MUT

Metilmalonil-CoA mutaza
Metilmalonil-CoA mutaza
	Trodimenzijski prikaz MCM-a
Identifikatori
Simbol	MCM
CAS broj	9023-90-9

MUT
Identifikatori
Aliasi
Vanjski ID-jevi	GeneCards: [1]
Ortolozi
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	Wikipodaci
Pogledaj/uredi – čovjek

Mitohondrijska etilmalonil-CoA mutaza (MCM), znana i kao metilmalonil-CoA izomeraza, jest enzim koji je kod ljudi kodiran genom MUT. Ovaj enzim ovisan je o vitamin B ₁₂, a katalizira izomerizaciju metilmalonil-CoA u sukcinil-CoA kod ljudi. Mutacije u genu MUT mogu dovesti do različitih tipova metilmalonske acidurije.^[1]

MCM je prvi put identificirana u pacovskoj jetri i ovčijim bubrezima 1955. U svom latentnom obliku, duga je 750 aminokiselina. Po ulasku u mitohondrije, sekvenca lidera mitohondrija od 32 aminokiseline na N-kraju proteina se cijepa, tvoreći potpuno obrađenu monomeru. Monomere se zatim povezuju u homodimere i vezuju AdoCbl (po jedan za svako monomerno aktivno mjesto), kako bi formirali konačni, aktivni holoenzimski oblik.^[2]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 750 aminokiselina, а molekulska težina 83.134 Da.^[3]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MLRAKNQLFL	LSPHYLRQVK	ESSGSRLIQQ	RLLHQQQPLH	PEWAALAKKQ
LKGKNPEDLI	WHTPEGISIK	PLYSKRDTMD	LPEELPGVKP	FTRGPYPTMY
TFRPWTIRQY	AGFSTVEESN	KFYKDNIKAG	QQGLSVAFDL	ATHRGYDSDN
PRVRGDVGMA	GVAIDTVEDT	KILFDGIPLE	KMSVSMTMNG	AVIPVLANFI
VTGEEQGVPK	EKLTGTIQND	ILKEFMVRNT	YIFPPEPSMK	IIADIFEYTA
KHMPKFNSIS	ISGYHMQEAG	ADAILELAYT	LADGLEYSRT	GLQAGLTIDE
FAPRLSFFWG	IGMNFYMEIA	KMRAGRRLWA	HLIEKMFQPK	NSKSLLLRAH
CQTSGWSLTE	QDPYNNIVRT	AIEAMAAVFG	GTQSLHTNSF	DEALGLPTVK
SARIARNTQI	IIQEESGIPK	VADPWGGSYM	MECLTNDVYD	AALKLINEIE
EMGGMAKAVA	EGIPKLRIEE	CAARRQARID	SGSEVIVGVN	KYQLEKEDAV
EVLAIDNTSV	RNRQIEKLKK	IKSSRDQALA	ERCLAALTEC	AASGDGNILA
LAVDASRARC	TVGEITDALK	KVFGEHKAND	RMVSGAYRQE	FGESKEITSA
IKRVHKFMER	EGRRPRLLVA	KMGQDGHDRG	AKVIATGFAD	LGFDVDIGPL
FQTPREVAQQ	AVDADVHAVG	ISTLAAGHKT	LVPELIKELN	SLGRPDILVM
CGGVIPPQDY	EFLFEVGVSN	VFGPGTRIPK	AAVQVLDDIE	KCLEKKQQSV

Struktura

Gen

Gen MUT nalazi se na hromosomskoj lokaciji 6p12.3; proteže se na preko 35 kb i sastoji se od 13 egzona^[4]

Protein

Zreli enzim je homodimer sa N-terminalnim domenom vezanja CoA i C-terminalnim domenom vezanja kobalamina.^[5]

Funkcija

Metilmalonil-CoA mutaza je eksprimirana u visokim koncentracijama u bubrezima, u srednjim koncentracijama u srcu, jajnicima, mozgu, mišićima i jetri, a u niskim koncentracijama u slezeni.^[2] Enzim se može naći u cijelom centralnom nervnom sistemu (CNS).^[2] MCM nalazi se u mitohondrijama, gdje se djeluje na niz tvari, uključujući aminokiseline razgranatog lanca izoleucin i valin, kao i metionin, treonin, timin i neparni lanac masnih kiselina, metabolizirajući se putem metilmalonatnog polualdehida (MMlSA) ili propionil-CoA (Pr-CoA), u uobičajeni jspoj – metilmalonil-CoA (MMl-CoA).

MCM katalizira reverzibilnu izomerizaciju l-metilmalonil-CoA u sukcinil -CoA, zahtijevajući kobalamin (vitamin B12) u obliku adenozilkobalamina (AdoCbl), kao kofaktor. Kao važan korak u katabolizmu propionata, ova reakcija je potrebna za razgradnju neparnih lanaca masnih kiselina, aminokiselina valin, izoleucin, metionin i treonin, te holesterola,^[6] a razgradnjom metabolita ovih aminokiselina usmjerava ih u ciklus trikarboksilne kiseline.^[7]

Metilmalonil-CoA mutaza katalizira sljedeću reakciju:

Razlažući enzim: Metilmalonil-CoA mutaza

Reverzni enzim: Metilmalonil-CoA mutaza

Podloga. L-metilmalonil-CoA

Proizvod: Sukcinil-CoA

Smjer reakcije: Reverzibilna ⇔ Povratna

Supstrat metilmalonil-CoA mutaze, metilmalonil-CoA, prvenstveno je izveden iz propionil-CoA, tvari nastale katabolizmom i digestijom izoleucina, valina, treonina, metionina, timina, holesterola ili masne kiseline sa neparnim lancem. Produkt enzima, sukcinil-CoA, ključna je molekula ciklusa trikarnonskih kiselina.

Mehanizam

Mehanizam rakcije MCM-a

Reakcijski mehanizam MCM-a počinje homoliznim cijepanjem veze C-Co (III) AdoB12, gdje atomi C i Co dobivaju po jedan od elektrona koji su formirali vezu razdvojenog para elektrona. Ion Co, dakle, fluktuira između oksidacionih stanja Co (III) i Co (II) [ta dva stanja se spektroskopski razlikuju: Co (III) je crven i dijamagneta (bez nesparenih elektrona), dok je Co (II) žuto i paramagneta (nespareni elektroni)]. Dakle, uloga koenzima B-12 u katalitskom procesu je uloga reverzibilnog generatora slobodnih radikala. Veza C-Co (III) je slaba, s energijom disocijacije = 109 kJ/mol i dodatno je oslabljena sternom interakcijom s enzimom. Homolitska reakcija je neuobičajena u biologiji, kao i prisutnost veze metal-ugljik.

Metilmalonil-CoA mutaza je član potporodice izomeraza, enzima zavisnih od adenozilkobalamina. Nadalje, klasificiran je kao klasa I, jer je to enzim 'DMB-off'/'His-on'. To se odnosi na prirodu AdoCbl kofaktora na aktivnom mjestu metilmalonil CoA.^[8] AdoCbl se sastoji od centralnog kobalta – koji sadrži korinski prsten, gornjeg aksijalnog liganda (β-aksijalnog liganda) i donjeg aksijalnog liganda (α-aksijalnog liganda). U metilmalonil-CoA mutazi, β-aksijalni ligand, 5’-deoksi-5’-adenozin, reverzibilno je disociran dajući dezoksiadenozil radikal. Α-aksijalni ligand, 5,6-dimetilbenzimidazol (DMB), uključen je u organizaciju aktivnog mjesta koje omogućava histidinu-610 da se veže sa Co, umjesto sa DMB (razlog za of DMB-a/His-on: isključenje - uključenje). Vezivanje ostatka histidina-610 povećava brzinu homolitskog β-aksijalnog liganda – pucanjem Co veze za faktor 10¹².^[9]

Aktivnomjesto MCM-a: Korinski prsten i α-aksijalni ligand (DMB): (žuti), β-aksijalni ligand: (zeleni), supstrat/proizvod: (cijan), ostaci u interakciji s β-aksijalnim ligandom: glu370, asn366, gly91, ala139 (plavi) , ostaci u interakciji sa supstratom: gln197, his244, arg207, tyr89 (crveni) i his610: (naranžasti).^[10] Referirano prema PDB 4REQ.^[11]

Ostali važni ostaci metilmalonil-CoA mutaze uključuju histidin-244, koji djeluje kao opća kiselina u blizini supstrata i štiti radikalne vrste od nuspojava koje uključuju kisik,^[12] glutamat-370, čija vodikova veza sa 2’-OH grupom riboze β-aksijalnog liganda prisiljava interakciju između radikalnih vrsta β-aksijalnog liganda i supstrata,^[13] i tirozin-89 koji stabilizira reaktivne radikalne međuprodukte i objašnjava stereo-selektivnost enzima.^[10]^[14]

Protein za preradu, protein MMAA, ispunjava važnu ulogu pomažući punjenju i razmjeni kofaktora.^[15]^[16] Protein MMAA pogoduje povezivanju s apoenzimom MCM i omogućava prijenos kofaktora AdoCbl na aktivno mjesto enzima.^[16] Nadalje, ako vezani AdoCbl nanese oksidativno oštećenje tokom normalnog funkcioniranja, protein MMAA podstiče izmjenu oštećenog kofaktora za novi AdoCbl, pomoću GTP-ovisnog puta.^[15]^[16]

Klinički značaj

Nedostatak ovog enzima odgovoran je za nasljedni poremećaj metabolizma, nedostatak metilmalonil-CoA mutaze, koji je jedan od uzroka pojave metilmalonske kiseline (MMA). MMA je autosomno recesivna urođena greška metabolizma, koju karakteriziraju ponavljajuće epizode povraćanja, letargija, duboka ketoacidoza, hiperamonemija i pancitopenija, a u djetinjstvu i mogu uzrokovati ranu smrt. Komplikacije uključuju bolesti kao što su kardiomiopatija, metabolički udar, pankreatitis i progresivna bubrežna insuficijencija.^[1]^[17]

Ili mutacije gena MUT (kodira metilmalonil-CoA mutazu) ili MMAA (kodira proteinski šaperon metilmalonil-CoA mutaza), MMAA protein mogu dovesti do metilmalonil acidemije.^[15] Mutacije na MUT đ mogu se kategorizirati ili kao MUT⁰ (ne pokazuje aktivnost čak ni u prisutnosti viška AdoCbl), ili kao MUT¹ (ispoljava vrlo nisku aktivnost u prisustvu viška AdoCbl).^[5] Više od polovine mutacija MUT-a su misens mutacije^[7] dok nonsens mutacije čine značajnu preostalu frakciju (približno 14%).^[18]

Uobičajeni metodi liječenja MMA uključuju transplantaciju jetre ili i jetre i transplantaciju bubrega za borbu protiv bubrežne bolesti zbog metilmalonske kiseline. Međutim, štetni neurološki učinci mogu nastaviti mučiti pacijente čak i nakon uspješne operacije. Smatra se da je to posljedica raširene prisutnosti metilmalonil-CoA mutaze u središnjem nervnom sistemu. Zbog gubitka funkcionalnosti enzima, nivoi supstrata se nakupljaju u CNS-u. Supstrat, L-metilmalonil-CoA hidrolizira i tvori metilmalonat (metilmalonska kiselina), neurotoksičnu dikarboksilnu kiselinu koja je zbog slabih transportnih sposobnosti dikarboksilne kiseline u [[krvno-moždana barijera|krvno-moždanoj barijeri učinkovito zarobljena u CNS-u, što dovodi do neurološkog slabljenja. Za suzbijanje ovih učinaka ne preporučuju se perioperativni antikatabolički režimi i prekid dijete.^[2]

Mišji model se pokazao kao adekvatan i tačan način proučavanja efekata VMA i potencijalnih metoda liječenja.^[19]^[20]

Interakcije

Nađeno je da ovaj MCM ima [[interakcija protein-protein|interakcije sa

Reference

^ ^a ^b Keyfi F, Sankian M, Moghaddassian M, Rolfs A, Varasteh AR (januar 2016). "Molecular, biochemical, and structural analysis of a novel mutation in patients with methylmalonyl-CoA mutase deficiency". Gene. 576 (1 Pt 2): 208–13. doi:10.1016/j.gene.2015.10.002. PMID 26449400.
^ ^a ^b ^c ^d Ballhausen D, Mittaz L, Boulat O, Bonafé L, Braissant O (decembar 2009). "Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain". Neuroscience. 164 (2): 578–87. doi:10.1016/j.neuroscience.2009.08.028. PMID 19699272. S2CID 34612963.
^ "UniProt, P22033" (jezik: engleski). Pristupljeno 3. 10. 2021.
^ Chandler RJ, Venditti CP (1. 10. 2016). "Genetic and genomic systems to study methylmalonic acidemia". Molecular Genetics and Metabolism. 86 (1–2): 34–43. doi:10.1016/j.ymgme.2005.07.020. PMC 2657357. PMID 16182581.
^ ^a ^b Drennan CL, Matthews RG, Rosenblatt DS, Ledley FD, Fenton WA, Ludwig ML (maj 1996). "Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase". Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5550–5. Bibcode:1996PNAS...93.5550D. doi:10.1073/pnas.93.11.5550. PMC 39284. PMID 8643613.
^ Martínez MA, Rincón A, Desviat LR, Merinero B, Ugarte M, Pérez B (april 2005). "Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants". Molecular Genetics and Metabolism. 84 (4): 317–25. doi:10.1016/j.ymgme.2004.11.011. PMID 15781192.
^ ^a ^b Forny P, Froese DS, Suormala T, Yue WW, Baumgartner MR (decembar 2014). "Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency". Human Mutation. 35 (12): 1449–58. doi:10.1002/humu.22633. PMC 4441004. PMID 25125334.
^ Takahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME (juni 2012). "Role of vitamin B12 on methylmalonyl-CoA mutase activity". Journal of Zhejiang University Science B. 13 (6): 423–37. doi:10.1631/jzus.B1100329. PMC 3370288. PMID 22661206.
^ Vlasie M, Chowdhury S, Banerjee R (maj 2002). "Importance of the histidine ligand to coenzyme B12 in the reaction catalyzed by methylmalonyl-CoA mutase". The Journal of Biological Chemistry. 277 (21): 18523–7. doi:10.1074/jbc.M111809200. PMID 11893736.
^ ^a ^b Mancia F, Smith GA, Evans PR (juni 1999). "Crystal structure of substrate complexes of methylmalonyl-CoA mutase". Biochemistry. 38 (25): 7999–8005. doi:10.1021/bi9903852. PMID 10387043.
^ Mancia F, Evans PR (juni 1998). "Conformational changes on substrate binding to methylmalonyl CoA mutase and new insights into the free radical mechanism". Structure. 6 (6): 711–20. doi:10.1016/s0969-2126(98)00073-2. PMID 9655823.
^ Maiti N, Widjaja L, Banerjee R (novembar 1999). "Proton transfer from histidine 244 may facilitate the 1,2 rearrangement reaction in coenzyme B(12)-dependent methylmalonyl-CoA mutase". The Journal of Biological Chemistry. 274 (46): 32733–7. doi:10.1074/jbc.274.46.32733. PMID 10551831.
^ Buckel W, Friedrich P, Golding BT (oktobar 2012). "Hydrogen bonds guide the short-lived 5'-deoxyadenosyl radical to the place of action". Angewandte Chemie. 51 (40): 9974–6. doi:10.1002/anie.201205299. PMID 22945861.
^ Thomä NH, Meier TW, Evans PR, Leadlay PF (oktobar 1998). "Stabilization of radical intermediates by an active-site tyrosine residue in methylmalonyl-CoA mutase". Biochemistry. 37 (41): 14386–93. CiteSeerX 10.1.1.608.304. doi:10.1021/bi981375o. PMID 9772164.
^ ^a ^b ^c Takahashi-Íñiguez T, García-Arellano H, Trujillo-Roldán MA, Flores ME (januar 2011). "Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein". Biochemical and Biophysical Research Communications. 404 (1): 443–7. doi:10.1016/j.bbrc.2010.11.141. PMID 21138732.
^ ^a ^b ^c ^d ^e Froese DS, Kochan G, Muniz JR, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW (decembar 2010). "Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation". The Journal of Biological Chemistry. 285 (49): 38204–13. doi:10.1074/jbc.M110.177717. PMC 2992254. PMID 20876572.
^ Dündar H, Özgül RK, Güzel-Ozantürk A, Dursun A, Sivri S, Aliefendioğlu D, Coşkun T, Tokatli A (august 2012). "Microarray based mutational analysis of patients with methylmalonic acidemia: identification of 10 novel mutations". Molecular Genetics and Metabolism. 106 (4): 419–23. doi:10.1016/j.ymgme.2012.05.014. PMID 22727635.
^ Buck NE, Wood LR, Hamilton NJ, Bennett MJ, Peters HL (novembar 2012). "Treatment of a methylmalonyl-CoA mutase stopcodon mutation". Biochemical and Biophysical Research Communications. 427 (4): 753–7. doi:10.1016/j.bbrc.2012.09.133. PMID 23041189.
^ Chandler RJ, Venditti CP (novembar 2012). "Pre-clinical efficacy and dosing of an AAV8 vector expressing human methylmalonyl-CoA mutase in a murine model of methylmalonic acidemia (MMA)". Molecular Genetics and Metabolism. 107 (3): 617–9. doi:10.1016/j.ymgme.2012.09.019. PMC 3522145. PMID 23046887.
^ Manoli I, Sysol JR, Li L, Houillier P, Garone C, Wang C, Zerfas PM, Cusmano-Ozog K, Young S, Trivedi NS, Cheng J, Sloan JL, Chandler RJ, Abu-Asab M, Tsokos M, Elkahloun AG, Rosen S, Enns GM, Berry GT, Hoffmann V, DiMauro S, Schnermann J, Venditti CP (august 2013). "Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia". Proceedings of the National Academy of Sciences of the United States of America. 110 (33): 13552–7. Bibcode:2013PNAS..11013552M. doi:10.1073/pnas.1302764110. PMC 3746875. PMID 23898205.
^ Padovani D, Labunska T, Banerjee R (juni 2006). "Energetics of interaction between the G-protein chaperone, MeaB, and B12-dependent methylmalonyl-CoA mutase". The Journal of Biological Chemistry. 281 (26): 17838–44. doi:10.1074/jbc.M600047200. PMID 16641088.
^ Taoka S, Padmakumar R, Lai MT, Liu HW, Banerjee R (decembar 1994). "Inhibition of the human methylmalonyl-CoA mutase by various CoA-esters". The Journal of Biological Chemistry. 269 (50): 31630–4. doi:10.1016/S0021-9258(18)31741-1. PMID 7989334.

Dopunska literatura

Ledley FD, Rosenblatt DS (1997). "Mutations in mut methylmalonic acidemia: clinical and enzymatic correlations". Human Mutation. 9 (1): 1–6. doi:10.1002/(SICI)1098-1004(1997)9:1<1::AID-HUMU1>3.0.CO;2-E. PMID 8990001.
Ludwig ML, Matthews RG (1997). "Structure-based perspectives on B12-dependent enzymes". Annual Review of Biochemistry. 66: 269–313. doi:10.1146/annurev.biochem.66.1.269. PMID 9242908.
Lubrano R, Elli M, Rossi M, Travasso E, Raggi C, Barsotti P, Carducci C, Berloco P (august 2007). "Renal transplant in methylmalonic acidemia: could it be the best option? Report on a case at 10 years and review of the literature". Pediatric Nephrology. 22 (8): 1209–14. doi:10.1007/s00467-007-0460-z. PMID 17401587. S2CID 24610554.
Frenkel EP, Kitchens RL (decembar 1975). "Intracellular localization of hepatic propionyl-CoA carboxylase and methylmalonyl-CoA mutase in humans and normal and vitamin B12 deficient rats". British Journal of Haematology. 31 (4): 501–13. doi:10.1111/j.1365-2141.1975.tb00885.x. PMID 24458. S2CID 1232083.
Crane AM, Jansen R, Andrews ER, Ledley FD (februar 1992). "Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut- methylmalonic aciduria". The Journal of Clinical Investigation. 89 (2): 385–91. doi:10.1172/JCI115597. PMC 442864. PMID 1346616.
Crane AM, Martin LS, Valle D, Ledley FD (maj 1992). "Phenotype of disease in three patients with identical mutations in methylmalonyl CoA mutase". Human Genetics. 89 (3): 259–64. doi:10.1007/BF00220536. PMID 1351030. S2CID 5624280.
Raff ML, Crane AM, Jansen R, Ledley FD, Rosenblatt DS (januar 1991). "Genetic characterization of a MUT locus mutation discriminating heterogeneity in mut0 and mut- methylmalonic aciduria by interallelic complementation". The Journal of Clinical Investigation. 87 (1): 203–7. doi:10.1172/JCI114972. PMC 295026. PMID 1670635.
Jansen R, Ledley FD (novembar 1990). "Heterozygous mutations at the mut locus in fibroblasts with mut0 methylmalonic acidemia identified by polymerase-chain-reaction cDNA cloning". American Journal of Human Genetics. 47 (5): 808–14. PMC 1683687. PMID 1977311.
Nham SU, Wilkemeyer MF, Ledley FD (decembar 1990). "Structure of the human methylmalonyl-CoA mutase (MUT) locus". Genomics. 8 (4): 710–6. doi:10.1016/0888-7543(90)90259-W. PMID 1980486.
Ledley FD, Lumetta M, Nguyen PN, Kolhouse JF, Allen RH (maj 1988). "Molecular cloning of L-methylmalonyl-CoA mutase: gene transfer and analysis of mut cell lines". Proceedings of the National Academy of Sciences of the United States of America. 85 (10): 3518–21. Bibcode:1988PNAS...85.3518L. doi:10.1073/pnas.85.10.3518. PMC 280243. PMID 2453061.
Jansen R, Kalousek F, Fenton WA, Rosenberg LE, Ledley FD (februar 1989). "Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction". Genomics. 4 (2): 198–205. doi:10.1016/0888-7543(89)90300-5. PMID 2567699.
Fenton WA, Hack AM, Kraus JP, Rosenberg LE (mart 1987). "Immunochemical studies of fibroblasts from patients with methylmalonyl-CoA mutase apoenzyme deficiency: detection of a mutation interfering with mitochondrial import". Proceedings of the National Academy of Sciences of the United States of America. 84 (5): 1421–4. Bibcode:1987PNAS...84.1421F. doi:10.1073/pnas.84.5.1421. PMC 304442. PMID 2881300.
Zoghbi HY, O'Brien WE, Ledley FD (novembar 1988). "Linkage relationships of the human methylmalonyl CoA mutase to the HLA and D6S4 loci on chromosome 6". Genomics. 3 (4): 396–8. doi:10.1016/0888-7543(88)90135-8. PMID 2907507.
Kolhouse JF, Utley C, Allen RH (april 1980). "Isolation and characterization of methylmalonyl-CoA mutase from human placenta". The Journal of Biological Chemistry. 255 (7): 2708–12. doi:10.1016/S0021-9258(19)85795-2. PMID 6102092.
Fenton WA, Hack AM, Willard HF, Gertler A, Rosenberg LE (april 1982). "Purification and properties of methylmalonyl coenzyme A mutase from human liver". Archives of Biochemistry and Biophysics. 214 (2): 815–23. doi:10.1016/0003-9861(82)90088-1. PMID 6124211.
Qureshi AA, Crane AM, Matiaszuk NV, Rezvani I, Ledley FD, Rosenblatt DS (april 1994). "Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria". The Journal of Clinical Investigation. 93 (4): 1812–9. doi:10.1172/JCI117166. PMC 294249. PMID 7909321.
Crane AM, Ledley FD (juli 1994). "Clustering of mutations in methylmalonyl CoA mutase associated with mut- methylmalonic acidemia". American Journal of Human Genetics. 55 (1): 42–50. PMC 1918235. PMID 7912889.
Janata J, Kogekar N, Fenton WA (septembar 1997). "Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut- phenotype: evidence for naturally occurring interallelic complementation". Human Molecular Genetics. 6 (9): 1457–64. doi:10.1093/hmg/6.9.1457. PMID 9285782.

Vanjski linkovi

GeneReviews/NIH/NCBI/UW entry on Methylmalonic Acidemia
Methylmalonyl-CoA Mutase na US National Library of Medicine Medical Subject Headings (MeSH)

Šablon:Enzimi metabolizna aminokiselina Šablon:Enzimi ciklusa limunske kiselineCitric acid cycle enzymes Šablon:Mutaze

Portal Biologija

[:0-1] Keyfi F, Sankian M, Moghaddassian M, Rolfs A, Varasteh AR (januar 2016). "Molecular, biochemical, and structural analysis of a novel mutation in patients with methylmalonyl-CoA mutase deficiency". Gene. 576 (1 Pt 2): 208–13. doi:10.1016/j.gene.2015.10.002. PMID 26449400.

[pmid19699272-2] Ballhausen D, Mittaz L, Boulat O, Bonafé L, Braissant O (decembar 2009). "Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain". Neuroscience. 164 (2): 578–87. doi:10.1016/j.neuroscience.2009.08.028. PMID 19699272. S2CID 34612963.

[UniProt-3] "UniProt, P22033" (jezik: engleski). Pristupljeno 3. 10. 2021.

[4] Chandler RJ, Venditti CP (1. 10. 2016). "Genetic and genomic systems to study methylmalonic acidemia". Molecular Genetics and Metabolism. 86 (1–2): 34–43. doi:10.1016/j.ymgme.2005.07.020. PMC 2657357. PMID 16182581.

[pmid8643613-5] Drennan CL, Matthews RG, Rosenblatt DS, Ledley FD, Fenton WA, Ludwig ML (maj 1996). "Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase". Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5550–5. Bibcode:1996PNAS...93.5550D. doi:10.1073/pnas.93.11.5550. PMC 39284. PMID 8643613.

[6] Martínez MA, Rincón A, Desviat LR, Merinero B, Ugarte M, Pérez B (april 2005). "Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants". Molecular Genetics and Metabolism. 84 (4): 317–25. doi:10.1016/j.ymgme.2004.11.011. PMID 15781192.

[pmid25125334-7] Forny P, Froese DS, Suormala T, Yue WW, Baumgartner MR (decembar 2014). "Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency". Human Mutation. 35 (12): 1449–58. doi:10.1002/humu.22633. PMC 4441004. PMID 25125334.

[pmid22661206-8] Takahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME (juni 2012). "Role of vitamin B12 on methylmalonyl-CoA mutase activity". Journal of Zhejiang University Science B. 13 (6): 423–37. doi:10.1631/jzus.B1100329. PMC 3370288. PMID 22661206.

[pmid11893736-9] Vlasie M, Chowdhury S, Banerjee R (maj 2002). "Importance of the histidine ligand to coenzyme B12 in the reaction catalyzed by methylmalonyl-CoA mutase". The Journal of Biological Chemistry. 277 (21): 18523–7. doi:10.1074/jbc.M111809200. PMID 11893736.

[pmid10387043-10] Mancia F, Smith GA, Evans PR (juni 1999). "Crystal structure of substrate complexes of methylmalonyl-CoA mutase". Biochemistry. 38 (25): 7999–8005. doi:10.1021/bi9903852. PMID 10387043.

[pmid9655823-11] Mancia F, Evans PR (juni 1998). "Conformational changes on substrate binding to methylmalonyl CoA mutase and new insights into the free radical mechanism". Structure. 6 (6): 711–20. doi:10.1016/s0969-2126(98)00073-2. PMID 9655823.

[pmid10551831-12] Maiti N, Widjaja L, Banerjee R (novembar 1999). "Proton transfer from histidine 244 may facilitate the 1,2 rearrangement reaction in coenzyme B(12)-dependent methylmalonyl-CoA mutase". The Journal of Biological Chemistry. 274 (46): 32733–7. doi:10.1074/jbc.274.46.32733. PMID 10551831.

[pmid22945861-13] Buckel W, Friedrich P, Golding BT (oktobar 2012). "Hydrogen bonds guide the short-lived 5'-deoxyadenosyl radical to the place of action". Angewandte Chemie. 51 (40): 9974–6. doi:10.1002/anie.201205299. PMID 22945861.

[pmid9772164-14] Thomä NH, Meier TW, Evans PR, Leadlay PF (oktobar 1998). "Stabilization of radical intermediates by an active-site tyrosine residue in methylmalonyl-CoA mutase". Biochemistry. 37 (41): 14386–93. CiteSeerX 10.1.1.608.304. doi:10.1021/bi981375o. PMID 9772164.

[pmid21138732-15] Takahashi-Íñiguez T, García-Arellano H, Trujillo-Roldán MA, Flores ME (januar 2011). "Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein". Biochemical and Biophysical Research Communications. 404 (1): 443–7. doi:10.1016/j.bbrc.2010.11.141. PMID 21138732.

[pmid20876572-16] Froese DS, Kochan G, Muniz JR, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW (decembar 2010). "Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation". The Journal of Biological Chemistry. 285 (49): 38204–13. doi:10.1074/jbc.M110.177717. PMC 2992254. PMID 20876572.

[17] Dündar H, Özgül RK, Güzel-Ozantürk A, Dursun A, Sivri S, Aliefendioğlu D, Coşkun T, Tokatli A (august 2012). "Microarray based mutational analysis of patients with methylmalonic acidemia: identification of 10 novel mutations". Molecular Genetics and Metabolism. 106 (4): 419–23. doi:10.1016/j.ymgme.2012.05.014. PMID 22727635.

[pmid23041189-18] Buck NE, Wood LR, Hamilton NJ, Bennett MJ, Peters HL (novembar 2012). "Treatment of a methylmalonyl-CoA mutase stopcodon mutation". Biochemical and Biophysical Research Communications. 427 (4): 753–7. doi:10.1016/j.bbrc.2012.09.133. PMID 23041189.

[pmid23046887-19] Chandler RJ, Venditti CP (novembar 2012). "Pre-clinical efficacy and dosing of an AAV8 vector expressing human methylmalonyl-CoA mutase in a murine model of methylmalonic acidemia (MMA)". Molecular Genetics and Metabolism. 107 (3): 617–9. doi:10.1016/j.ymgme.2012.09.019. PMC 3522145. PMID 23046887.

[pmid23898205-20] Manoli I, Sysol JR, Li L, Houillier P, Garone C, Wang C, Zerfas PM, Cusmano-Ozog K, Young S, Trivedi NS, Cheng J, Sloan JL, Chandler RJ, Abu-Asab M, Tsokos M, Elkahloun AG, Rosen S, Enns GM, Berry GT, Hoffmann V, DiMauro S, Schnermann J, Venditti CP (august 2013). "Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia". Proceedings of the National Academy of Sciences of the United States of America. 110 (33): 13552–7. Bibcode:2013PNAS..11013552M. doi:10.1073/pnas.1302764110. PMC 3746875. PMID 23898205.

[21] Padovani D, Labunska T, Banerjee R (juni 2006). "Energetics of interaction between the G-protein chaperone, MeaB, and B12-dependent methylmalonyl-CoA mutase". The Journal of Biological Chemistry. 281 (26): 17838–44. doi:10.1074/jbc.M600047200. PMID 16641088.

[22] Taoka S, Padmakumar R, Lai MT, Liu HW, Banerjee R (decembar 1994). "Inhibition of the human methylmalonyl-CoA mutase by various CoA-esters". The Journal of Biological Chemistry. 269 (50): 31630–4. doi:10.1016/S0021-9258(18)31741-1. PMID 7989334.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]