Idi na sadržaj

COMT

S Wikipedije, slobodne enciklopedije
COMT
Identifikatori
Aliasi
Vanjski ID-jeviGeneCards: [1]
Ortolozi
VrsteČovjekMiš
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n
a

n/a

RefSeq (mRNK)

n/a

n/a

RefSeq (bjelančevina)

n/a

n/a

Lokacija (UCSC)n/an/a
PubMed pretragan/an/a
Wikipodaci
Pogledaj/uredi – čovjek
Katehol-O–metiltransferaza
Identifikatori
SimbolCOMT
CAS broj9012-25-3
Razgradnja norepinefrina. Katehol-O– metiltransferaza je prikazana u zelenim kutijama.[1][2]

Katehol-O–metiltransferaza (COMT; EC 2.1.1.6) je jedan od nekoliko enzima koji razgrađuju kateholamine (neurotransmiteri kao što su dopamin, epinefrin i norepinefrin), kateholestrogeni i razni lijekovi i supstance koje imaju kateholsku strukturu.[3] In humans, catechol-O-methyltransferase protein is encoded by the COMT gene.[4] Proizvode se dvije izoforme COMT-a: topljivi kratki oblik (S-COMT) i dugi oblik vezan na membranu (MB-COMT). Kako je regulacija kateholamina poremećena u brojnim zdravstvenim stanjima, nekoliko farmaceutskih lijekova cilja na COMT, kako bi promijenili njegovu aktivnost i stoga dostupnost kateholamina.[5] COMT je prvi otkrio biohemičar Julius Axelrod 1957.[6]

Funkcija

[uredi | uredi izvor]

Katehol-O–metiltransferaza uključena je u inaktivaciju kateholaminskih neurotransmitera (dopamin, epinefrin i noradrenalin). Enzim uvodi metil grupu u kateholamin, koju donira S-adenozil metionin (SAM). Supstrati COMT-a je bilo koji spoj koji ima kateholnu strukturu, kao što su kateholestrogeni i flavonoidi koji sadrže katehol.

Levodopa, prekursor kateholamina, važan je supstrat COMT-a. Inhibitori COMT-a, poput entakapona, spašavaju levodopu od COMT-a i produžavaju djelovanje levodopa.[7] Entakapon je široko korišteni pomoćni lijek u terapiji levodopom. Kada se daje sa inhibitorom dopa dekarboksilaze (karbidopa ili benzerazid), levodopa se optimalno štedi. Ova "trostruka terapija" postaje standard u liječenju Parkinsonove bolesti.

Specifične reakcije koje katalizira COMT uključuju:

U mozgu, COMT-ovisna degradacija dopamina je od posebne važnosti u regijama mozga sa niskom ekspresijom presinapsnog dopaminskog transportera (DAT), kao što je prečeoni korteks.[8][9][10][11] (U PFC, dopamin se također uklanja presinapsnim norepinefrinskim transporterima (NET) i razgrađuje monoamin-oksidaza.)[12] Controversy exists about the predominance and orientation of membrane bound COMT in the CNS,[13][14][15]

Rastvorljivi COMT se također može naći van ćelija, iako vanćelijski COMT i,a manje značajnu ulogu u CNS-u nego u perifernom sistemu.[16]:210 Unatoč svom značaju u neuronima, COMT je zapravo primarno eksprimiran u jetri.[16]:135

Genetika kod ljudi

[uredi | uredi izvor]

COMT protein je kodiran genom "COMT". Gen je povezan sa alelnim varijantama. Najbolje proučavan je Val158Met.[11] Ostali koji su proučavani su rs737865 i rs165599, npr. za povezanost sa karakterom ličnosti,[17] odgovorom na antidepresivne lijekove,[18] i rizikom od psihoze povezanim sa Alzheimerovom bolešću.[19] COMT je proučavan kao potencijalni gen u patogenezi shizofrenije; međutim meta-analize ne pronalaze povezanost između rizika od shizofrenije i brojnih polimorfizama,[20] including Val158Met.[21][22][23]

Polimorfizam Val158Met

[uredi | uredi izvor]

Funkcionalni jednonukleotidni polimorfizam (uobičajena normalna varijanta) gena za katehol-O–metiltransferazu rezultira mutacijama valina u metionin na poziciji 158 (Val< sup>158Met) rs4680.[11] In vitro, homozigotna Val varijanta metabolizira dopamin do četiri puta brže od svog metioninskog parnjaka.[18] Međutim, in vivo Met varijanta je pretjerano eksprimirana u mozgu,[24] što rezultira smanjenjem od 40% (umjesto 75% ) funkcionalne aktivnosti enzima.[25] Niže stope katabolizma za Met alel rezultiraju višim nivoima sinapsnog dopamina nakon oslobađanja neurotransmitera, u konačnici povećavajući dopaminsku stimulaciju postsinapsnog neurona. S obzirom na preferencijalnu ulogu COMT-a u prečeonoj degradaciji dopamina, smatra se da polimorfizam Val158Met ispoljava svoje efekte na kogniciju, modulacijom dopaminske signalizacije u čeonom režnju.

Pokazalo se da varijanta gena utiče na kognitivne zadatke koji su široko povezani sa izvršnim funkcijama, kao što su pomeranje skupa, inhibicija odgovora, apstraktna misao i usvajanje pravila ili strukture zadatka.[26][27][28]

Uporedivi efekti na slične kognitivne zadatke, čeone režnjeve i neurotransmiter dopamin također su povezani sa shizofrenijom.[29][30] Predloženo je da je naslijeđena varijanta COMT jedan od genetičkih faktora koji mogu predisponirati nekoga da razvije shizofreniju kasnije u životu.[31] Novija studija dovela je u sumnju predloženu vezu između ovog gena i bilo kakvog navodnog slučajnog efekta kanabisa na razvoj shizofrenije.[32]Šablon:Unreliable medical source

Utvrđeno je da je nesinonimni jednonukleotidni polimorfizam rs4680 povezan s depresivnim faktorom skala pozitivnog i negativnog sindroma (PANSS) i efikasnošću emocija kod oboljelih od shizofrenije.[33] Sve se više priznaje da su alelne varijacije na COMT genu takođe relevantne za obradu emocija, jer izgleda da utiču na interakciju između prečeonog i limbnog regiona. Istraživanje sprovedeno na Sekciji za neurobiologiju psihoze, Instituta za psihijatriju, King's College-a u Londonu, pokazalo je dejstvo COMT-a i kod pacijenata sa bipolarnim poremećajem i kod njihovih rođaka.[34] Polimorfizam COMT Val158Met također ima plejotrpni uticaj na obradu emocija.[35]

Nadalje, pokazalo se da polimorfizam utiče na ocjene subjektivno blagostanje. Kada je kod 621 žene izmjerena pomoću praćen obrazac iskustva, što je slično procjeni raspoloženja kao odgovoru na bip sat, oblik met/met daje dvostruko subjektivniji mentalni osjećaj blagostanja od širokog spektra dnevnih događaja. Sposobnost doživljavanja nagrade povećavala se s brojem Met alela.[36] Jedan pregled otkrio je da su oni sa Val/Val skloniji da budu ekstrovertniji, više traže novitet i manje su neurotični od onih sa Met/Met alelom. [37]

Disfunkcija temporomandibulskog zgloba

[uredi | uredi izvor]

Disfunkcija temporomandibulskog zgloba (TMD) ne izgleda kao klasični genetički poremećaj, međutim sugerirano je da su varijacije u genu koji kodira COMT odgovorne za nasljeđivanje predispozicije za razvoj TMD-a tokom života.[38]

Nomenklatura

[uredi | uredi izvor]

COMT je ime dato genu koji kodira ovaj enzim. O u nazivu označava kisik, a ne orto.

Inhibitori COMT-a

[uredi | uredi izvor]

COMT inhibitori uključuju entacapon, tolkapon, opikapon i nitekapon. Svi osim nitekapona se koriste u liječenju Parkinsonove bolesti.[39] Rizik od trovnja jetrajetre i srodnih probavnih poremećaja ograničava upotrebu tolkapona.[40]

Također pogledajte

[uredi | uredi izvor]

Dodatne slike

[uredi | uredi izvor]
Degeneracija dopamina


Reference

[uredi | uredi izvor]
  1. ^ Flower R, Rang HP, Dale MM, Ritter JM (2007). "Figure 11-4". Rang & Dale's pharmacology (6th izd.). Edinburgh: Churchill Livingstone. ISBN 978-0-443-06911-6.
  2. ^ Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G (2011). "Figure 14.4". Rang & Dale's Pharmacology. Student consult (7th izd.). Elsevier Health Sciences. ISBN 978-0-7020-4504-2.
  3. ^ "Test ID: COMT: Catechol-O-Methyltransferase Genotype". www.mayomedicallaboratories.com. Mayo Clinic: Mayo Medical Laboratories. Arhivirano s originala, September 18, 2008. Pristupljeno November 16, 2016.
  4. ^ Grossman MH, Emanuel BS, Budarf ML (April 1992). "Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1----q11.2". Genomics. 12 (4): 822–5. doi:10.1016/0888-7543(92)90316-K. PMID 1572656.
  5. ^ Tai CH, Wu RM (February 2002). "Catechol-O-methyltransferase and Parkinson's disease". Acta Medica Okayama. 56 (1): 1–6. PMID 11873938.
  6. ^ Axelrod J (August 1957). "O-Methylation of Epinephrine and Other Catechols in vitro and in vivo". Science. 126 (3270): 400–1. Bibcode:1957Sci...126..400A. doi:10.1126/science.126.3270.400. PMID 13467217.
  7. ^ Ruottinen HM, Rinne UK (November 1998). "COMT inhibition in the treatment of Parkinson's disease". Journal of Neurology. 245 (11 Suppl 3): P25–34. doi:10.1007/PL00007743. PMID 9808337. S2CID 26793445.
         Goetz CG (May 1998). "Influence of COMT inhibition on levodopa pharmacology and therapy". Neurology. 50 (5 Suppl 5): S26–30. doi:10.1212/WNL.50.5_Suppl_5.S26. PMID 9591519. S2CID 32448444.
  8. ^ Brodal P (2016). "Chapter 5: Neurotransmitters and their receptors". The Central Nervous System. Oxford University Press. str. 75. ISBN 978-0-19-022896-5.
  9. ^ Scheggia D, Sannino S, Scattoni ML, Papaleo F (May 2012). "COMT as a drug target for cognitive functions and dysfunctions". CNS & Neurological Disorders Drug Targets. 11 (3): 209–21. doi:10.2174/187152712800672481. PMID 22483296.
  10. ^ Diaz-Asper CM, Weinberger DR, Goldberg TE (January 2006). "Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics". NeuroRx. 3 (1): 97–105. doi:10.1016/j.nurx.2005.12.010. PMC 3593358. PMID 16490416.
  11. ^ a b c Schacht, Joseph P. (October 2016). "COMT val158met moderation of dopaminergic drug effects on cognitive function: A critical review". Pharmacogenomics Journal. 16 (5): 430–438. doi:10.1038/tpj.2016.43. PMC 5028240. PMID 27241058.
  12. ^ Juarez B, Han MH (September 2016). "Diversity of Dopaminergic Neural Circuits in Response to Drug Exposure". Neuropsychopharmacology. 41 (10): 2424–46. doi:10.1038/npp.2016.32. PMC 4987841. PMID 26934955.
  13. ^ Nissinen E, ured. (2010). Basic Aspects of Catechol-O-Methyltransferase and the Clinical Applications of its Inhibitors. Academic Press. str. 34. ISBN 978-0-12-381327-5 – preko Google books.
  14. ^ Chen J, Song J, Yuan P, Tian Q, Ji Y, Ren-Patterson R, Liu G, Sei Y, Weinberger DR (October 2011). "Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development". The Journal of Biological Chemistry. 286 (40): 34752–60. doi:10.1074/jbc.M111.262790. PMC 3186432. PMID 21846718. The cellular distribution of MB-COMT in cortical neurons remains unclear and the orientation of MB-COMT on the cellular membrane is controversial.
  15. ^ Schott BH, Frischknecht R, Debska-Vielhaber G, John N, Behnisch G, Düzel E, Gundelfinger ED, Seidenbecher CI (2010). "Membrane-Bound Catechol-O-Methyl Transferase in Cortical Neurons and Glial Cells is Intracellularly Oriented". Frontiers in Psychiatry. 1: 142. doi:10.3389/fpsyt.2010.00142. PMC 3059651. PMID 21423451. It has been a matter of debate whether in neural cells of the CNS the enzymatic domain of MB-COMT is oriented toward the cytoplasmic or the extracellular compartment.
  16. ^ a b Golan DE, Tashjian AH (2011-12-15). Principles of pharmacology (3rd izd.). Philadelphia: Wolters Kluwer Health. ISBN 978-1-60831-270-2. OCLC 705260923.
  17. ^ Gold MS, Blum K, Oscar-Berman M, Braverman ER (January 2014). "Low dopamine function in attention deficit/hyperactivity disorder: should genotyping signify early diagnosis in children?". Postgraduate Medicine. 126 (1): 153–77. doi:10.3810/pgm.2014.01.2735. PMC 4074363. PMID 24393762.
  18. ^ a b Porcelli S, Drago A, Fabbri C, Gibiino S, Calati R, Serretti A (March 2011). "Pharmacogenetics of antidepressant response". Journal of Psychiatry & Neuroscience. 36 (2): 87–113. doi:10.1503/jpn.100059. PMC 3044192. PMID 21172166.
  19. ^ DeMichele-Sweet MA, Sweet RA (2010). "Genetics of psychosis in Alzheimer's disease: a review". Journal of Alzheimer's Disease. 19 (3): 761–80. doi:10.3233/JAD-2010-1274. PMC 2942073. PMID 20157235.
  20. ^ Okochi T, Ikeda M, Kishi T, Kawashima K, Kinoshita Y, Kitajima T, Yamanouchi Y, Tomita M, Inada T, Ozaki N, Iwata N (May 2009). "Meta-analysis of association between genetic variants in COMT and schizophrenia: an update". Schizophrenia Research. 110 (1–3): 140–8. doi:10.1016/j.schres.2009.02.019. PMID 19329282. S2CID 22875066.
  21. ^ Glatt SJ, Faraone SV, Tsuang MT (March 2003). "Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies". The American Journal of Psychiatry. 160 (3): 469–76. doi:10.1176/appi.ajp.160.3.469. PMID 12611827. S2CID 25352000.
  22. ^ Munafò MR, Bowes L, Clark TG, Flint J (August 2005). "Lack of association of the COMT (Val158/108Met) gene and schizophrenia: a meta-analysis of case-control studies". Molecular Psychiatry. 10 (8): 765–70. doi:10.1038/sj.mp.4001664. PMID 15824744.
  23. ^ Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, Feng GY, St Clair D, He L (January 2005). "Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis". Biological Psychiatry. 57 (2): 139–44. doi:10.1016/j.biopsych.2004.10.018. PMID 15652872. S2CID 23416733.
  24. ^ Zhu G, Lipsky RH, Xu K, Ali S, Hyde T, Kleinman J, Akhtar LA, Mash DC, Goldman D (December 2004). "Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5′ nuclease assay". Psychopharmacology. 177 (1–2): 178–84. doi:10.1007/s00213-004-1938-z. PMID 15295009. S2CID 33013401.
  25. ^ Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR (November 2004). "Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain". American Journal of Human Genetics. 75 (5): 807–21. doi:10.1086/425589. PMC 1182110. PMID 15457404.
  26. ^ Bruder GE, Keilp JG, Xu H, Shikhman M, Schori E, Gorman JM, Gilliam TC (December 2005). "Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations". Biological Psychiatry. 58 (11): 901–7. doi:10.1016/j.biopsych.2005.05.010. PMID 16043133. S2CID 17902043.
  27. ^ Robinson S, Goddard L, Dritschel B, Wisley M, Howlin P (December 2009). "Executive functions in children with autism spectrum disorders". Brain and Cognition. 71 (3): 362–8. doi:10.1016/j.bandc.2009.06.007. PMID 19628325. S2CID 14587250.
  28. ^ Diamond A, Briand L, Fossella J, Gehlbach L (January 2004). "Genetic and neurochemical modulation of prefrontal cognitive functions in children". The American Journal of Psychiatry. 161 (1): 125–32. doi:10.1176/appi.ajp.161.1.125. PMID 14702260.
  29. ^ NIH Record Daniel R. Weinberger to Give Milder Lecture Arhivirano 22. 5. 2015. na Wayback Machine, October 7, 2005
  30. ^ The News and Editorial Staffs Breakthrough of the Year: The Runner Up A Quest, Science Magazine, December 19, 2003.
  31. ^ Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW (May 2005). "Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction". Biological Psychiatry. 57 (10): 1117–27. doi:10.1016/j.biopsych.2005.01.026. PMID 15866551. S2CID 39405111.
  32. ^ Zammit S, Spurlock G, Williams H, Norton N, Williams N, O'Donovan MC, Owen MJ (November 2007). "Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use". The British Journal of Psychiatry. 191 (5): 402–7. doi:10.1192/bjp.bp.107.036129. PMID 17978319. Sažetak – MedWireNews.
  33. ^ Punchaichira TJ, Kukshal P, Bhatia T, Deshpande SN, Thelma BK (2020). "The effect of rs1076560 (DRD2) and rs4680 (COMT) on tardive dyskinesia and cognition in schizophrenia subjects". Psychiatric Genetics. 30 (5): 125–135. doi:10.1097/YPG.0000000000000258. PMID 32931693. S2CID 221718209.
  34. ^ Lelli-Chiesa G, Kempton MJ, Jogia J, Tatarelli R, Girardi P, Powell J, Collier DA, Frangou S (April 2011). "The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives" (PDF). Psychological Medicine. 41 (4): 779–88. doi:10.1017/S0033291710001431. PMID 20667170. S2CID 206251638.
  35. ^ Kempton MJ, Haldane M, Jogia J, Christodoulou T, Powell J, Collier D, Williams SC, Frangou S (April 2009). "The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition: a fMRI study". The International Journal of Neuropsychopharmacology. 12 (3): 371–81. doi:10.1017/S1461145708009395. PMID 18796186.
  36. ^ Wichers M, Aguilera M, Kenis G, Krabbendam L, Myin-Germeys I, Jacobs N, Peeters F, Derom C, Vlietinck R, Mengelers R, Delespaul P, van Os J (December 2008). "The catechol-O-methyl transferase Val158Met polymorphism and experience of reward in the flow of daily life". Neuropsychopharmacology. 33 (13): 3030–6. doi:10.1038/sj.npp.1301520. PMID 17687265.
  37. ^ Montag C, Jurkiewicz M, Reuter M (May 2012). "The role of the catechol-O-methyltransferase (COMT) gene in personality and related psychopathological disorders". CNS & Neurological Disorders Drug Targets. 11 (3): 236–50. doi:10.2174/187152712800672382. PMC 4345409. PMID 22483293.
  38. ^ Cairns BE (May 2010). "Pathophysiology of TMD pain--basic mechanisms and their implications for pharmacotherapy". Journal of Oral Rehabilitation. 37 (6): 391–410. doi:10.1111/j.1365-2842.2010.02074.x. PMID 20337865.
  39. ^ Bonifácio MJ, Palma PN, Almeida L, Soares-da-Silva P (2007). "Catechol-O-methyltransferase and its inhibitors in Parkinson's disease". CNS Drug Reviews. 13 (3): 352–79. doi:10.1111/j.1527-3458.2007.00020.x. PMC 6494163. PMID 17894650.
  40. ^ Jatana N, Apoorva N, Malik S, Sharma A, Latha N (January 2013). "Inhibitors of catechol-O-methyltransferase in the treatment of neurological disorders". Central Nervous System Agents in Medicinal Chemistry. 13 (3): 166–94. doi:10.2174/1871524913666140109113341. PMID 24450388. Two of the nitrocatechols, entacapone ... and tolcapone ... have been demonstrated to reduce the dose of L-DOPA required and also cause improvement in clinical symptoms, although tolcapone emerged to be more efficacious due to its greater bioavailability and a longer half-life when compared to entacapone. However, tolcapone is clinically restricted owing to its increased hepatotoxicity and other related digestive disorders.

Dopunska literatura

[uredi | uredi izvor]
  • Greenberg, Gary (November 7, 2018). "What If the Placebo Effect Isn't a Trick?". New York Times Magazine.

Vanjski linkovi

[uredi | uredi izvor]
Commons logo
Commons logo
Commons ima datoteke na temu: COMT

Šablon:Enzimi metabilizma neurotransmitera Šablon:Jednougljične transferaze

Šablon:Modulatori monoaminskog metabolizma

Portal iconPortal Biologija
Preuzeto iz "https://bs.wikipedia.org/w/index.php?title=COMT&oldid=3630696"