DHSO_HUMAN
ID DHSO_HUMAN Reviewed; 357 AA.
AC Q00796; B2R655; B7Z3A6; J3JZZ5; Q16682; Q9UMD6;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 23-MAR-2010, sequence version 4.
DT 03-AUG-2022, entry version 222.
DE RecName: Full=Sorbitol dehydrogenase {ECO:0000303|PubMed:12962626, ECO:0000303|PubMed:3365415, ECO:0000303|PubMed:8088829};
DE Short=SDH {ECO:0000303|PubMed:12962626};
DE EC=1.1.1.- {ECO:0000269|PubMed:12962626, ECO:0000269|PubMed:3365415};
DE AltName: Full=(R,R)-butanediol dehydrogenase {ECO:0000305|PubMed:3365415};
DE EC=1.1.1.4 {ECO:0000269|PubMed:3365415};
DE AltName: Full=L-iditol 2-dehydrogenase;
DE EC=1.1.1.14 {ECO:0000250|UniProtKB:P07846};
DE AltName: Full=Polyol dehydrogenase {ECO:0000303|PubMed:3365415};
DE AltName: Full=Ribitol dehydrogenase {ECO:0000305|PubMed:3365415};
DE Short=RDH;
DE EC=1.1.1.56 {ECO:0000269|PubMed:3365415};
DE AltName: Full=Xylitol dehydrogenase {ECO:0000303|PubMed:3365415};
DE Short=XDH;
DE EC=1.1.1.9 {ECO:0000269|PubMed:3365415};
GN Name=SORD;
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), AND VARIANT THR-269.
RC TISSUE=Liver;
RX PubMed=8088829; DOI=10.1006/geno.1994.1276;
RA Lee F.K., Cheung M.C., Chung S.;
RT "The human sorbitol dehydrogenase gene: cDNA cloning, sequence
RT determination, and mapping by fluorescence in situ hybridization.";
RL Genomics 21:354-358(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND VARIANTS LEU-239
RP AND THR-269.
RX PubMed=7782086; DOI=10.1016/0888-7543(95)80082-w;
RA Iwata T., Popescu N.C., Zimonjic D.B., Karlsson C., Hoeoeg J.-O., Vaca G.,
RA Rodriguez I.R., Carper D.;
RT "Structural organization of the human sorbitol dehydrogenase gene (SORD).";
RL Genomics 26:55-62(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT THR-269.
RX PubMed=9183016; DOI=10.1111/j.1432-1033.1997.00760.x;
RA Carr I.M., Markham A.F., Coletta P.L.;
RT "Identification and characterisation of a sequence related to human
RT sorbitol dehydrogenase.";
RL Eur. J. Biochem. 245:760-767(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP THR-269.
RC TISSUE=Brain, and Hippocampus;
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 [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT THR-269.
RC TISSUE=Brain, and Lymph;
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 [7]
RP PROTEIN SEQUENCE OF 2-357.
RC TISSUE=Liver;
RX PubMed=2691249; DOI=10.1111/j.1432-1033.1989.tb15240.x;
RA Karlsson C., Maret W., Auld D.S., Hoeoeg J.-O., Joernvall H.;
RT "Variability within mammalian sorbitol dehydrogenases. The primary
RT structure of the human liver enzyme.";
RL Eur. J. Biochem. 186:543-550(1989).
RN [8]
RP PROTEIN SEQUENCE OF 2-21.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R.,
RA Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass spectrometric
RT identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, COFACTOR, ACTIVITY REGULATION, SUBUNIT, AND TISSUE SPECIFICITY.
RX PubMed=3365415; DOI=10.1021/bi00405a035;
RA Maret W., Auld D.S.;
RT "Purification and characterization of human liver sorbitol dehydrogenase.";
RL Biochemistry 27:1622-1628(1988).
RN [10]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16278369; DOI=10.2164/jandrol.05108;
RA Frenette G., Thabet M., Sullivan R.;
RT "Polyol pathway in human epididymis and semen.";
RL J. Androl. 27:233-239(2006).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [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 [12]
RP TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=20372835; DOI=10.3892/or_00000755;
RA Szabo Z., Hamalainen J., Loikkanen I., Moilanen A.M., Hirvikoski P.,
RA Vaisanen T., Paavonen T.K., Vaarala M.H.;
RT "Sorbitol dehydrogenase expression is regulated by androgens in the human
RT prostate.";
RL Oncol. Rep. 23:1233-1239(2010).
RN [13]
RP TISSUE SPECIFICITY.
RX PubMed=19423711; DOI=10.1074/jbc.m109.001792;
RA Lanaspa M.A., Andres-Hernando A., Rivard C.J., Dai Y., Li N., Berl T.;
RT "ZAC1 is up-regulated by hypertonicity and decreases sorbitol dehydrogenase
RT expression, allowing accumulation of sorbitol in kidney cells.";
RL J. Biol. Chem. 284:19974-19981(2009).
RN [14]
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 [15]
RP REVIEW, AND ROLE OF THE POLYOL PATHWAY IN DIABETIC RETINOPATHY.
RX PubMed=25105142; DOI=10.1155/2014/801269;
RA Safi S.Z., Qvist R., Kumar S., Batumalaie K., Ismail I.S.;
RT "Molecular mechanisms of diabetic retinopathy, general preventive
RT strategies, and novel therapeutic targets.";
RL Biomed. Res. Int. 2014:801269-801269(2014).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-211 AND SER-225, AND
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 ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [18]
RP REVIEW, AND ROLE OF THE POLYOL PATHWAY IN DIABETIC NEUROPATHY.
RX PubMed=29966615; DOI=10.1016/j.ejphar.2018.06.034;
RA Dewanjee S., Das S., Das A.K., Bhattacharjee N., Dihingia A., Dua T.K.,
RA Kalita J., Manna P.;
RT "Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic
RT targets.";
RL Eur. J. Pharmacol. 833:472-523(2018).
RN [19] {ECO:0007744|PDB:1PL6, ECO:0007744|PDB:1PL7, ECO:0007744|PDB:1PL8}
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEXES WITH ZINC; NAD AND
RP INHIBITOR CP-166,572, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, ACTIVITY REGULATION, SUBUNIT, AND REACTION MECHANISM.
RX PubMed=12962626; DOI=10.1016/s0969-2126(03)00167-9;
RA Pauly T.A., Ekstrom J.L., Beebe D.A., Chrunyk B., Cunningham D.,
RA Griffor M., Kamath A., Lee S.E., Madura R., Mcguire D., Subashi T.,
RA Wasilko D., Watts P., Mylari B.L., Oates P.J., Adams P.D., Rath V.L.;
RT "X-ray crystallographic and kinetic studies of human sorbitol
RT dehydrogenase.";
RL Structure 11:1071-1085(2003).
RN [20]
RP VARIANTS SORDD PHE-10; 100-ARG--PRO-357 DEL; PRO-110; ASP-153;
RP 299-ARG--PRO-357 DEL AND ILE-322, AND INVOLVEMENT IN SORDD.
RX PubMed=32367058; DOI=10.1038/s41588-020-0615-4;
RG Inherited Neuropathy Consortium;
RA Cortese A., Zhu Y., Rebelo A.P., Negri S., Courel S., Abreu L., Bacon C.J.,
RA Bai Y., Bis-Brewer D.M., Bugiardini E., Buglo E., Danzi M.C., Feely S.M.E.,
RA Athanasiou-Fragkouli A., Haridy N.A., Isasi R., Khan A., Laura M.,
RA Magri S., Pipis M., Pisciotta C., Powell E., Rossor A.M., Saveri P.,
RA Sowden J.E., Tozza S., Vandrovcova J., Dallman J., Grignani E.,
RA Marchioni E., Scherer S.S., Tang B., Lin Z., Al-Ajmi A., Schuele R.,
RA Synofzik M., Maisonobe T., Stojkovic T., Auer-Grumbach M., Abdelhamed M.A.,
RA Hamed S.A., Zhang R., Manganelli F., Santoro L., Taroni F., Pareyson D.,
RA Houlden H., Herrmann D.N., Reilly M.M., Shy M.E., Zhai R.G., Zuchner S.;
RT "Biallelic mutations in SORD cause a common and potentially treatable
RT hereditary neuropathy with implications for diabetes.";
RL Nat. Genet. 52:473-481(2020).
RN [21]
RP ERRATUM.
RX PubMed=32457452; DOI=10.1038/s41588-020-0649-7;
RG Inherited Neuropathy Consortium;
RA Cortese A., Zhu Y., Rebelo A.P., Negri S., Courel S., Abreu L., Bacon C.J.,
RA Bai Y., Bis-Brewer D.M., Bugiardini E., Buglo E., Danzi M.C., Feely S.M.E.,
RA Athanasiou-Fragkouli A., Haridy N.A., Isasi R., Khan A., Laura M.,
RA Magri S., Pipis M., Pisciotta C., Powell E., Rossor A.M., Saveri P.,
RA Sowden J.E., Tozza S., Vandrovcova J., Dallman J., Grignani E.,
RA Marchioni E., Scherer S.S., Tang B., Lin Z., Al-Ajmi A., Schuele R.,
RA Synofzik M., Maisonobe T., Stojkovic T., Auer-Grumbach M., Abdelhamed M.A.,
RA Hamed S.A., Zhang R., Manganelli F., Santoro L., Taroni F., Pareyson D.,
RA Houlden H., Herrmann D.N., Reilly M.M., Shy M.E., Zhai R.G., Zuchner S.;
RL Nat. Genet. 52:640-640(2020).
RN [22]
RP VARIANT SORDD 209-ARG--PRO-357 DEL, AND INVOLVEMENT IN SORDD.
RX PubMed=33314640; DOI=10.1002/acn3.51268;
RA Yuan R.Y., Ye Z.L., Zhang X.R., Xu L.Q., He J.;
RT "Evaluation of SORD mutations as a novel cause of Charcot-Marie-Tooth
RT disease.";
RL Ann. Clin. Transl. Neurol. 8:266-270(2021).
RN [23]
RP VARIANT SORDD ARG-135, AND CHARACTERIZATION OF VARIANTS SORDD PRO-110;
RP ARG-135 AND ASP-153.
RX PubMed=33397963; DOI=10.1038/s41525-020-00165-6;
RA Dong H.L., Li J.Q., Liu G.L., Yu H., Wu Z.Y.;
RT "Biallelic SORD pathogenic variants cause Chinese patients with distal
RT hereditary motor neuropathy.";
RL NPJ Genom. Med. 6:1-1(2021).
CC -!- FUNCTION: Polyol dehydrogenase that catalyzes the reversible NAD(+)-
CC dependent oxidation of various sugar alcohols. Is mostly active with D-
CC sorbitol (D-glucitol), L-threitol, xylitol and ribitol as substrates,
CC leading to the C2-oxidized products D-fructose, L-erythrulose, D-
CC xylulose, and D-ribulose, respectively (PubMed:3365415). Is a key
CC enzyme in the polyol pathway that interconverts glucose and fructose
CC via sorbitol, which constitutes an important alternate route for
CC glucose metabolism. The polyol pathway is believed to be involved in
CC the etiology of diabetic complications, such as diabetic neuropathy and
CC retinopathy, induced by hyperglycemia (PubMed:12962626,
CC PubMed:29966615, PubMed:25105142). May play a role in sperm motility by
CC using sorbitol as an alternative energy source for sperm motility
CC (PubMed:16278369). May have a more general function in the metabolism
CC of secondary alcohols since it also catalyzes the stereospecific
CC oxidation of (2R,3R)-2,3-butanediol. To a lesser extent, can also
CC oxidize L-arabinitol, galactitol and D-mannitol and glycerol in vitro.
CC Oxidizes neither ethanol nor other primary alcohols. Cannot use NADP(+)
CC as the electron acceptor (PubMed:3365415).
CC {ECO:0000269|PubMed:16278369, ECO:0000269|PubMed:3365415,
CC ECO:0000303|PubMed:25105142, ECO:0000303|PubMed:29966615,
CC ECO:0000305|PubMed:12962626}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + keto-D-fructose + NADH = D-sorbitol + NAD(+);
CC Xref=Rhea:RHEA:33031, ChEBI:CHEBI:15378, ChEBI:CHEBI:17924,
CC ChEBI:CHEBI:48095, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000269|PubMed:12962626, ECO:0000269|PubMed:3365415};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:33033;
CC Evidence={ECO:0000305|PubMed:12962626};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-threitol + NAD(+) = H(+) + L-erythrulose + NADH;
CC Xref=Rhea:RHEA:48760, ChEBI:CHEBI:15378, ChEBI:CHEBI:27913,
CC ChEBI:CHEBI:42090, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000269|PubMed:3365415};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NAD(+) + xylitol = D-xylulose + H(+) + NADH;
CC Xref=Rhea:RHEA:20433, ChEBI:CHEBI:15378, ChEBI:CHEBI:17140,
CC ChEBI:CHEBI:17151, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.9;
CC Evidence={ECO:0000269|PubMed:3365415};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NAD(+) + ribitol = D-ribulose + H(+) + NADH;
CC Xref=Rhea:RHEA:20053, ChEBI:CHEBI:15378, ChEBI:CHEBI:15963,
CC ChEBI:CHEBI:17173, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.56;
CC Evidence={ECO:0000269|PubMed:3365415};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R,R)-butane-2,3-diol + NAD(+) = (R)-acetoin + H(+) + NADH;
CC Xref=Rhea:RHEA:24340, ChEBI:CHEBI:15378, ChEBI:CHEBI:15686,
CC ChEBI:CHEBI:16982, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.4;
CC Evidence={ECO:0000269|PubMed:3365415};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-iditol + NAD(+) = H(+) + keto-L-sorbose + NADH;
CC Xref=Rhea:RHEA:10160, ChEBI:CHEBI:13172, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:18202, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.14;
CC Evidence={ECO:0000250|UniProtKB:P07846};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:12962626, ECO:0000269|PubMed:3365415};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:12962626,
CC ECO:0000269|PubMed:3365415};
CC -!- ACTIVITY REGULATION: Inhibited by CP-166,572, an inhibitor that is
CC competitive with fructose (PubMed:12962626). Also competitively
CC inhibited by phenanthroline and 4-methylpyrazole in vitro
CC (PubMed:3365415). {ECO:0000269|PubMed:12962626,
CC ECO:0000269|PubMed:3365415}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.5 mM for sorbitol {ECO:0000269|PubMed:12962626};
CC KM=225 uM for NAD(+) {ECO:0000269|PubMed:12962626};
CC KM=210 uM for NADH {ECO:0000269|PubMed:12962626};
CC KM=0.62 mM for D-sorbitol (at pH 7.1) {ECO:0000269|PubMed:3365415};
CC KM=0.67 mM for D-sorbitol (at pH 10.0) {ECO:0000269|PubMed:3365415};
CC KM=0.22 mM for xylitol (at pH 10.0) {ECO:0000269|PubMed:3365415};
CC KM=2.7 mM for L-threitol (at pH 10.0) {ECO:0000269|PubMed:3365415};
CC KM=9.5 mM for (2R,3R)-2,3-butanediol (at pH 10.0)
CC {ECO:0000269|PubMed:3365415};
CC KM=0.14 M for D-fructose (at pH 7.1) {ECO:0000269|PubMed:3365415};
CC Note=kcat is 1.7 sec(-1) for the oxidation of D-sorbitol at pH 7.1,
CC and 5.2 sec(-1) at pH 10.0. kcat is 5.9 sec(-1) the oxidation of
CC xylitol as substrate at pH 10.0. kcat is 5.3 sec(-1) the oxidation of
CC L-threitol as substrate at pH 10.0. kcat is 4.2 sec(-1) the oxidation
CC of (2R,3R)-2,3-butanediol as substrate at pH 10.0. kcat is 45 sec(-1)
CC for the reduction of D-fructose at pH 7.1.
CC {ECO:0000269|PubMed:3365415};
CC -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:12962626,
CC ECO:0000269|PubMed:3365415}.
CC -!- INTERACTION:
CC Q00796; Q00796: SORD; NbExp=6; IntAct=EBI-750068, EBI-750068;
CC -!- SUBCELLULAR LOCATION: Mitochondrion membrane
CC {ECO:0000250|UniProtKB:Q64442}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q64442}. Cell projection, cilium, flagellum
CC {ECO:0000250|UniProtKB:Q64442}. Note=Associated with mitochondria of
CC the midpiece and near the plasma membrane in the principal piece of the
CC flagellum. Also found in the epididymosome, secreted by the epididymal
CC epithelium and that transfers proteins from the epididymal fluid to the
CC sperm surface. {ECO:0000250|UniProtKB:Q64442}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q00796-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q00796-2; Sequence=VSP_056353, VSP_056354;
CC -!- TISSUE SPECIFICITY: Expressed in liver (PubMed:3365415). Expressed in
CC kidney and epithelial cells of both benign and malignant prostate
CC tissue. Expressed in epididymis (at protein level).
CC {ECO:0000269|PubMed:16278369, ECO:0000269|PubMed:19423711,
CC ECO:0000269|PubMed:20372835, ECO:0000269|PubMed:3365415}.
CC -!- INDUCTION: Up-regulated by androgens and down-regulated by castration.
CC {ECO:0000269|PubMed:20372835}.
CC -!- DISEASE: Sorbitol dehydrogenase deficiency with peripheral neuropathy
CC (SORDD) [MIM:618912]: An autosomal recessive disorder characterized by
CC motor axonal neuropathy, slowly progressive distal muscle weakness
CC mainly affecting the lower limbs, difficulty walking, and increased
CC serum sorbitol. Additional variable features are distal sensory
CC impairment, upper limb tremor, scoliosis, and mild hearing loss.
CC {ECO:0000269|PubMed:32367058, ECO:0000269|PubMed:33314640,
CC ECO:0000269|PubMed:33397963}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the zinc-containing alcohol dehydrogenase
CC family. {ECO:0000305}.
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DR EMBL; U07361; AAA66064.1; -; mRNA.
DR EMBL; L29008; AAA80565.1; -; mRNA.
DR EMBL; L29254; AAA80566.1; -; Genomic_DNA.
DR EMBL; L29249; AAA80566.1; JOINED; Genomic_DNA.
DR EMBL; L29250; AAA80566.1; JOINED; Genomic_DNA.
DR EMBL; L29251; AAA80566.1; JOINED; Genomic_DNA.
DR EMBL; L29252; AAA80566.1; JOINED; Genomic_DNA.
DR EMBL; L29253; AAA80566.1; JOINED; Genomic_DNA.
DR EMBL; U67243; AAB61898.1; -; Genomic_DNA.
DR EMBL; U67236; AAB61898.1; JOINED; Genomic_DNA.
DR EMBL; U67237; AAB61898.1; JOINED; Genomic_DNA.
DR EMBL; U67238; AAB61898.1; JOINED; Genomic_DNA.
DR EMBL; U67239; AAB61898.1; JOINED; Genomic_DNA.
DR EMBL; U67240; AAB61898.1; JOINED; Genomic_DNA.
DR EMBL; U67241; AAB61898.1; JOINED; Genomic_DNA.
DR EMBL; U67242; AAB61898.1; JOINED; Genomic_DNA.
DR EMBL; AK295656; BAH12142.1; -; mRNA.
DR EMBL; AK312444; BAG35352.1; -; mRNA.
DR EMBL; AC090888; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC091117; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC021085; AAH21085.1; -; mRNA.
DR EMBL; BC025295; AAH25295.1; -; mRNA.
DR CCDS; CCDS10116.1; -. [Q00796-1]
DR PIR; A54674; A54674.
DR RefSeq; NP_003095.2; NM_003104.5. [Q00796-1]
DR PDB; 1PL6; X-ray; 2.00 A; A/B/C/D=2-357.
DR PDB; 1PL7; X-ray; 2.20 A; A/B/C/D=2-357.
DR PDB; 1PL8; X-ray; 1.90 A; A/B/C/D=2-357.
DR PDBsum; 1PL6; -.
DR PDBsum; 1PL7; -.
DR PDBsum; 1PL8; -.
DR AlphaFoldDB; Q00796; -.
DR SMR; Q00796; -.
DR BioGRID; 112535; 88.
DR IntAct; Q00796; 15.
DR MINT; Q00796; -.
DR STRING; 9606.ENSP00000267814; -.
DR BindingDB; Q00796; -.
DR ChEMBL; CHEMBL2275; -.
DR DrugBank; DB04478; Cp-166572, 2-Hydroxymethyl-4-(4-N,N-Dimethylaminosulfonyl-1-Piperazino)-Pyrimidine.
DR DrugBank; DB00157; NADH.
DR DrugCentral; Q00796; -.
DR iPTMnet; Q00796; -.
DR MetOSite; Q00796; -.
DR PhosphoSitePlus; Q00796; -.
DR SwissPalm; Q00796; -.
DR BioMuta; SORD; -.
DR DMDM; 292495088; -.
DR REPRODUCTION-2DPAGE; IPI00216057; -.
DR EPD; Q00796; -.
DR jPOST; Q00796; -.
DR MassIVE; Q00796; -.
DR MaxQB; Q00796; -.
DR PaxDb; Q00796; -.
DR PeptideAtlas; Q00796; -.
DR PRIDE; Q00796; -.
DR ProteomicsDB; 57873; -. [Q00796-1]
DR ProteomicsDB; 6501; -.
DR Antibodypedia; 24307; 573 antibodies from 32 providers.
DR DNASU; 6652; -.
DR Ensembl; ENST00000267814.14; ENSP00000267814.9; ENSG00000140263.15. [Q00796-1]
DR Ensembl; ENST00000558789.5; ENSP00000453904.1; ENSG00000140263.15. [Q00796-2]
DR GeneID; 6652; -.
DR KEGG; hsa:6652; -.
DR MANE-Select; ENST00000267814.14; ENSP00000267814.9; NM_003104.6; NP_003095.2.
DR UCSC; uc001zul.5; human. [Q00796-1]
DR CTD; 6652; -.
DR DisGeNET; 6652; -.
DR GeneCards; SORD; -.
DR HGNC; HGNC:11184; SORD.
DR HPA; ENSG00000140263; Tissue enhanced (cervix, liver).
DR MalaCards; SORD; -.
DR MIM; 182500; gene.
DR MIM; 618912; phenotype.
DR neXtProt; NX_Q00796; -.
DR OpenTargets; ENSG00000140263; -.
DR PharmGKB; PA36021; -.
DR VEuPathDB; HostDB:ENSG00000140263; -.
DR eggNOG; KOG0024; Eukaryota.
DR GeneTree; ENSGT00550000074781; -.
DR HOGENOM; CLU_168382_0_0_1; -.
DR InParanoid; Q00796; -.
DR OMA; ETWYAMS; -.
DR OrthoDB; 1019156at2759; -.
DR PhylomeDB; Q00796; -.
DR TreeFam; TF313060; -.
DR BRENDA; 1.1.1.14; 2681.
DR PathwayCommons; Q00796; -.
DR Reactome; R-HSA-5652227; Fructose biosynthesis.
DR Reactome; R-HSA-5661270; Formation of xylulose-5-phosphate.
DR SABIO-RK; Q00796; -.
DR SignaLink; Q00796; -.
DR BioGRID-ORCS; 6652; 15 hits in 1077 CRISPR screens.
DR ChiTaRS; SORD; human.
DR EvolutionaryTrace; Q00796; -.
DR GeneWiki; SORD; -.
DR GenomeRNAi; 6652; -.
DR Pharos; Q00796; Tchem.
DR PRO; PR:Q00796; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; Q00796; protein.
DR Bgee; ENSG00000140263; Expressed in right lobe of thyroid gland and 126 other tissues.
DR ExpressionAtlas; Q00796; baseline and differential.
DR Genevisible; Q00796; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; TAS:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031514; C:motile cilium; ISS:UniProtKB.
DR GO; GO:0000721; F:(R,R)-butanediol dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0030246; F:carbohydrate binding; NAS:UniProtKB.
DR GO; GO:0047833; F:D-sorbitol dehydrogenase (acceptor) activity; IEA:Ensembl.
DR GO; GO:0046526; F:D-xylulose reductase activity; IEA:UniProtKB-EC.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0003939; F:L-iditol 2-dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0051287; F:NAD binding; IDA:UniProtKB.
DR GO; GO:0050255; F:ribitol 2-dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0030317; P:flagellated sperm motility; ISS:UniProtKB.
DR GO; GO:0046370; P:fructose biosynthetic process; IDA:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; TAS:UniProtKB.
DR GO; GO:0051160; P:L-xylitol catabolic process; IDA:UniProtKB.
DR GO; GO:0051164; P:L-xylitol metabolic process; IDA:UniProtKB.
DR GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl.
DR GO; GO:0046688; P:response to copper ion; IEA:Ensembl.
DR GO; GO:0009725; P:response to hormone; IEA:Ensembl.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR GO; GO:0006970; P:response to osmotic stress; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0006062; P:sorbitol catabolic process; IDA:UniProtKB.
DR CDD; cd05285; sorbitol_DH; 1.
DR InterPro; IPR013149; ADH-like_C.
DR InterPro; IPR013154; ADH_N.
DR InterPro; IPR002328; ADH_Zn_CS.
DR InterPro; IPR011032; GroES-like_sf.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020843; PKS_ER.
DR InterPro; IPR045306; SDH-like.
DR Pfam; PF08240; ADH_N; 1.
DR Pfam; PF00107; ADH_zinc_N; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00059; ADH_ZINC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell projection; Cilium;
KW Direct protein sequencing; Disease variant; Flagellum; Membrane;
KW Metal-binding; Mitochondrion; NAD; Neuropathy; Oxidoreductase;
KW Phosphoprotein; Reference proteome; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:12665801,
FT ECO:0000269|PubMed:2691249, ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:25944712"
FT CHAIN 2..357
FT /note="Sorbitol dehydrogenase"
FT /id="PRO_0000160817"
FT BINDING 45
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:12962626,
FT ECO:0007744|PDB:1PL7, ECO:0007744|PDB:1PL8"
FT BINDING 51
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P07846"
FT BINDING 70
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:12962626,
FT ECO:0007744|PDB:1PL7, ECO:0007744|PDB:1PL8"
FT BINDING 71
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:12962626,
FT ECO:0007744|PDB:1PL7, ECO:0007744|PDB:1PL8"
FT BINDING 156
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P07846"
FT BINDING 184
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:12962626,
FT ECO:0007744|PDB:1PL6, ECO:0007744|PDB:1PL8"
FT BINDING 204
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:12962626,
FT ECO:0007744|PDB:1PL6, ECO:0007744|PDB:1PL8"
FT BINDING 209
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:12962626,
FT ECO:0007744|PDB:1PL6, ECO:0007744|PDB:1PL8"
FT BINDING 273..275
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:12962626,
FT ECO:0007744|PDB:1PL6, ECO:0007744|PDB:1PL8"
FT BINDING 297..299
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:12962626,
FT ECO:0007744|PDB:1PL6, ECO:0007744|PDB:1PL8"
FT BINDING 299
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P07846"
FT BINDING 300
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P07846"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:25944712"
FT MOD_RES 211
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 225
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT VAR_SEQ 90..99
FT /note="DRVAIEPGAP -> FLTMSPLRKA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056353"
FT VAR_SEQ 100..356
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056354"
FT VARIANT 10
FT /note="L -> F (in SORDD)"
FT /evidence="ECO:0000269|PubMed:32367058"
FT /id="VAR_084362"
FT VARIANT 100..357
FT /note="Missing (in SORDD)"
FT /evidence="ECO:0000269|PubMed:32367058"
FT /id="VAR_084363"
FT VARIANT 110
FT /note="R -> P (in SORDD; results in protein aggregation)"
FT /evidence="ECO:0000269|PubMed:32367058,
FT ECO:0000269|PubMed:33397963"
FT /id="VAR_084364"
FT VARIANT 135
FT /note="H -> R (in SORDD; results in protein aggregation)"
FT /evidence="ECO:0000269|PubMed:33397963"
FT /id="VAR_084365"
FT VARIANT 153
FT /note="A -> D (in SORDD; unknown pathological significance;
FT results in protein aggregation; dbSNP:rs145813597)"
FT /evidence="ECO:0000269|PubMed:32367058,
FT ECO:0000269|PubMed:33397963"
FT /id="VAR_084366"
FT VARIANT 209..357
FT /note="Missing (in SORDD)"
FT /evidence="ECO:0000269|PubMed:33314640"
FT /id="VAR_084367"
FT VARIANT 239
FT /note="Q -> L (in dbSNP:rs1042079)"
FT /evidence="ECO:0000269|PubMed:7782086"
FT /id="VAR_000430"
FT VARIANT 269
FT /note="N -> T (in dbSNP:rs930337)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:7782086,
FT ECO:0000269|PubMed:8088829, ECO:0000269|PubMed:9183016"
FT /id="VAR_060351"
FT VARIANT 299..357
FT /note="Missing (in SORDD)"
FT /evidence="ECO:0000269|PubMed:32367058"
FT /id="VAR_084368"
FT VARIANT 322
FT /note="V -> I (in SORDD; unknown pathological significance;
FT dbSNP:rs149975952)"
FT /evidence="ECO:0000269|PubMed:32367058"
FT /id="VAR_084369"
FT CONFLICT 5
FT /note="Missing (in Ref. 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 59
FT /note="N -> D (in Ref. 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 186
FT /note="M -> E (in Ref. 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 281
FT /note="T -> S (in Ref. 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 289
FT /note="I -> T (in Ref. 7; AA sequence)"
FT /evidence="ECO:0000305"
FT STRAND 10..16
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 19..24
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 34..44
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 46..54
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 55..57
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 71..79
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 91..94
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 96..98
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 104..107
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 111..113
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 130..136
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 137..139
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 140..142
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 149..168
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 175..179
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 183..194
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 198..205
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 207..215
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 219..223
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 229..240
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 245..249
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 254..263
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 269..272
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 284..289
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 293..296
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 304..312
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 319..321
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 322..327
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 328..330
FT /evidence="ECO:0007829|PDB:1PL8"
FT HELIX 331..339
FT /evidence="ECO:0007829|PDB:1PL8"
FT STRAND 344..349
FT /evidence="ECO:0007829|PDB:1PL8"
SQ SEQUENCE 357 AA; 38325 MW; FF13DDD5EBE47754 CRC64;
MAAAAKPNNL SLVVHGPGDL RLENYPIPEP GPNEVLLRMH SVGICGSDVH YWEYGRIGNF
IVKKPMVLGH EASGTVEKVG SSVKHLKPGD RVAIEPGAPR ENDEFCKMGR YNLSPSIFFC
ATPPDDGNLC RFYKHNAAFC YKLPDNVTFE EGALIEPLSV GIHACRRGGV TLGHKVLVCG
AGPIGMVTLL VAKAMGAAQV VVTDLSATRL SKAKEIGADL VLQISKESPQ EIARKVEGQL
GCKPEVTIEC TGAEASIQAG IYATRSGGNL VLVGLGSEMT TVPLLHAAIR EVDIKGVFRY
CNTWPVAISM LASKSVNVKP LVTHRFPLEK ALEAFETFKK GLGLKIMLKC DPSDQNP
