the "warrior" gene hypothesis". N. Z. Med. J. 120 (1250): U2441. PMID 17339897. http://www.nzma.org.nz/journal/120-1250/2441. 
20. ^ "Maori 'warrior gene' claims appalling, says geneticist". News. NZ Herald News. http://www.nzherald.co.nz/category/story.cfm?c_id=204&objectid=10395491. Retrieved 2009-01-27. 
21. ^ Whanau Tu, Whanau Ora (2007). Hui Whakapiripiri Report. www.hrc.govt.nz. ISBN 978-0-908700-73-3. http://www.hrc.govt.nz/assets/pdfs/publications/Hui%20Report%2006%20FINAL.pdf. Retrieved 2009-01-27. 
22. ^ "Scientist debunks 'warrior gene'". News. NZ Herald News. http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10596821. Retrieved 2009-09-11. 
23. ^ Barber N (2010-07-13). "Pity the poor murderer, his genes made him do it". The Human Beast: Why we do what we do. Psychology Today. http://www.psychologytoday.com/blog/the-human-beast/201007/pity-the-poor-murderer-his-genes-made-him-do-it. Retrieved 2010-10-17. 
24. ^ Hagerty BB (2010-07-01). "Can Your Genes Make You Murder?". News > Science > Inside The Criminal Brain. National Public Radio. http://www.npr.org/templates/story/story.php?storyId=128043329. Retrieved 2010-10-17. 

Further reading

• "'Warrior Gene' Predicts Aggressive Behavior After Provocation". Science News. Science Daily. 2009-01-23. http://www.sciencedaily.com/releases/2009/01/090121093343.htm. 
• McDermott R, Tingley D, Cowden J, Frazzetto G, Johnson DD (January 2009). "Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation". Proc. Natl. Acad. Sci. U.S.A. 106 (7): 2118–23. doi:10.1073/pnas.0808376106. PMC 2650118. PMID 19168625. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2650118. 
• Edmondson DE, Binda C, Mattevi A (2004). "The FAD binding sites of human monoamine oxidases A and B". Neurotoxicology 25 (1–2): 63–72. doi:10.1016/S0161-813X(03)00114-1. PMID 14697881. 
• Craig IW (2007). "The importance of stress and genetic variation in human aggression". Bioessays 29 (3): 227–36. doi:10.1002/bies.20538. PMID 17295220.