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Gene Review

HSD17B10  -  hydroxysteroid (17-beta) dehydrogenase 10

Homo sapiens

Synonyms: 17-beta-HSD 10, 17-beta-hydroxysteroid dehydrogenase 10, 17b-HSD10, 3-hydroxy-2-methylbutyryl-CoA dehydrogenase, 3-hydroxyacyl-CoA dehydrogenase type II, ...
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Disease relevance of HSD17B10


Psychiatry related information on HSD17B10

  • It binds an intracellular polypeptide known as ERAB, thought to be a hydroxysteroid dehydrogenase enzyme, which is expressed in normal tissues, but is overexpressed in neurons affected in Alzheimer's disease [6].

High impact information on HSD17B10

  • The toxic effect of amyloid-beta on these cells is prevented by blocking ERAB and is enhanced by overexpression of ERAB [6].
  • The gene (HADH2) encoding l-3-hydroxyacyl-CoA dehydrogenase II displayed a sequence alteration (c.574 C-->A; p.R192R) in all patients and carrier females that was absent in unaffected male family members and could not be found in 2,500 control X chromosomes, including in those of 500 healthy males [1].
  • The Reduced Expression of the HADH2 Protein Causes X-Linked Mental Retardation, Choreoathetosis, and Abnormal Behavior [1].
  • 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene [7].
  • 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency is a novel inborn error of isoleucine degradation [7].

Chemical compound and disease context of HSD17B10


Biological context of HSD17B10

  • Eutherian mammal HADH2 genes revealed some highly conserved noncoding regions, which may indicate the presence of functional elements, namely in the upstream region about 1 kb of the transcription start site and in the first part of intron 1 [9].
  • The human homolog of this bovine enzyme is a short-chain 3-hydroxyacyl-CoA dehydrogenase, also known as the "endoplasmic reticulum-associated amyloid-beta binding protein" (ERAB) [7].
  • The presumed function of the SCHAD enzyme in glucose-stimulated insulin secretion led us to the hypothesis that common variants in HADHSC on chromosome 4q22-26 might be associated with development of type 2 diabetes [10].
  • Although COS cells cotransfected to overexpress wild-type ERAB/HADH II and variant beta-amyloid precursor protein (betaAPP(V717G)) showed DNA fragmentation, cotransfection with Y168G/K172G-altered ERAB and betaAPP(V717G) was without effect [11].
  • The contribution of ERAB/HADH II enzymatic activity to Abeta-mediated cellular dysfunction was studied by site-directed mutagenesis in the catalytic domain (Y168G/K172G) [11].

Anatomical context of HSD17B10

  • Mitochondria have been demonstrated to be the proper location of this NAD+-dependent dehydrogenase in cells, although its primary structure is identical to an amyloid beta-peptide binding protein reportedly associated with the endoplasmic reticulum (ERAB) [12].
  • The intracellular amyloid beta-peptide (A beta) binding protein, ERAB, a member of the short-chain dehydrogenase/reductase (SDR) family, is known to mediate apoptosis in different cell lines and to be a class II hydroxyacyl-CoA dehydrogenase [2].
  • We have established that protocols employed to investigate the subcellular distribution of ERAB yield ER fractions rich in mitochondria [13].
  • The gene for the Alzheimer-associated beta-amyloid-binding protein (ERAB) is differentially expressed in the testicular Leydig cells of the azoospermic by w/w(v) mouse [14].
  • The primary report indicated that a signal sequence is absent in ERAB suggesting that it is bound to the cytoplasmic aspect of cellular membranes [15].

Associations of HSD17B10 with chemical compounds

  • Addition of micromolar levels of synthetic Abeta(1-40) to purified ERAB/HADH II inhibited, in parallel, reduction of S-acetoacetyl-CoA (Ki approximately 1.6 microM), as well as oxidation of 17beta-estradiol (Ki approximately 3.2 microM) and (-)-2-octanol (Ki approximately 2.6 microM) [11].
  • Purified recombinant ERAB/HADH II catalyzed the NADH-dependent reduction of S-acetoacetyl-CoA with a Km of approximately 68 microM and a Vmax of approximately 430 micromol/min/mg [11].
  • We thus asked whether the enzyme might recognize alcohol substrates of which the aldehyde products could be cytotoxic; ERAB/HADH II catalyzed oxidation of a variety of simple alcohols (C2-C10) to their respective aldehydes in the presence of NAD+ and NAD-dependent oxidation of 17beta-estradiol [11].
  • We report the crystal structure of rat HADH II/ABAD as a binary complex with its NADH cofactor to 2.0 A resolution, as a ternary complex with NAD(+) and 3-ketobutyrate (acetoacetate) to 1.4 A resolution, and as a ternary complex with NADH and 17 beta-estradiol to 1.7 A resolution [16].
  • The possibility that ERAB mediates quinone reduction is therefore investigated, thus giving the potential of redoxcycling and production of reactive oxygen species, leading to lipid peroxidation [17].

Physical interactions of HSD17B10

  • Our finding that an integral membrane form of ERAB can bind to Abeta in the lumen of transport vesicles and other cytoplasmic receptors provides a basis for understanding its role in AD [15].
  • Immunocytochemical studies demonstrate that this protein, which has been referred to as ER-associated amyloid beta-binding protein (ERAB), is not detectable in the ER of normal tissues [13].

Regulatory relationships of HSD17B10

  • ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction [18].

Other interactions of HSD17B10


Analytical, diagnostic and therapeutic context of HSD17B10

  • The silent C-->A substitution is located in exon 5 and was shown by western blot to reduce the amount of HADH2 protein by 60%-70% in the patient [1].
  • Sequence analysis of the involved X-chromosome gene (HADH2), revealed the presence of 364C -->G mutation in the patient [4].
  • METHODS: We categorized 383 patients with ABAD enrolled in the International Registry of Acute Aortic Dissection into two strata (aged less than 70 years and aged 70 years or more) and compared their clinical features and in-hospital outcomes [22].
  • Fish were caught using electric fishing at four sites (Chalous and Babolsar cities, Khazar Abad and Miankaleh regions) in the Mazandaran provinces of Iran. Quantitative determination of the lindane was performed by gas chromatography electron-capture detection (GC-ECD) [23].


  1. The Reduced Expression of the HADH2 Protein Causes X-Linked Mental Retardation, Choreoathetosis, and Abnormal Behavior. Lenski, C., Frank Kooy, R., Reyniers, E., Loessner, D., Wanders, R.J., Winnepenninckx, B., Hellebrand, H., Engert, S., Schwartz, C.E., Meindl, A., Ramser, J. Am. J. Hum. Genet. (2007) [Pubmed]
  2. Binding of amyloid beta-peptide to mitochondrial hydroxyacyl-CoA dehydrogenase (ERAB): regulation of an SDR enzyme activity with implications for apoptosis in Alzheimer's disease. Oppermann, U.C., Salim, S., Tjernberg, L.O., Terenius, L., Jörnvall, H. FEBS Lett. (1999) [Pubmed]
  3. 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: an X-linked inborn error of isoleucine metabolism that may mimic a mitochondrial disease. García-Villoria, J., Ofman, R., Sala, P.R., Merinero, B., Ramos, J., García-Silva, M.T., Beseler, B., Dalmau, J., Wanders, R.J., Ugarte, M. Pediatr. Res. (2005) [Pubmed]
  4. Spastic diplegia and periventricular white matter abnormalities in 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, a defect of isoleucine metabolism: differential diagnosis with hypoxic-ischemic brain diseases. Poll-The, B.T., Wanders, R.J., Ruiter, J.P., Ofman, R., Majoie, C.B., Barth, P.G., Duran, M. Mol. Genet. Metab. (2004) [Pubmed]
  5. Inborn errors of isoleucine degradation: A review. Korman, S.H. Mol. Genet. Metab. (2006) [Pubmed]
  6. An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease. Yan, S.D., Fu, J., Soto, C., Chen, X., Zhu, H., Al-Mohanna, F., Collison, K., Zhu, A., Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A., Stern, D. Nature (1997) [Pubmed]
  7. 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene. Ofman, R., Ruiter, J.P., Feenstra, M., Duran, M., Poll-The, B.T., Zschocke, J., Ensenauer, R., Lehnert, W., Sass, J.O., Sperl, W., Wanders, R.J. Am. J. Hum. Genet. (2003) [Pubmed]
  8. Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics. Kissinger, C.R., Rejto, P.A., Pelletier, L.A., Thomson, J.A., Showalter, R.E., Abreo, M.A., Agree, C.S., Margosiak, S., Meng, J.J., Aust, R.M., Vanderpool, D., Li, B., Tempczyk-Russell, A., Villafranca, J.E. J. Mol. Biol. (2004) [Pubmed]
  9. Comparative evolutionary genomics of the HADH2 gene encoding Abeta-binding alcohol dehydrogenase/17beta-hydroxysteroid dehydrogenase type 10 (ABAD/HSD10). Marques, A.T., Antunes, A., Fernandes, P.A., Ramos, M.J. BMC Genomics (2006) [Pubmed]
  10. The HADHSC Gene Encoding Short-Chain L-3-Hydroxyacyl-CoA Dehydrogenase (SCHAD) and Type 2 Diabetes Susceptibility: The DAMAGE Study. van Hove, E.C., Hansen, T., Dekker, J.M., Reiling, E., Nijpels, G., J??rgensen, T., Borch-Johnsen, K., Hamid, Y.H., Heine, R.J., Pedersen, O., Maassen, J.A., 't Hart, L.M. Diabetes (2006) [Pubmed]
  11. Role of ERAB/L-3-hydroxyacyl-coenzyme A dehydrogenase type II activity in Abeta-induced cytotoxicity. Yan, S.D., Shi, Y., Zhu, A., Fu, J., Zhu, H., Zhu, Y., Gibson, L., Stern, E., Collison, K., Al-Mohanna, F., Ogawa, S., Roher, A., Clarke, S.G., Stern, D.M. J. Biol. Chem. (1999) [Pubmed]
  12. Human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase is a single-domain multifunctional enzyme. Characterization of a novel 17beta-hydroxysteroid dehydrogenase. He, X.Y., Merz, G., Mehta, P., Schulz, H., Yang, S.Y. J. Biol. Chem. (1999) [Pubmed]
  13. Characterization and localization of human type10 17beta-hydroxysteroid dehydrogenase. He, X.Y., Merz, G., Yang, Y.Z., Mehta, P., Schulz, H., Yang, S.Y. Eur. J. Biochem. (2001) [Pubmed]
  14. The gene for the Alzheimer-associated beta-amyloid-binding protein (ERAB) is differentially expressed in the testicular Leydig cells of the azoospermic by w/w(v) mouse. Hansis, C., Jähner, D., Spiess, A.N., Boettcher, K., Ivell, R. Eur. J. Biochem. (1998) [Pubmed]
  15. ERAB contains a putative noncleavable signal peptide. Sambamurti, K., Lahiri, D.K. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  16. Recognition of structurally diverse substrates by type II 3-hydroxyacyl-CoA dehydrogenase (HADH II)/amyloid-beta binding alcohol dehydrogenase (ABAD). Powell, A.J., Read, J.A., Banfield, M.J., Gunn-Moore, F., Yan, S.D., Lustbader, J., Stern, A.R., Stern, D.M., Brady, R.L. J. Mol. Biol. (2000) [Pubmed]
  17. Lack of quinone reductase activity suggests that amyloid-beta peptide/ERAB induced lipid peroxidation is not directly related to production of reactive oxygen species by redoxcycling. Salim, S., Filling, C., Mårtensson, E., Oppermann, U.C. Toxicology (2000) [Pubmed]
  18. ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. Takuma, K., Yao, J., Huang, J., Xu, H., Chen, X., Luddy, J., Trillat, A.C., Stern, D.M., Arancio, O., Yan, S.S. FASEB J. (2005) [Pubmed]
  19. Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid beta-peptide. Yan, S.D., Roher, A., Chaney, M., Zlokovic, B., Schmidt, A.M., Stern, D. Biochim. Biophys. Acta (2000) [Pubmed]
  20. Mitochondrial fatty acid beta-oxidation in the human eye and brain: implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Tyni, T., Paetau, A., Strauss, A.W., Middleton, B., Kivelä, T. Pediatr. Res. (2004) [Pubmed]
  21. Deposition of Alzheimer's vascular amyloid-beta is associated with decreased expression of brain L-3-hydroxyacyl-coenzyme A dehydrogenase (ERAB). Frackowiak, J., Mazur-Kolecka, B., Kaczmarski, W., Dickson, D. Brain Res. (2001) [Pubmed]
  22. Acute type B aortic dissection in elderly patients: clinical features, outcomes, and simple risk stratification rule. Mehta, R.H., Bossone, E., Evangelista, A., O'Gara, P.T., Smith, D.E., Cooper, J.V., Oh, J.K., Januzzi, J.L., Hutchison, S., Gilon, D., Pape, L.A., Nienaber, C.A., Isselbacher, E.M., Eagle, K.A. Ann. Thorac. Surg. (2004) [Pubmed]
  23. A survey and measurement of residues of lindane (organochlorine pesticides) in four species of the most consumed fish in the Caspian Sea (Iran). Ebadi, A.G., Shokrzadeh, M. Toxicology and industrial health. (2006) [Pubmed]
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