ID   TREA_HUMAN              Reviewed;         583 AA.
AC   O43280; Q32MB9; Q53FY8;
DT   15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT   23-SEP-2008, sequence version 2.
DT   27-MAR-2024, entry version 182.
DE   RecName: Full=Trehalase {ECO:0000303|PubMed:9427547};
DE            EC=3.2.1.28 {ECO:0000269|PubMed:8773341, ECO:0000269|PubMed:9427547};
DE   AltName: Full=Alpha,alpha-trehalase;
DE   AltName: Full=Alpha,alpha-trehalose glucohydrolase;
DE   Flags: Precursor;
GN   Name=TREH {ECO:0000312|HGNC:HGNC:12266}; Synonyms=TREA;
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] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY, AND
RP   TISSUE SPECIFICITY.
RC   TISSUE=Kidney;
RX   PubMed=9427547; DOI=10.1016/s0378-1119(97)00455-1;
RA   Ishihara R., Taketani S., Sasai-Takedatsu M., Kino M., Tokunaga R.,
RA   Kobayashi Y.;
RT   "Molecular cloning, sequencing and expression of cDNA encoding human
RT   trehalase.";
RL   Gene 202:69-74(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Kidney;
RA   Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA   Tanaka A., Yokoyama S.;
RL   Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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   PARTIAL PROTEIN SEQUENCE, FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=8773341; DOI=10.1159/000189037;
RA   Sasai-Takedatsu M., Taketani S., Nagata N., Furukawa T., Tokunaga R.,
RA   Kojima T., Kobayashi Y.;
RT   "Human trehalase: characterization, localization, and its increase in urine
RT   by renal proximal tubular damage.";
RL   Nephron 73:179-185(1996).
RN   [6]
RP   INVOLVEMENT IN TREHD.
RX   PubMed=28406212; DOI=10.1038/nature22034;
RA   Saleheen D., Natarajan P., Armean I.M., Zhao W., Rasheed A.,
RA   Khetarpal S.A., Won H.H., Karczewski K.J., O'Donnell-Luria A.H.,
RA   Samocha K.E., Weisburd B., Gupta N., Zaidi M., Samuel M., Imran A.,
RA   Abbas S., Majeed F., Ishaq M., Akhtar S., Trindade K., Mucksavage M.,
RA   Qamar N., Zaman K.S., Yaqoob Z., Saghir T., Rizvi S.N.H., Memon A.,
RA   Hayyat Mallick N., Ishaq M., Rasheed S.Z., Memon F.U., Mahmood K.,
RA   Ahmed N., Do R., Krauss R.M., MacArthur D.G., Gabriel S., Lander E.S.,
RA   Daly M.J., Frossard P., Danesh J., Rader D.J., Kathiresan S.;
RT   "Human knockouts and phenotypic analysis in a cohort with a high rate of
RT   consanguinity.";
RL   Nature 544:235-239(2017).
CC   -!- FUNCTION: Intestinal trehalase is probably involved in the hydrolysis
CC       of ingested trehalose. {ECO:0000269|PubMed:8773341,
CC       ECO:0000269|PubMed:9427547}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=alpha,alpha-trehalose + H2O = alpha-D-glucose + beta-D-
CC         glucose; Xref=Rhea:RHEA:32675, ChEBI:CHEBI:15377, ChEBI:CHEBI:15903,
CC         ChEBI:CHEBI:16551, ChEBI:CHEBI:17925; EC=3.2.1.28;
CC         Evidence={ECO:0000269|PubMed:8773341, ECO:0000269|PubMed:9427547};
CC   -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000250|UniProtKB:P19813}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P19813};
CC       Lipid-anchor, GPI-anchor {ECO:0000250|UniProtKB:P19813}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=O43280-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=O43280-2; Sequence=VSP_035440;
CC   -!- TISSUE SPECIFICITY: Expressed in kidney, liver and small intestine.
CC       Also more weakly expressed in pancreas. {ECO:0000269|PubMed:9427547}.
CC   -!- DISEASE: Trehalase deficiency (TREHD) [MIM:612119]: An autosomal
CC       recessive condition characterized by the inability to digest trehalose,
CC       a disaccharide found in mushrooms, products containing baker's yeast,
CC       and dried food. Individuals with trehalase deficiency suffer from
CC       abdominal pain, increased rectal flatulence, and diarrhea due to
CC       osmotic water flow into the colon. {ECO:0000269|PubMed:28406212}.
CC       Note=The gene represented in this entry is involved in disease
CC       pathogenesis.
CC   -!- SIMILARITY: Belongs to the glycosyl hydrolase 37 family. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=Trehalase entry;
CC       URL="https://en.wikipedia.org/wiki/Trehalase";
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DR   EMBL; AB000824; BAA24381.1; -; mRNA.
DR   EMBL; AK223140; BAD96860.1; -; mRNA.
DR   EMBL; AK223143; BAD96863.1; -; mRNA.
DR   EMBL; CH471065; EAW67409.1; -; Genomic_DNA.
DR   EMBL; BC109206; AAI09207.1; -; mRNA.
DR   CCDS; CCDS73401.1; -. [O43280-2]
DR   CCDS; CCDS73402.1; -. [O43280-1]
DR   PIR; JC6504; JC6504.
DR   RefSeq; NP_001287994.1; NM_001301065.1. [O43280-2]
DR   RefSeq; NP_009111.2; NM_007180.2. [O43280-1]
DR   AlphaFoldDB; O43280; -.
DR   SMR; O43280; -.
DR   BioGRID; 116351; 6.
DR   IntAct; O43280; 1.
DR   STRING; 9606.ENSP00000264029; -.
DR   BindingDB; O43280; -.
DR   ChEMBL; CHEMBL3087; -.
DR   CAZy; GH37; Glycoside Hydrolase Family 37.
DR   GlyCosmos; O43280; 4 sites, No reported glycans.
DR   GlyGen; O43280; 4 sites.
DR   iPTMnet; O43280; -.
DR   PhosphoSitePlus; O43280; -.
DR   BioMuta; TREH; -.
DR   MassIVE; O43280; -.
DR   PaxDb; 9606-ENSP00000264029; -.
DR   PeptideAtlas; O43280; -.
DR   ProteomicsDB; 48848; -. [O43280-1]
DR   ProteomicsDB; 48849; -. [O43280-2]
DR   Antibodypedia; 48758; 137 antibodies from 20 providers.
DR   DNASU; 11181; -.
DR   Ensembl; ENST00000264029.9; ENSP00000264029.5; ENSG00000118094.12. [O43280-1]
DR   Ensembl; ENST00000397925.2; ENSP00000381020.2; ENSG00000118094.12. [O43280-2]
DR   GeneID; 11181; -.
DR   KEGG; hsa:11181; -.
DR   MANE-Select; ENST00000264029.9; ENSP00000264029.5; NM_007180.3; NP_009111.2.
DR   UCSC; uc031ygn.2; human. [O43280-1]
DR   AGR; HGNC:12266; -.
DR   CTD; 11181; -.
DR   DisGeNET; 11181; -.
DR   GeneCards; TREH; -.
DR   HGNC; HGNC:12266; TREH.
DR   HPA; ENSG00000118094; Tissue enriched (intestine).
DR   MalaCards; TREH; -.
DR   MIM; 275360; gene.
DR   MIM; 612119; phenotype.
DR   neXtProt; NX_O43280; -.
DR   OpenTargets; ENSG00000118094; -.
DR   Orphanet; 103909; Trehalase deficiency.
DR   PharmGKB; PA36946; -.
DR   VEuPathDB; HostDB:ENSG00000118094; -.
DR   eggNOG; KOG0602; Eukaryota.
DR   GeneTree; ENSGT00390000006949; -.
DR   HOGENOM; CLU_006451_4_3_1; -.
DR   InParanoid; O43280; -.
DR   OMA; NRYWDAS; -.
DR   OrthoDB; 1329212at2759; -.
DR   PhylomeDB; O43280; -.
DR   TreeFam; TF314239; -.
DR   BRENDA; 3.2.1.28; 2681.
DR   PathwayCommons; O43280; -.
DR   Reactome; R-HSA-189085; Digestion of dietary carbohydrate.
DR   SignaLink; O43280; -.
DR   BioGRID-ORCS; 11181; 9 hits in 378 CRISPR screens.
DR   GenomeRNAi; 11181; -.
DR   Pharos; O43280; Tchem.
DR   PRO; PR:O43280; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   RNAct; O43280; Protein.
DR   Bgee; ENSG00000118094; Expressed in jejunal mucosa and 96 other cell types or tissues.
DR   ExpressionAtlas; O43280; baseline and differential.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; TAS:UniProtKB.
DR   GO; GO:0098552; C:side of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0004555; F:alpha,alpha-trehalase activity; IDA:UniProtKB.
DR   GO; GO:0009887; P:animal organ morphogenesis; IEA:Ensembl.
DR   GO; GO:0005993; P:trehalose catabolic process; IDA:UniProtKB.
DR   GO; GO:0005991; P:trehalose metabolic process; NAS:UniProtKB.
DR   Gene3D; 1.50.10.10; -; 1.
DR   InterPro; IPR008928; 6-hairpin_glycosidase_sf.
DR   InterPro; IPR012341; 6hp_glycosidase-like_sf.
DR   InterPro; IPR001661; Glyco_hydro_37.
DR   InterPro; IPR018232; Glyco_hydro_37_CS.
DR   PANTHER; PTHR23403; TREHALASE; 1.
DR   PANTHER; PTHR23403:SF1; TREHALASE; 1.
DR   Pfam; PF01204; Trehalase; 1.
DR   PRINTS; PR00744; GLHYDRLASE37.
DR   SUPFAM; SSF48208; Six-hairpin glycosidases; 1.
DR   PROSITE; PS00927; TREHALASE_1; 1.
DR   PROSITE; PS00928; TREHALASE_2; 1.
DR   Genevisible; O43280; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cell membrane; Direct protein sequencing;
KW   Disulfide bond; Glycoprotein; Glycosidase; GPI-anchor; Hydrolase;
KW   Lipoprotein; Membrane; Reference proteome; Signal.
FT   SIGNAL          1..23
FT                   /evidence="ECO:0000255"
FT   CHAIN           24..556
FT                   /note="Trehalase"
FT                   /id="PRO_0000012051"
FT   PROPEP          557..583
FT                   /note="Removed in mature form"
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000012052"
FT   ACT_SITE        321
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:P13482"
FT   ACT_SITE        514
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:P13482"
FT   BINDING         168
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P13482"
FT   BINDING         175..176
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P13482"
FT   BINDING         212
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P13482"
FT   BINDING         221..223
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P13482"
FT   BINDING         286..288
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P13482"
FT   BINDING         319
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P13482"
FT   BINDING         529
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P13482"
FT   LIPID           556
FT                   /note="GPI-anchor amidated serine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        78
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT   CARBOHYD        239
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT   CARBOHYD        261
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT   CARBOHYD        369
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT   VAR_SEQ         175..206
FT                   /note="WDSYWVMEGLLLSEMAETVKGMLQNFLDLVKT -> C (in isoform
FT                   2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_035440"
FT   VARIANT         389
FT                   /note="T -> A (in dbSNP:rs2276065)"
FT                   /id="VAR_049205"
FT   VARIANT         449
FT                   /note="Y -> H (in dbSNP:rs11827611)"
FT                   /id="VAR_049206"
FT   VARIANT         486
FT                   /note="R -> W (in dbSNP:rs2276064)"
FT                   /id="VAR_049207"
FT   VARIANT         558
FT                   /note="A -> P (in dbSNP:rs6589671)"
FT                   /id="VAR_049208"
FT   VARIANT         561
FT                   /note="A -> P (in dbSNP:rs6589670)"
FT                   /id="VAR_061191"
FT   CONFLICT        539..540
FT                   /note="TN -> DE (in Ref. 1; BAA24381)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   583 AA;  66568 MW;  3EE4D312B82185F9 CRC64;
     MPGRTWELCL LLLLGLGLGS QEALPPPCES EIYCHGELLN QVQMAKLYQD DKQFVDMPLS
     IAPEQVLQTF TELSRDHNHS IPREQLQAFV HEHFQAKGQE LQPWTPADWK DSPQFLQKIS
     DAKLRAWAGQ LHQLWKKLGK KMKPEVLSHP ERFSLIYSEH PFIVPGGRFV EFYYWDSYWV
     MEGLLLSEMA ETVKGMLQNF LDLVKTYGHV PNGGRVYYLQ RSQPPLLTLM MDCYLTHTND
     TAFLQENIET LALELDFWTK NRTVSVSLEG KNYLLNRYYV PYGGPRPESY SKDVELADTL
     PEGDREALWA ELKAGAESGW DFSSRWLIGG PNPNSLSGIR TSKLVPVDLN AFLCQAEELM
     SNFYSRLGND SQATKYRILR SQRLAALNTV LWDEQTGAWF DYDLEKKKKN REFYPSNLTP
     LWAGCFSDPG VADKALKYLE DNRILTYQYG IPTSLQKTGQ QWDFPNAWAP LQDLVIRGLA
     KAPLRRAQEV AFQLAQNWIR TNFDVYSQKS AMYEKYDVSN GGQPGGGGEY EVQEGFGWTN
     GVVLMLLDRY GDRLTSGAKL AFLEPHCLAA TLLPSLLLSL LPW
//