HSD17B10

17beta-hydroxysteroid dehydrogenase 10 is a member of the short-chain dehydrogenase/reductase superfamily.{{cite journal | vauthors = Yang SY, He XY, Schulz H | title = Multiple functions of type 10 17beta-hydroxysteroid dehydrogenase | journal = Trends in Endocrinology and Metabolism | volume = 16 | issue = 4 | pages = 167–75 | year = 2005 | pmid = 15860413 | doi = 10.1016/j.tem.2005.03.006 | s2cid = 53221489 }} This homotetrameric mitochondrial multifunctional enzyme catalyzes the oxidation of neuroactive steroids and the degradation of isoleucine.{{cite journal | vauthors = Yang SY, He XY, Olpin SE, Sutton VR, McMenamin J, Philipp M, Denman RB, Malik M | title = Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 35 | pages = 14820–4 | date = Sep 2009 | pmid = 19706438 | pmc = 2728107 | doi = 10.1073/pnas.0902377106 | bibcode = 2009PNAS..10614820Y | doi-access = free }} This enzyme is capable of binding to other peptides, such as estrogen receptor α, amyloid-β, and tRNA methyltransferase 10C. Missense mutations of the HSD17B10 gene result in 17β-HSD10 deficiency, an infantile neurodegeneration characterized by progressive psychomotor regression and alteration of mitochondria morphology. 17β-HSD10 exhibits only a negligible alcohol dehydrogenase activity, and is not localized in the endoplasmic reticulum or plasma membrane. Its alternate name – Aβ binding alcohol dehydrogenase (ABAD) – is a misnomer predicated on the mistaken belief that this enzyme is alcohol dehydrogenase.

The Human HSD17B10 gene has 6 exons residing on the X chromosome at p11.22.

The gene product is a mitochondrial protein that catalyzes the oxidation of a wide variety of fatty acids and steroids, and is a subunit of mitochondrial ribonuclease P, which is involved in tRNA maturation. The molecular weight of 17β-HSD10 that is composed of four identical subunits is 108 kDa; each subunit consists of 261 amino acid residues.{{cite journal | vauthors = He XY, Schulz H, Yang SY | title = A human brain L-3-hydroxyacyl-coenzyme A dehydrogenase is identical to an amyloid beta-peptide-binding protein involved in Alzheimer's disease | journal = The Journal of Biological Chemistry | volume = 273 | issue = 17 | pages = 10741–6 | date = Apr 1998 | pmid = 9553139 | doi=10.1074/jbc.273.17.10741| doi-access = free }} Although the endoplasmic reticulum (ER)-associated amyloid-β peptide binding protein (ERAB) was reported to be associated with the ER and to consist of 262 residues with a molecular weight of 27 kDa,{{cite journal | vauthors = Beyreuther K, Masters CL | title = Alzheimer's disease. The ins and outs of amyloid-beta | journal = Nature | volume = 389 | issue = 6652 | pages = 677–8 | date = Oct 1997 | pmid = 9338775 | doi = 10.1038/39479 | bibcode = 1997Natur.389..677B | doi-access = free }} ERAB is actually identical to 17β-HSD10 that is localized in mitochondria but not ER.

Abnormal expression, as well as mutations of the HSD17B10 gene leads to impairment of the structure, function, and dynamics of mitochondria. This may underlie the pathogenesis of the synaptic and neuronal deficiency exhibited in 17β-HSD10 related diseases, including 17β-HSD10 deficiency and Alzheimer's disease (AD). Missense and silent mutations in the gene are the cause of hydroxysteroid (17β) dehydrogenase X (HSD10) deficiency, formerly MHBD deficiency, and X-linked mental retardation, choreoathetosis, and abnormal behavior (MRXS10), respectively.{{cite journal | vauthors = Seaver LH, He XY, Abe K, Cowan T, Enns GM, Sweetman L, Philipp M, Lee S, Malik M, Yang SY | title = A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e27348 | date = November 2011 | pmid = 22132097 | pmc = 3222643 | doi = 10.1371/journal.pone.0027348 | bibcode = 2011PLoSO...627348S | doi-access = free }}{{cite journal | vauthors = Lenski C, Kooy RF, Reyniers E, Loessner D, Wanders RJ, Winnepenninckx B, Hellebrand H, Engert S, Schwartz CE, Meindl A, Ramser J | title = The reduced expression of the HADH2 protein causes X-linked mental retardation, choreoathetosis, and abnormal behavior | journal = American Journal of Human Genetics | volume = 80 | issue = 2 | pages = 372–7 | date = Feb 2007 | pmid = 17236142 | pmc = 1785340 | doi = 10.1086/511527 }} Restoration of steroid homeostasis could be achieved by the supplementation of neuroactive steroids with a proper dosing and treatment regimen or by the adjustment of 17β-HSD10 activity to protect neurons. The discovery of this enzyme's true function has opened a new therapeutic avenue for treating AD.

HSD17B10 has been shown to interact with Amyloid precursor protein.

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• {{cite journal | vauthors = Vredendaal PJ, van den Berg IE, Malingré HE, Stroobants AK, Olde Weghuis DE, Berger R | title = Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence | journal = Biochemical and Biophysical Research Communications | volume = 223 | issue = 3 | pages = 718–23 | date = Jun 1996 | pmid = 8687463 | doi = 10.1006/bbrc.1996.0961 }}
• {{cite journal | vauthors = Yang SY, He XY, Schulz H | title = 3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease | journal = The FEBS Journal | volume = 272 | issue = 19 | pages = 4874–83 | date = Oct 2005 | pmid = 16176262 | doi = 10.1111/j.1742-4658.2005.04911.x | doi-access = free }}
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• {{cite journal | vauthors = He XY, Schulz H, Yang SY | title = A human brain L-3-hydroxyacyl-coenzyme A dehydrogenase is identical to an amyloid beta-peptide-binding protein involved in Alzheimer's disease | journal = The Journal of Biological Chemistry | volume = 273 | issue = 17 | pages = 10741–6 | date = Apr 1998 | pmid = 9553139 | doi = 10.1074/jbc.273.17.10741 | doi-access = free }}
• {{cite journal | vauthors = Miller AP, Willard HF | title = Chromosomal basis of X chromosome inactivation: identification of a multigene domain in Xp11.21-p11.22 that escapes X inactivation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 15 | pages = 8709–14 | date = Jul 1998 | pmid = 9671743 | pmc = 21141 | doi = 10.1073/pnas.95.15.8709 | bibcode = 1998PNAS...95.8709M | doi-access = free }}
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• {{cite journal | vauthors = Oppermann UC, Salim S, Tjernberg LO, Terenius L, Jörnvall H | title = 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 | journal = FEBS Letters | volume = 451 | issue = 3 | pages = 238–42 | date = May 1999 | pmid = 10371197 | doi = 10.1016/S0014-5793(99)00586-4 | doi-access = free }}
• {{cite journal | vauthors = He XY, Yang YZ, Schulz H, Yang SY | title = Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase | journal = The Biochemical Journal | volume = 345 | issue = 1 | pages = 139–43 | date = Jan 2000 | pmid = 10600649 | pmc = 1220740 | doi = 10.1042/bj3450139 }}
• {{Cite book | vauthors = Yang SY, He XY | title = Neuropathology and Genetics of Dementia | chapter = Role of Type 10 17ß-Hydroxysteroid Dehydrogenase in the Pathogenesis of Alzheimer's Disease | series = Advances in Experimental Medicine and Biology | volume = 487 | pages = 101–10 | year = 2001 | pmid = 11403151 | doi = 10.1007/978-1-4615-1249-3_8 | isbn = 978-1-4613-5461-1 }}
• {{cite journal | vauthors = Frackowiak J, Mazur-Kolecka B, Kaczmarski W, Dickson D | title = Deposition of Alzheimer's vascular amyloid-beta is associated with decreased expression of brain L-3-hydroxyacyl-coenzyme A dehydrogenase (ERAB) | journal = Brain Research | volume = 907 | issue = 1–2 | pages = 44–53 | date = Jul 2001 | pmid = 11430884 | doi = 10.1016/S0006-8993(01)02497-0 | s2cid = 22800813 }}
• {{cite journal | vauthors = He XY, Merz G, Yang YZ, Mehta P, Schulz H, Yang SY | title = Characterization and localization of human type10 17beta-hydroxysteroid dehydrogenase | journal = European Journal of Biochemistry | volume = 268 | issue = 18 | pages = 4899–907 | date = Sep 2001 | pmid = 11559359 | doi = 10.1046/j.0014-2956.2001.02421.2421.x | doi-access = free }}
• {{cite journal | vauthors = He XY, Wen GY, Merz G, Lin D, Yang YZ, Mehta P, Schulz H, Yang SY | title = Abundant type 10 17 beta-hydroxysteroid dehydrogenase in the hippocampus of mouse Alzheimer's disease model | journal = Brain Research. Molecular Brain Research | volume = 99 | issue = 1 | pages = 46–53 | date = Feb 2002 | pmid = 11869808 | doi = 10.1016/S0169-328X(02)00102-X }}
• {{cite journal | vauthors = Ofman R, Ruiter JP, Feenstra M, Duran M, Poll-The BT, Zschocke J, Ensenauer R, Lehnert W, Sass JO, Sperl W, Wanders RJ | title = 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene | journal = American Journal of Human Genetics | volume = 72 | issue = 5 | pages = 1300–7 | date = May 2003 | pmid = 12696021 | pmc = 1180283 | doi = 10.1086/375116 }}

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