NNMT
Nikotinamid N-metiltransferaza (NNMT) je enzim koji je kod ljudi kodiran genom NNMT.[5] NNMT katalizira metilaciju nikotinamida i sličnih spojeva, koristeći donatora metila S-adenozil metionin (SAM-e) za proizvodnju S-adenozil-L-homocisteina (SAH) i 1-metilnikotinamida.[6]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 264 aminokiseline, а molekulska masa 29.574 Da.[7]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MESGFTSKDT | YLSHFNPRDY | LEKYYKFGSR | HSAESQILKH | LLKNLFKIFC | ||||
| LDGVKGDLLI | DIGSGPTIYQ | LLSACESFKE | IVVTDYSDQN | LQELEKWLKK | ||||
| EPEAFDWSPV | VTYVCDLEGN | RVKGPEKEEK | LRQAVKQVLK | CDVTQSQPLG | ||||
| AVPLPPADCV | LSTLCLDAAC | PDLPTYCRAL | RNLGSLLKPG | GFLVIMDALK | ||||
| SSYYMIGEQK | FSSLPLGREA | VEAAVKEAGY | TIEWFEVISQ | SYSSTMANNE | ||||
| GLFSLVARKL | SRPL |
Funkcija
urediMetilacija nikotinamida pomoću NNMT i SAM-e glavni je put razgradnje nikotinamida koji dovodi do izlučivanja urinom.[6]
Klinički značaj
urediNNMT je visoko eksprimiran u ljudskoj jetri.[6][8] N-metilacija je jedan od metoda pomoću kojeg se lijek i drugi ksenobiotski spojevi metaboliziraju putem jetre.[6] NNMT ekspresija u masnom tkivu je povezan sa gojaznošću i insulinskom rezistencijom.[6][9] Nasuprot negativnim efektima povećanog NNMT-a u masnom tkivu, povećani NNMT u jetri povezan je s boljim metaboličkim profilom, smanjenjem serumskih triglicerida i slobodnih masnih kiselina.[9] U masnom tkivu, NNMT može dovesti do iscrpljivanja metilacije, dok zbog mnogih enzima metilacije u jetri NNMT ima zanemariv učinak na njenu metilaciju.[6] Ali u jetri, 1-metilnikotinamid koji proizvodi NNMT, razgradnja nikotinamida povećava sirtuin 1 (SIRT1), inhibiranjem razgradnje tog proteina.[9] Pokazalo se da nadekspresija SIRT1 kod miševa smanjuje razinu insulina i glukozu natašte, kao i da povećava metabolizam i fizičku funkciju.[10]
Obilna dostupnost nikotinamida dovodi do iscrpljivanja i nikotinamid-adenin dinukleotida (NAD+) i SAM-e, što rezultira jetrenim steatozama i fibrozama, uzrokujući napredovanje od nealkoholnu masnu bolest jetre (NAFLD) do bezalkoholnih steatohepatitisa (NASH).[11]
Vjeruje se da ljudski embrionskim matičnim ćelijama ekspresija NNMT pomaže u održavanju ćelija u nevinom stanju.[6]
Ekspresija NNMT je značajno povećano regulirana kod mnogih vrsta raka, uključujući rak gušterače, gdje nivoi NNMT enzima koreliraju s povećanim rizikom od smrti.[12] Uzrok ovih korelacija nije utvrđen, ali može biti povezan s činjenicom da je enzim NNMT inhibitor popravka DNK.[12] NNMT i 1-metilnikotinamid inhibiraju autofagiju u raku dojke, štiteći ćelije raka dojke od oksidativnog stresa.[13] Predloženo je da je NNMT biomarker raka.[12]
Reference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000166741 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032271 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Aksoy S, Brandriff BF, Ward A, Little PF, Weinshilboum RM (Mar 1996). "Human nicotinamide N-methyltransferase gene: molecular cloning, structural characterization and chromosomal localization". Genomics. 29 (3): 555–61. doi:10.1006/geno.1995.9966. PMID 8575745.
- ^ a b c d e f g Pissios P (2017). "Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzym". Trends in Endocrinology and Metabolism. 28 (5): 340–353. doi:10.1016/j.tem.2017.02.004. PMC 5446048. PMID 28291578.
- ^ "UniProt, P40261". Pristupljeno 25. 8. 2021.
- ^ Hwang ES, Song SB (2017). "Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells". Cellular and Molecular Life Sciences. 74 (18): 3347–3362. doi:10.1007/s00018-017-2527-8. PMID 28417163.
- ^ a b c Guarino M, Dufour J (2019). "Nicotinamide and NAFLD: Is There Nothing New Under the Sun?". Metabolites. 9 (9): 180. doi:10.3390/metabo9090180. PMC 6780119. PMID 31510030.
- ^ Bordone L, Cohen D, Robinson A, Motta MC, Guarente L (2007). "SIRT1 transgenic mice show phenotypes resembling calorie restriction". Aging Cell. 6 (6): 759–767. doi:10.1111/j.1474-9726.2007.00335.x. PMID 17877786.
- ^ Komatsu M, Kanda T, Wakino S, Itoh H (2018). "NNMT activation can contribute to the development of fatty liver disease by modulating the NAD + metabolism". Scientific Reports. 8 (1): 8637. doi:10.1038/s41598-018-26882-8. PMC 5988709. PMID 29872122.
- ^ a b c Lu XM, Long H (2018). "Nicotinamide N-methyltransferase as a Potential Marker for Cancer". Neoplasma. 65 (5): 656–663. doi:10.4149/neo_2018_171024N680. PMID 29940773.
- ^ Yu H, Zhou X, Wang Y, Zhang J (2018). "Nicotinamide N-methyltransferase inhibits autophagy induced by oxidative stress through suppressing the AMPK pathway in breast cancer cells". Cancer Cell International. 20: 191. doi:10.1186/s12935-020-01279-8. PMC 7247246. PMID 32489327.
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