Wikipedia

COMT

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]

COMT
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Katehol-O–metiltransferaza
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SimbolCOMT
CAS broj9012-25-3
Razgradnja norepinefrina. Katehol-O– metiltransferaza je prikazana u zelenim kutijama.[1][2]

Funkcija

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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

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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

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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

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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

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

Inhibitori COMT-a

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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

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Dodatne slike

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Degeneracija dopamina


Reference

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  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.
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  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.
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  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

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

Vanjski linkovi

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