MMAC_HUMAN
ID MMAC_HUMAN Reviewed; 282 AA.
AC Q9Y4U1; Q5T157; Q9BRQ7;
DT 10-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 10-JAN-2006, sequence version 3.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Cyanocobalamin reductase / alkylcobalamin dealkylase;
DE AltName: Full=Alkylcobalamin:glutathione S-alkyltransferase;
DE EC=2.5.1.151 {ECO:0000269|PubMed:19801555, ECO:0000269|PubMed:21697092, ECO:0000269|PubMed:22642810, ECO:0000269|PubMed:25809485};
DE AltName: Full=CblC {ECO:0000303|PubMed:23415655, ECO:0000303|PubMed:25809485};
DE AltName: Full=Cyanocobalamin reductase (cyanide-eliminating);
DE EC=1.16.1.6 {ECO:0000269|PubMed:18779575, ECO:0000269|PubMed:19700356, ECO:0000269|PubMed:21697092, ECO:0000269|PubMed:25809485};
DE AltName: Full=Methylmalonic aciduria and homocystinuria type C protein {ECO:0000303|PubMed:19700356};
DE Short=MMACHC;
GN Name=MMACHC {ECO:0000312|HGNC:HGNC:24525};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 4-282.
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-245, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [5]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=18779575; DOI=10.1073/pnas.0805989105;
RA Kim J., Gherasim C., Banerjee R.;
RT "Decyanation of vitamin B12 by a trafficking chaperone.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:14551-14554(2008).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [7]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, CATALYTIC ACTIVITY, AND SUBSTRATE
RP SPECIFICITY.
RX PubMed=19801555; DOI=10.1074/jbc.m109.057877;
RA Kim J., Hannibal L., Gherasim C., Jacobsen D.W., Banerjee R.;
RT "A human vitamin B12 trafficking protein uses glutathione transferase
RT activity for processing alkylcobalamins.";
RL J. Biol. Chem. 284:33418-33424(2009).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, CHARACTERIZATION OF VARIANTS MAHCC
RP ASP-147 AND GLN-161, AND MUTAGENESIS OF HIS-122.
RX PubMed=19700356; DOI=10.1016/j.ymgme.2009.07.014;
RA Froese D.S., Zhang J., Healy S., Gravel R.A.;
RT "Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria
RT with homocystinuria.";
RL Mol. Genet. Metab. 98:338-343(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-275, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-247; SER-275 AND SER-279, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP FUNCTION, AND INTERACTION WITH MMADHC.
RX PubMed=21071249; DOI=10.1016/j.ymgme.2010.10.011;
RA Plesa M., Kim J., Paquette S.G., Gagnon H., Ng-Thow-Hing C., Gibbs B.F.,
RA Hancock M.A., Rosenblatt D.S., Coulton J.W.;
RT "Interaction between MMACHC and MMADHC, two human proteins participating in
RT intracellular vitamin B(1)(2) metabolism.";
RL Mol. Genet. Metab. 102:139-148(2011).
RN [13]
RP INTERACTION WITH MMADHC.
RX PubMed=23415655; DOI=10.1016/j.biochi.2013.02.003;
RA Gherasim C., Hannibal L., Rajagopalan D., Jacobsen D.W., Banerjee R.;
RT "The C-terminal domain of CblD interacts with CblC and influences
RT intracellular cobalamin partitioning.";
RL Biochimie 95:1023-1032(2013).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-275, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [15]
RP SUBCELLULAR LOCATION.
RX PubMed=23270877; DOI=10.1016/j.ymgme.2012.11.284;
RA Mah W., Deme J.C., Watkins D., Fung S., Janer A., Shoubridge E.A.,
RA Rosenblatt D.S., Coulton J.W.;
RT "Subcellular location of MMACHC and MMADHC, two human proteins central to
RT intracellular vitamin B(12) metabolism.";
RL Mol. Genet. Metab. 108:112-118(2013).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [17]
RP FUNCTION, AND INTERACTION WITH LMBRD1 AND ABCD4.
RX PubMed=25535791; DOI=10.3109/09687688.2014.990998;
RA Deme J.C., Hancock M.A., Xia X., Shintre C.A., Plesa M., Kim J.C.,
RA Carpenter E.P., Rosenblatt D.S., Coulton J.W.;
RT "Purification and interaction analyses of two human lysosomal vitamin B12
RT transporters: LMBD1 and ABCD4.";
RL Mol. Membr. Biol. 31:250-261(2014).
RN [18]
RP INTERACTION WITH MMADHC.
RX PubMed=26483544; DOI=10.1074/jbc.m115.683268;
RA Froese D.S., Kopec J., Fitzpatrick F., Schuller M., McCorvie T.J.,
RA Chalk R., Plessl T., Fettelschoss V., Fowler B., Baumgartner M.R.,
RA Yue W.W.;
RT "Structural insights into the MMACHC-MMADHC protein complex involved in
RT vitamin B12 trafficking.";
RL J. Biol. Chem. 290:29167-29177(2015).
RN [19]
RP FUNCTION, AND INTERACTION WITH MMADHC; MTR AND MTRR.
RX PubMed=27771510; DOI=10.1016/j.bbadis.2016.10.016;
RA Bassila C., Ghemrawi R., Flayac J., Froese D.S., Baumgartner M.R.,
RA Gueant J.L., Coelho D.;
RT "Methionine synthase and methionine synthase reductase interact with MMACHC
RT and with MMADHC.";
RL Biochim. Biophys. Acta 1863:103-112(2017).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 1-238 IN COMPLEX WITH
RP METHYLCOBALAMIN, FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND SUBUNIT.
RX PubMed=21697092; DOI=10.1074/jbc.m111.261370;
RA Koutmos M., Gherasim C., Smith J.L., Banerjee R.;
RT "Structural basis of multifunctionality in a vitamin B12-processing
RT enzyme.";
RL J. Biol. Chem. 286:29780-29787(2011).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) IN COMPLEX WITH ADENOSYLCOBALAMIN,
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, CHARACTERIZATION OF VARIANT MAHCC
RP GLN-161, AND MUTAGENESIS OF ARG-206 AND ARG-230.
RX PubMed=22642810; DOI=10.1021/bi300150y;
RA Froese D.S., Krojer T., Wu X., Shrestha R., Kiyani W., von Delft F.,
RA Gravel R.A., Oppermann U., Yue W.W.;
RT "Structure of MMACHC reveals an arginine-rich pocket and a domain-swapped
RT dimer for its B12 processing function.";
RL Biochemistry 51:5083-5090(2012).
RN [22]
RP VARIANTS MAHCC ARG-27; PRO-116; ARG-122; HIS-130; ASP-147; ALA-147;
RP ASP-156; CYS-157; GLY-161; GLN-161; SER-189; PRO-193; TRP-206 AND PRO-206,
RP AND TISSUE SPECIFICITY.
RX PubMed=16311595; DOI=10.1038/ng1683;
RA Lerner-Ellis J.P., Tirone J.C., Pawelek P.D., Dore C., Atkinson J.L.,
RA Watkins D., Morel C.F., Fujiwara T.M., Moras E., Hosack A.R., Dunbar G.V.,
RA Antonicka H., Forgetta V., Dobson C.M., Leclerc D., Gravel R.A.,
RA Shoubridge E.A., Coulton J.W., Lepage P., Rommens J.M., Morgan K.,
RA Rosenblatt D.S.;
RT "Identification of the gene responsible for methylmalonic aciduria and
RT homocystinuria, cblC type.";
RL Nat. Genet. 38:93-100(2006).
RN [23]
RP CHARACTERIZATION OF VARIANT MAHCC GLN-161.
RX PubMed=20219402; DOI=10.1016/j.ymgme.2010.02.005;
RA Froese D.S., Healy S., McDonald M., Kochan G., Oppermann U., Niesen F.H.,
RA Gravel R.A.;
RT "Thermolability of mutant MMACHC protein in the vitamin B12-responsive cblC
RT disorder.";
RL Mol. Genet. Metab. 100:29-36(2010).
RN [24]
RP CHARACTERIZATION OF VARIANTS MAHCC GLY-161 AND GLN-161, FUNCTION, AND
RP CATALYTIC ACTIVITY.
RX PubMed=25809485; DOI=10.1074/jbc.m115.637132;
RA Gherasim C., Ruetz M., Li Z., Hudolin S., Banerjee R.;
RT "Pathogenic mutations differentially affect the catalytic activities of the
RT human B12-processing chaperone CblC and increase futile redox cycling.";
RL J. Biol. Chem. 290:11393-11402(2015).
CC -!- FUNCTION: Cobalamin (vitamin B12) cytosolic chaperone that catalyzes
CC the reductive decyanation of cyanocob(III)alamin (cyanocobalamin,
CC CNCbl) to yield cob(II)alamin and cyanide, using FAD or FMN as
CC cofactors and NADPH as cosubstrate (PubMed:18779575, PubMed:19700356,
CC PubMed:21697092, PubMed:25809485). Cyanocobalamin constitutes the
CC inactive form of vitamin B12 introduced from the diet, and is converted
CC into the active cofactors methylcobalamin (MeCbl) involved in
CC methionine biosynthesis, and 5'-deoxyadenosylcobalamin (AdoCbl)
CC involved in the TCA cycle (PubMed:19801555). Forms a complex with the
CC lysosomal transporter ABCD4 and its chaperone LMBRD1, to transport
CC cobalamin across the lysosomal membrane into the cytosol
CC (PubMed:25535791). The processing of cobalamin in the cytosol occurs in
CC a multiprotein complex composed of at least MMACHC, MMADHC, MTRR
CC (methionine synthase reductase) and MTR (methionine synthase) which may
CC contribute to shuttle safely and efficiently cobalamin towards MTR in
CC order to produce methionine (PubMed:21071249, PubMed:27771510). Also
CC acts as a glutathione transferase by catalyzing the dealkylation of the
CC alkylcob(III)alamins MeCbl and AdoCbl, using the thiolate of
CC glutathione for nucleophilic displacement to generate cob(I)alamin and
CC the corresponding glutathione thioether (PubMed:19801555,
CC PubMed:21697092, PubMed:22642810, PubMed:25809485). The conversion of
CC incoming MeCbl or AdoCbl into a common intermediate cob(I)alamin is
CC necessary to meet the cellular needs for both cofactors
CC (PubMed:19801555). Cysteine and homocysteine cannot substitute for
CC glutathione in this reaction (PubMed:19801555).
CC {ECO:0000269|PubMed:18779575, ECO:0000269|PubMed:19700356,
CC ECO:0000269|PubMed:19801555, ECO:0000269|PubMed:21071249,
CC ECO:0000269|PubMed:21697092, ECO:0000269|PubMed:22642810,
CC ECO:0000269|PubMed:25809485, ECO:0000269|PubMed:27771510,
CC ECO:0000303|PubMed:19801555, ECO:0000303|PubMed:25535791}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 cob(II)alamin-[cyanocobalamin reductase] + 2 hydrogen
CC cyanide + NADP(+) = 2 apo-[cyanocobalamin reductase] + 2
CC cyanocob(III)alamin + H(+) + NADPH; Xref=Rhea:RHEA:16113, Rhea:RHEA-
CC COMP:14717, Rhea:RHEA-COMP:14718, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16304, ChEBI:CHEBI:17439, ChEBI:CHEBI:18407,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:83228; EC=1.16.1.6;
CC Evidence={ECO:0000269|PubMed:18779575, ECO:0000269|PubMed:19700356,
CC ECO:0000269|PubMed:21697092, ECO:0000269|PubMed:25809485};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:16115;
CC Evidence={ECO:0000305|PubMed:19700356};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an R-cob(III)alamin + apo-[alkylcobalamin reductase] +
CC glutathione = an S-substituted glutathione + cob(I)alamin-
CC [alkylcobalamin reductase] + H(+); Xref=Rhea:RHEA:40719, Rhea:RHEA-
CC COMP:14730, Rhea:RHEA-COMP:14731, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57925, ChEBI:CHEBI:60488, ChEBI:CHEBI:83228,
CC ChEBI:CHEBI:90779, ChEBI:CHEBI:140785; EC=2.5.1.151;
CC Evidence={ECO:0000269|PubMed:19801555, ECO:0000269|PubMed:21697092,
CC ECO:0000269|PubMed:22642810, ECO:0000269|PubMed:25809485};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40720;
CC Evidence={ECO:0000305|PubMed:25809485};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=apo-[alkylcobalamin reductase] + glutathione +
CC methylcob(III)alamin = cob(I)alamin-[alkylcobalamin reductase] + H(+)
CC + S-methyl glutathione; Xref=Rhea:RHEA:63132, Rhea:RHEA-COMP:14730,
CC Rhea:RHEA-COMP:14731, ChEBI:CHEBI:15378, ChEBI:CHEBI:28115,
CC ChEBI:CHEBI:57925, ChEBI:CHEBI:60488, ChEBI:CHEBI:83228,
CC ChEBI:CHEBI:141467; EC=2.5.1.151;
CC Evidence={ECO:0000269|PubMed:19801555, ECO:0000269|PubMed:22642810,
CC ECO:0000269|PubMed:25809485};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63133;
CC Evidence={ECO:0000305|PubMed:25809485};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=adenosylcob(III)alamin + apo-[alkylcobalamin reductase] +
CC glutathione = cob(I)alamin-[alkylcobalamin reductase] + H(+) + S-
CC adenosylglutathione; Xref=Rhea:RHEA:63136, Rhea:RHEA-COMP:14730,
CC Rhea:RHEA-COMP:14731, ChEBI:CHEBI:15378, ChEBI:CHEBI:18408,
CC ChEBI:CHEBI:57925, ChEBI:CHEBI:60488, ChEBI:CHEBI:83228,
CC ChEBI:CHEBI:146184; EC=2.5.1.151;
CC Evidence={ECO:0000269|PubMed:19801555};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63137;
CC Evidence={ECO:0000305|PubMed:19801555};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:19700356, ECO:0000269|PubMed:21697092};
CC Name=FMN; Xref=ChEBI:CHEBI:58210;
CC Evidence={ECO:0000269|PubMed:19700356, ECO:0000269|PubMed:21697092};
CC Note=Can utilize both FAD and FMN. {ECO:0000269|PubMed:19700356,
CC ECO:0000269|PubMed:21697092};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=27.7 uM for glutathione {ECO:0000269|PubMed:19801555};
CC Note=kcat is 11.7 h(-1) for the dealkylation of methylcobalamin
CC (MeCbl) (PubMed:19801555). kcat is 0.006 h(-1) for the dealkylation
CC of 5'-deoxyadenosylcobalamin (AdoCbl) (PubMed:19801555).
CC {ECO:0000269|PubMed:19801555};
CC -!- SUBUNIT: Monomer in the absence of bound substrate (PubMed:21697092,
CC PubMed:22642810). Homodimer; dimerization is triggered by binding to
CC FMN or adenosylcobalamin (PubMed:22642810). Interacts with LMBRD1 and
CC ABCD4; the interaction ensures the transport of cobalamin from the
CC lysosome to the cytoplasm (PubMed:25535791). Forms a multiprotein
CC complex with MMADHC, MTR and MTRR; the interaction with MTR could
CC modulate MMACHC-dependent processing of cobalamin (PubMed:27771510).
CC Heterodimer with MMADHC; the interaction might play a role in the
CC regulation of the balance between AdoCbl and MeCbl synthesis
CC (PubMed:21071249, PubMed:23415655, PubMed:26483544).
CC {ECO:0000269|PubMed:21071249, ECO:0000269|PubMed:21697092,
CC ECO:0000269|PubMed:22642810, ECO:0000269|PubMed:23415655,
CC ECO:0000269|PubMed:25535791, ECO:0000269|PubMed:26483544,
CC ECO:0000269|PubMed:27771510}.
CC -!- INTERACTION:
CC Q9Y4U1; Q99707: MTR; NbExp=3; IntAct=EBI-9775184, EBI-1045782;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:23270877}.
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed at higher level in
CC fetal liver. Also expressed in spleen, lymph node, thymus and bone
CC marrow. Weakly or not expressed in peripheral blood leukocytes.
CC {ECO:0000269|PubMed:16311595}.
CC -!- DISEASE: Methylmalonic aciduria and homocystinuria, cblC type (MAHCC)
CC [MIM:277400]: An autosomal recessive disorder of cobalamin metabolism
CC characterized by decreased levels of the coenzymes adenosylcobalamin
CC (AdoCbl) and methylcobalamin (MeCbl). Affected individuals may have
CC developmental, hematologic, neurologic, metabolic, ophthalmologic, and
CC dermatologic clinical findings. Although considered a disease of
CC infancy or childhood, some individuals develop symptoms in adulthood.
CC {ECO:0000269|PubMed:16311595, ECO:0000269|PubMed:19700356,
CC ECO:0000269|PubMed:20219402, ECO:0000269|PubMed:22642810,
CC ECO:0000269|PubMed:25809485}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the MMACHC family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH06122.3; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AL080062; CAB45693.2; -; mRNA.
DR EMBL; AL451136; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC006122; AAH06122.3; ALT_INIT; mRNA.
DR CCDS; CCDS41324.1; -.
DR PIR; T12462; T12462.
DR RefSeq; NP_001317469.1; NM_001330540.1.
DR RefSeq; NP_056321.2; NM_015506.2.
DR PDB; 3SBY; X-ray; 2.71 A; A/B=1-244.
DR PDB; 3SBZ; X-ray; 2.00 A; A=1-244.
DR PDB; 3SC0; X-ray; 1.95 A; A=1-238.
DR PDB; 3SOM; X-ray; 2.40 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P=1-282.
DR PDB; 5UOS; X-ray; 2.51 A; A=1-238.
DR PDBsum; 3SBY; -.
DR PDBsum; 3SBZ; -.
DR PDBsum; 3SC0; -.
DR PDBsum; 3SOM; -.
DR PDBsum; 5UOS; -.
DR AlphaFoldDB; Q9Y4U1; -.
DR SMR; Q9Y4U1; -.
DR BioGRID; 117458; 18.
DR IntAct; Q9Y4U1; 2.
DR STRING; 9606.ENSP00000383840; -.
DR DrugBank; DB00115; Cyanocobalamin.
DR DrugBank; DB00200; Hydroxocobalamin.
DR iPTMnet; Q9Y4U1; -.
DR PhosphoSitePlus; Q9Y4U1; -.
DR BioMuta; MMACHC; -.
DR DMDM; 85681045; -.
DR EPD; Q9Y4U1; -.
DR jPOST; Q9Y4U1; -.
DR MassIVE; Q9Y4U1; -.
DR MaxQB; Q9Y4U1; -.
DR PaxDb; Q9Y4U1; -.
DR PeptideAtlas; Q9Y4U1; -.
DR PRIDE; Q9Y4U1; -.
DR ProteomicsDB; 86249; -.
DR TopDownProteomics; Q9Y4U1; -.
DR ABCD; Q9Y4U1; 1 sequenced antibody.
DR Antibodypedia; 32641; 404 antibodies from 31 providers.
DR DNASU; 25974; -.
DR Ensembl; ENST00000401061.9; ENSP00000383840.4; ENSG00000132763.15.
DR GeneID; 25974; -.
DR KEGG; hsa:25974; -.
DR MANE-Select; ENST00000401061.9; ENSP00000383840.4; NM_015506.3; NP_056321.2.
DR UCSC; uc009vxv.4; human.
DR CTD; 25974; -.
DR DisGeNET; 25974; -.
DR GeneCards; MMACHC; -.
DR GeneReviews; MMACHC; -.
DR HGNC; HGNC:24525; MMACHC.
DR HPA; ENSG00000132763; Tissue enhanced (liver).
DR MalaCards; MMACHC; -.
DR MIM; 277400; phenotype.
DR MIM; 609831; gene.
DR neXtProt; NX_Q9Y4U1; -.
DR OpenTargets; ENSG00000132763; -.
DR Orphanet; 79282; Methylmalonic acidemia with homocystinuria, type cblC.
DR PharmGKB; PA142671348; -.
DR VEuPathDB; HostDB:ENSG00000132763; -.
DR eggNOG; KOG4552; Eukaryota.
DR GeneTree; ENSGT00390000003464; -.
DR HOGENOM; CLU_095722_0_0_1; -.
DR InParanoid; Q9Y4U1; -.
DR OMA; QMEVIAD; -.
DR OrthoDB; 1375709at2759; -.
DR PhylomeDB; Q9Y4U1; -.
DR TreeFam; TF332476; -.
DR BioCyc; MetaCyc:ENSG00000132763-MON; -.
DR BRENDA; 2.5.1.151; 2681.
DR PathwayCommons; Q9Y4U1; -.
DR Reactome; R-HSA-3359473; Defective MMADHC causes MMAHCD.
DR Reactome; R-HSA-3359474; Defective MMACHC causes MAHCC.
DR Reactome; R-HSA-9759218; Cobalamin (Cbl) metabolism.
DR SignaLink; Q9Y4U1; -.
DR BioGRID-ORCS; 25974; 58 hits in 1084 CRISPR screens.
DR ChiTaRS; MMACHC; human.
DR EvolutionaryTrace; Q9Y4U1; -.
DR GeneWiki; MMACHC; -.
DR GenomeRNAi; 25974; -.
DR Pharos; Q9Y4U1; Tbio.
DR PRO; PR:Q9Y4U1; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9Y4U1; protein.
DR Bgee; ENSG00000132763; Expressed in right lobe of liver and 107 other tissues.
DR ExpressionAtlas; Q9Y4U1; baseline and differential.
DR Genevisible; Q9Y4U1; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:0031419; F:cobalamin binding; IEA:UniProtKB-KW.
DR GO; GO:0033787; F:cyanocobalamin reductase (cyanide-eliminating) activity; IDA:UniProtKB.
DR GO; GO:0032451; F:demethylase activity; IDA:UniProtKB.
DR GO; GO:0071949; F:FAD binding; IDA:UniProtKB.
DR GO; GO:0043295; F:glutathione binding; IDA:UniProtKB.
DR GO; GO:0016491; F:oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB.
DR GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW.
DR GO; GO:0009235; P:cobalamin metabolic process; IDA:UniProtKB.
DR GO; GO:0070988; P:demethylation; IDA:UniProtKB.
DR GO; GO:0006749; P:glutathione metabolic process; IDA:UniProtKB.
DR CDD; cd12959; MMACHC-like; 1.
DR InterPro; IPR032037; MMACHC.
DR PANTHER; PTHR31457; PTHR31457; 1.
DR Pfam; PF16690; MMACHC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cobalamin; Cobalt; Cytoplasm; Disease variant; FAD;
KW Flavoprotein; FMN; NADP; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Transferase.
FT CHAIN 1..282
FT /note="Cyanocobalamin reductase / alkylcobalamin
FT dealkylase"
FT /id="PRO_0000076258"
FT REGION 234..282
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 244..258
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 104
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21697092,
FT ECO:0000269|PubMed:22642810, ECO:0007744|PDB:3SC0,
FT ECO:0007744|PDB:3SOM"
FT BINDING 115..118
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21697092,
FT ECO:0000269|PubMed:22642810, ECO:0007744|PDB:3SC0,
FT ECO:0007744|PDB:3SOM"
FT BINDING 129..131
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21697092,
FT ECO:0000269|PubMed:22642810, ECO:0007744|PDB:3SC0,
FT ECO:0007744|PDB:3SOM"
FT BINDING 149
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21697092,
FT ECO:0000269|PubMed:22642810, ECO:0007744|PDB:3SC0,
FT ECO:0007744|PDB:3SOM"
FT BINDING 160
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21697092,
FT ECO:0000269|PubMed:22642810, ECO:0007744|PDB:3SC0,
FT ECO:0007744|PDB:3SOM"
FT MOD_RES 245
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 247
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT MOD_RES 275
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT MOD_RES 279
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT VARIANT 27
FT /note="Q -> R (in MAHCC; dbSNP:rs546099787)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024770"
FT VARIANT 116
FT /note="L -> P (in MAHCC; dbSNP:rs121918240)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024771"
FT VARIANT 122
FT /note="H -> R (in MAHCC)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024772"
FT VARIANT 130
FT /note="Y -> H (in MAHCC; dbSNP:rs372670428)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024773"
FT VARIANT 147
FT /note="G -> A (in MAHCC; dbSNP:rs140522266)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024774"
FT VARIANT 147
FT /note="G -> D (in MAHCC; loss of cyanocobalamin binding;
FT dbSNP:rs140522266)"
FT /evidence="ECO:0000269|PubMed:16311595,
FT ECO:0000269|PubMed:19700356"
FT /id="VAR_024775"
FT VARIANT 156
FT /note="G -> D (in MAHCC; dbSNP:rs1553162910)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024776"
FT VARIANT 157
FT /note="W -> C (in MAHCC; dbSNP:rs1002571805)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024777"
FT VARIANT 161
FT /note="R -> G (in MAHCC; results in decreased stability and
FT decreased methylcobalamin dealkylation activity;
FT dbSNP:rs370596113)"
FT /evidence="ECO:0000269|PubMed:16311595,
FT ECO:0000269|PubMed:25809485"
FT /id="VAR_024778"
FT VARIANT 161
FT /note="R -> Q (in MAHCC; results in decreased stability and
FT reduced stabilization induced by cobalamin binding; has
FT reduced affinity for cyanocobalamin and reduced activity in
FT dealkylation of methylcobalamin; dbSNP:rs121918243)"
FT /evidence="ECO:0000269|PubMed:16311595,
FT ECO:0000269|PubMed:19700356, ECO:0000269|PubMed:20219402,
FT ECO:0000269|PubMed:22642810, ECO:0000269|PubMed:25809485"
FT /id="VAR_024779"
FT VARIANT 189
FT /note="R -> S (in MAHCC; dbSNP:rs200895671)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024780"
FT VARIANT 193
FT /note="L -> P (in MAHCC; dbSNP:rs1233135084)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024781"
FT VARIANT 206
FT /note="R -> P (in MAHCC; dbSNP:rs371753672)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024782"
FT VARIANT 206
FT /note="R -> W (in MAHCC; dbSNP:rs538023671)"
FT /evidence="ECO:0000269|PubMed:16311595"
FT /id="VAR_024783"
FT VARIANT 271
FT /note="S -> G (in dbSNP:rs35219601)"
FT /id="VAR_038805"
FT MUTAGEN 122
FT /note="H->A: Reduced affinity for cyanocobalamin."
FT /evidence="ECO:0000269|PubMed:19700356"
FT MUTAGEN 206
FT /note="R->Q: Impairs protein folding."
FT /evidence="ECO:0000269|PubMed:22642810"
FT MUTAGEN 230
FT /note="R->Q: Reduced activity in dealkylation of
FT methylcobalamin."
FT /evidence="ECO:0000269|PubMed:22642810"
FT CONFLICT 100
FT /note="E -> G (in Ref. 1; CAB45693)"
FT /evidence="ECO:0000305"
FT HELIX 3..16
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 17..19
FT /evidence="ECO:0007829|PDB:3SC0"
FT STRAND 21..27
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 28..32
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 37..39
FT /evidence="ECO:0007829|PDB:3SC0"
FT STRAND 47..54
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 58..61
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 63..66
FT /evidence="ECO:0007829|PDB:3SC0"
FT STRAND 74..76
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 78..93
FT /evidence="ECO:0007829|PDB:3SC0"
FT STRAND 100..103
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 104..106
FT /evidence="ECO:0007829|PDB:3SBY"
FT STRAND 113..115
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 117..123
FT /evidence="ECO:0007829|PDB:3SC0"
FT STRAND 126..130
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 132..134
FT /evidence="ECO:0007829|PDB:3SC0"
FT STRAND 135..137
FT /evidence="ECO:0007829|PDB:3SOM"
FT TURN 139..142
FT /evidence="ECO:0007829|PDB:3SBY"
FT STRAND 148..151
FT /evidence="ECO:0007829|PDB:3SC0"
FT TURN 152..154
FT /evidence="ECO:0007829|PDB:3SC0"
FT STRAND 159..170
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 186..198
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 200..202
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 204..207
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 217..222
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 226..229
FT /evidence="ECO:0007829|PDB:3SC0"
FT HELIX 230..233
FT /evidence="ECO:0007829|PDB:5UOS"
FT TURN 235..237
FT /evidence="ECO:0007829|PDB:3SC0"
SQ SEQUENCE 282 AA; 31728 MW; 3A7E6BC774CB5D17 CRC64;
MEPKVAELKQ KIEDTLCPFG FEVYPFQVAW YNELLPPAFH LPLPGPTLAF LVLSTPAMFD
RALKPFLQSC HLRMLTDPVD QCVAYHLGRV RESLPELQIE IIADYEVHPN RRPKILAQTA
AHVAGAAYYY QRQDVEADPW GNQRISGVCI HPRFGGWFAI RGVVLLPGIE VPDLPPRKPH
DCVPTRADRI ALLEGFNFHW RDWTYRDAVT PQERYSEEQK AYFSTPPAQR LALLGLAQPS
EKPSSPSPDL PFTTPAPKKP GNPSRARSWL SPRVSPPASP GP
