ID   MA2A2_HUMAN             Reviewed;        1150 AA.
AC   P49641; A6NH12; A8K1E8; Q13754;
DT   01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT   21-SEP-2011, sequence version 3.
DT   27-MAR-2024, entry version 200.
DE   RecName: Full=Alpha-mannosidase 2x;
DE            EC=3.2.1.114 {ECO:0000250|UniProtKB:P28494};
DE   AltName: Full=Alpha-mannosidase IIx;
DE            Short=Man IIx;
DE   AltName: Full=Mannosidase alpha class 2A member 2;
DE   AltName: Full=Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase;
GN   Name=MAN2A2; Synonyms=MANA2X;
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 [MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Melanoma;
RX   PubMed=8524845; DOI=10.1073/pnas.92.25.11766;
RA   Misago M., Liao Y.-F., Kudo S., Eto S., Mattei M.-G., Moremen K.W.,
RA   Fukuda M.N.;
RT   "Molecular cloning and expression of cDNAs encoding human alpha-mannosidase
RT   II and a previously unrecognized alpha-mannosidase IIx isozyme.";
RL   Proc. Natl. Acad. Sci. U.S.A. 92:11766-11770(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC   TISSUE=Brain;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16572171; DOI=10.1038/nature04601;
RA   Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA   Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA   FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA   Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA   Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA   DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA   Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA   Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA   Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA   O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA   Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA   Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT   "Analysis of the DNA sequence and duplication history of human chromosome
RT   15.";
RL   Nature 440:671-675(2006).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC   TISSUE=Testis;
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   [5]
RP   SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
RX   PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8;
RA   Hillman R.T., Green R.E., Brenner S.E.;
RT   "An unappreciated role for RNA surveillance.";
RL   Genome Biol. 5:R8.1-R8.16(2004).
CC   -!- FUNCTION: Catalyzes the first committed step in the biosynthesis of
CC       complex N-glycans. It controls conversion of high mannose to complex N-
CC       glycans; the final hydrolytic step in the N-glycan maturation pathway.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=2 H2O + N(4)-{beta-D-GlcNAc-(1->2)-alpha-D-Man-(1->3)-[alpha-
CC         D-Man-(1->3)-[alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-
CC         (1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc}-L-asparaginyl-[protein] =
CC         2 alpha-D-mannopyranose + N(4)-{beta-D-GlcNAc-(1->2)-alpha-D-Man-
CC         (1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-
CC         beta-D-GlcNAc}-L-asparaginyl-[protein]; Xref=Rhea:RHEA:56052,
CC         Rhea:RHEA-COMP:14368, Rhea:RHEA-COMP:14369, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:28729, ChEBI:CHEBI:60615, ChEBI:CHEBI:60625;
CC         EC=3.2.1.114; Evidence={ECO:0000250|UniProtKB:P28494};
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 1 zinc ion per subunit. {ECO:0000250};
CC   -!- PATHWAY: Protein modification; protein glycosylation.
CC   -!- SUBUNIT: Homodimer; disulfide-linked (By similarity). Interacts with
CC       MGAT4D (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q8BRK9}.
CC   -!- SUBCELLULAR LOCATION: Golgi apparatus membrane {ECO:0000250}; Single-
CC       pass type II membrane protein {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC         Comment=Additional isoforms seem to exist.;
CC       Name=3;
CC         IsoId=P49641-3; Sequence=Displayed;
CC       Name=1; Synonyms=Long;
CC         IsoId=P49641-1; Sequence=VSP_041732, VSP_041734;
CC       Name=2; Synonyms=Short;
CC         IsoId=P49641-2; Sequence=VSP_041733;
CC   -!- MISCELLANEOUS: [Isoform 2]: May be produced at very low levels due to a
CC       premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC       decay. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the glycosyl hydrolase 38 family. {ECO:0000305}.
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DR   EMBL; D55649; BAA09510.1; -; mRNA.
DR   EMBL; L28821; AAA92022.1; -; mRNA.
DR   EMBL; AK289863; BAF82552.1; -; mRNA.
DR   EMBL; AC067986; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC068831; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC136448; AAI36449.1; -; mRNA.
DR   CCDS; CCDS32332.1; -. [P49641-3]
DR   RefSeq; NP_006113.2; NM_006122.3. [P49641-3]
DR   RefSeq; XP_016877674.1; XM_017022185.1. [P49641-3]
DR   AlphaFoldDB; P49641; -.
DR   SMR; P49641; -.
DR   BioGRID; 110295; 148.
DR   IntAct; P49641; 26.
DR   STRING; 9606.ENSP00000452948; -.
DR   CAZy; GH38; Glycoside Hydrolase Family 38.
DR   GlyCosmos; P49641; 7 sites, 3 glycans.
DR   GlyGen; P49641; 7 sites, 3 O-linked glycans (3 sites).
DR   iPTMnet; P49641; -.
DR   PhosphoSitePlus; P49641; -.
DR   SwissPalm; P49641; -.
DR   BioMuta; MAN2A2; -.
DR   DMDM; 347595795; -.
DR   EPD; P49641; -.
DR   jPOST; P49641; -.
DR   MassIVE; P49641; -.
DR   MaxQB; P49641; -.
DR   PaxDb; 9606-ENSP00000452948; -.
DR   PeptideAtlas; P49641; -.
DR   ProteomicsDB; 56037; -. [P49641-3]
DR   ProteomicsDB; 56038; -. [P49641-1]
DR   ProteomicsDB; 56039; -. [P49641-2]
DR   Pumba; P49641; -.
DR   Antibodypedia; 2725; 106 antibodies from 17 providers.
DR   DNASU; 4122; -.
DR   Ensembl; ENST00000360468.7; ENSP00000353655.3; ENSG00000196547.15. [P49641-3]
DR   Ensembl; ENST00000559717.6; ENSP00000452948.1; ENSG00000196547.15. [P49641-3]
DR   GeneID; 4122; -.
DR   KEGG; hsa:4122; -.
DR   MANE-Select; ENST00000559717.6; ENSP00000452948.1; NM_006122.4; NP_006113.2.
DR   UCSC; uc002bqc.4; human. [P49641-3]
DR   AGR; HGNC:6825; -.
DR   CTD; 4122; -.
DR   DisGeNET; 4122; -.
DR   GeneCards; MAN2A2; -.
DR   HGNC; HGNC:6825; MAN2A2.
DR   HPA; ENSG00000196547; Low tissue specificity.
DR   MIM; 600988; gene.
DR   neXtProt; NX_P49641; -.
DR   OpenTargets; ENSG00000196547; -.
DR   PharmGKB; PA30574; -.
DR   VEuPathDB; HostDB:ENSG00000196547; -.
DR   eggNOG; KOG1958; Eukaryota.
DR   GeneTree; ENSGT01030000234638; -.
DR   InParanoid; P49641; -.
DR   OMA; GHQWLKY; -.
DR   OrthoDB; 5474711at2759; -.
DR   PhylomeDB; P49641; -.
DR   TreeFam; TF313152; -.
DR   BioCyc; MetaCyc:HS11961-MONOMER; -.
DR   PathwayCommons; P49641; -.
DR   Reactome; R-HSA-6811438; Intra-Golgi traffic.
DR   Reactome; R-HSA-975578; Reactions specific to the complex N-glycan synthesis pathway.
DR   SignaLink; P49641; -.
DR   UniPathway; UPA00378; -.
DR   BioGRID-ORCS; 4122; 11 hits in 1159 CRISPR screens.
DR   ChiTaRS; MAN2A2; human.
DR   GenomeRNAi; 4122; -.
DR   Pharos; P49641; Tbio.
DR   PRO; PR:P49641; -.
DR   Proteomes; UP000005640; Chromosome 15.
DR   RNAct; P49641; Protein.
DR   Bgee; ENSG00000196547; Expressed in right hemisphere of cerebellum and 208 other cell types or tissues.
DR   ExpressionAtlas; P49641; baseline and differential.
DR   GO; GO:0000139; C:Golgi membrane; IBA:GO_Central.
DR   GO; GO:0004559; F:alpha-mannosidase activity; IBA:GO_Central.
DR   GO; GO:0030246; F:carbohydrate binding; IEA:InterPro.
DR   GO; GO:0016799; F:hydrolase activity, hydrolyzing N-glycosyl compounds; IEA:Ensembl.
DR   GO; GO:0004572; F:mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase activity; IEA:UniProtKB-EC.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0006013; P:mannose metabolic process; IEA:InterPro.
DR   GO; GO:0006491; P:N-glycan processing; IBA:GO_Central.
DR   GO; GO:0006486; P:protein glycosylation; IEA:UniProtKB-UniPathway.
DR   CDD; cd11667; GH38N_Man2A2; 1.
DR   Gene3D; 3.20.110.10; Glycoside hydrolase 38, N terminal domain; 1.
DR   Gene3D; 1.20.1270.50; Glycoside hydrolase family 38, central domain; 1.
DR   Gene3D; 2.60.40.1180; Golgi alpha-mannosidase II; 1.
DR   InterPro; IPR011013; Gal_mutarotase_sf_dom.
DR   InterPro; IPR011330; Glyco_hydro/deAcase_b/a-brl.
DR   InterPro; IPR011682; Glyco_hydro_38_C.
DR   InterPro; IPR015341; Glyco_hydro_38_cen.
DR   InterPro; IPR037094; Glyco_hydro_38_cen_sf.
DR   InterPro; IPR000602; Glyco_hydro_38_N.
DR   InterPro; IPR027291; Glyco_hydro_38_N_sf.
DR   InterPro; IPR028995; Glyco_hydro_57/38_cen_sf.
DR   InterPro; IPR013780; Glyco_hydro_b.
DR   PANTHER; PTHR11607; ALPHA-MANNOSIDASE; 1.
DR   PANTHER; PTHR11607:SF57; ALPHA-MANNOSIDASE 2X; 1.
DR   Pfam; PF09261; Alpha-mann_mid; 1.
DR   Pfam; PF07748; Glyco_hydro_38C; 1.
DR   Pfam; PF01074; Glyco_hydro_38N; 1.
DR   SMART; SM00872; Alpha-mann_mid; 1.
DR   SUPFAM; SSF88688; Families 57/38 glycoside transferase middle domain; 1.
DR   SUPFAM; SSF74650; Galactose mutarotase-like; 1.
DR   SUPFAM; SSF88713; Glycoside hydrolase/deacetylase; 1.
DR   Genevisible; P49641; HS.
PE   2: Evidence at transcript level;
KW   Alternative splicing; Disulfide bond; Glycoprotein; Glycosidase;
KW   Golgi apparatus; Hydrolase; Membrane; Metal-binding; Reference proteome;
KW   Signal-anchor; Transmembrane; Transmembrane helix; Zinc.
FT   CHAIN           1..1150
FT                   /note="Alpha-mannosidase 2x"
FT                   /id="PRO_0000206905"
FT   TOPO_DOM        1..5
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        6..26
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        27..796
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   ACT_SITE        289
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000250"
FT   BINDING         175
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250"
FT   BINDING         177
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250"
FT   BINDING         289
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250"
FT   BINDING         569
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        95
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        305
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        1093
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        1131
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         783..796
FT                   /note="SIRRVDEEHEQQVD -> GSGLCFLAEHPKGG (in isoform 1)"
FT                   /evidence="ECO:0000303|PubMed:8524845"
FT                   /id="VSP_041732"
FT   VAR_SEQ         797..1150
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:8524845"
FT                   /id="VSP_041733"
FT   VAR_SEQ         823..906
FT                   /note="KPYVPKEPPVLRVTEGPFFSEVVAYYEHIHQAVRLYNLPGVEGLSLDISSLV
FT                   DIRDYVNKELALHIHTDIDSQGIFFTDLNGFQ -> SPTSPRSPPCCVSLKALSSQRWL
FT                   RTMSTFTRRSGFTICQGWRGCLWTYHPWWTSGTTSTRSWPCTSIQTSTAR (in
FT                   isoform 1)"
FT                   /evidence="ECO:0000303|PubMed:8524845"
FT                   /id="VSP_041734"
FT   VARIANT         412
FT                   /note="Q -> R (in dbSNP:rs2106673)"
FT                   /id="VAR_047912"
FT   VARIANT         665
FT                   /note="S -> F (in dbSNP:rs1266494)"
FT                   /id="VAR_047913"
SQ   SEQUENCE   1150 AA;  130539 MW;  BFB3D763A6A55444 CRC64;
     MKLKKQVTVC GAAIFCVAVF SLYLMLDRVQ HDPTRHQNGG NFPRSQISVL QNRIEQLEQL
     LEENHEIISH IKDSVLELTA NAEGPPAMLP YYTVNGSWVV PPEPRPSFFS ISPQDCQFAL
     GGRGQKPELQ MLTVSEELPF DNVDGGVWRQ GFDISYDPHD WDAEDLQVFV VPHSHNDPGW
     IKTFDKYYTE QTQHILNSMV SKLQEDPRRR FLWAEVSFFA KWWDNINVQK RAAVRRLVGN
     GQLEIATGGW VMPDEANSHY FALIDQLIEG HQWLERNLGA TPRSGWAVDP FGYSSTMPYL
     LRRANLTSML IQRVHYAIKK HFAATHSLEF MWRQTWDSDS STDIFCHMMP FYSYDVPHTC
     GPDPKICCQF DFKRLPGGRI NCPWKVPPRA ITEANVAERA ALLLDQYRKK SQLFRSNVLL
     VPLGDDFRYD KPQEWDAQFF NYQRLFDFFN SRPNLHVQAQ FGTLSDYFDA LYKRTGVEPG
     ARPPGFPVLS GDFFSYADRE DHYWTGYYTS RPFYKSLDRV LEAHLRGAEV LYSLAAAHAR
     RSGLAGRYPL SDFTLLTEAR RTLGLFQHHD AITGTAKEAV VVDYGVRLLR SLVNLKQVII
     HAAHYLVLGD KETYHFDPEA PFLQVDDTRL SHDALPERTV IQLDSSPRFV VLFNPLEQER
     FSMVSLLVNS PRVRVLSEEG QPLAVQISAH WSSATEAVPD VYQVSVPVRL PALGLGVLQL
     QLGLDGHRTL PSSVRIYLHG RQLSVSRHEA FPLRVIDSGT SDFALSNRYM QVWFSGLTGL
     LKSIRRVDEE HEQQVDMQVL VYGTRTSKDK SGAYLFLPDG EAKPYVPKEP PVLRVTEGPF
     FSEVVAYYEH IHQAVRLYNL PGVEGLSLDI SSLVDIRDYV NKELALHIHT DIDSQGIFFT
     DLNGFQVQPR RYLKKLPLQA NFYPMPVMAY IQDAQKRLTL HTAQALGVSS LKDGQLEVIL
     DRRLMQDDNR GLGQGLKDNK RTCNRFRLLL ERRTVGSEVQ DSHSTSYPSL LSHLTSMYLN
     APALALPVAR MQLPGPGLRS FHPLASSLPC DFHLLNLRTL QAEEDTLPSA ETALILHRKG
     FDCGLEAKNL GFNCTTSQGK VALGSLFHGL DVVFLQPTSL TLLYPLASPS NSTDVYLEPM
     EIATFRLRLG
//