HSD17B10 explained

17-β-Hydroxysteroid dehydrogenase X (HSD10) also known as 3-hydroxyacyl-CoA dehydrogenase type-2 is a mitochondrial enzyme that in humans is encoded by the HSD17B10 (hydroxysteroid (17β) dehydrogenase 10) gene.^{[1] [2] [3] [4] [5]} Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined.^[6] Human HSD10 cDNA was cloned from the brain (NM_004493), and the resulting protein, a homotetramer, was first characterized as a short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD).^[7] Active sites of this enzyme can accommodate different substrates; 17β-HSD10 is involved in the oxidation of isoleucine, branched-chain fatty acids, and xenobiotics as well as the metabolism of sex hormones and neuroactive steroids.^{[8] [9]}

Function

17beta-hydroxysteroid dehydrogenase 10 is a member of the short-chain dehydrogenase/reductase superfamily.^[10] This homotetrameric mitochondrial multifunctional enzyme catalyzes the oxidation of neuroactive steroids and the degradation of isoleucine.^[11] 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.^[9]

Structure

Gene

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

Protein

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.^[6] The molecular weight of 17β-HSD10 that is composed of four identical subunits is 108 kDa; each subunit consists of 261 amino acid residues.^[12] 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,^[13] ERAB is actually identical to 17β-HSD10 that is localized in mitochondria but not ER.^[3]

Clinical significance

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.^{[11] [14] [15]} 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.^[9] The discovery of this enzyme's true function has opened a new therapeutic avenue for treating AD.

Interactions

HSD17B10 has been shown to interact with Amyloid precursor protein.

Further reading

• Vredendaal PJ, van den Berg IE, Malingré HE, Stroobants AK, Olde Weghuis DE, Berger R . Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence . Biochemical and Biophysical Research Communications . 223 . 3 . 718–23 . Jun 1996 . 8687463 . 10.1006/bbrc.1996.0961 .
• Yang SY, He XY, Schulz H . 3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease . The FEBS Journal . 272 . 19 . 4874–83 . Oct 2005 . 16176262 . 10.1111/j.1742-4658.2005.04911.x . free .
• Yang SY, He XY, Miller D . HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids . Molecular Genetics and Metabolism . 92 . 1–2 . 36–42 . 2007 . 17618155 . 10.1016/j.ymgme.2007.06.001 .
• Furuta S, Kobayashi A, Miyazawa S, Hashimoto T . Cloning and expression of cDNA for a newly identified isozyme of bovine liver 3-hydroxyacyl-CoA dehydrogenase and its import into mitochondria . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1350 . 3 . 317–24 . Feb 1997 . 9061028 . 10.1016/s0167-4781(96)00171-6 .
• He XY, Schulz H, Yang SY . A human brain L-3-hydroxyacyl-coenzyme A dehydrogenase is identical to an amyloid beta-peptide-binding protein involved in Alzheimer's disease . The Journal of Biological Chemistry . 273 . 17 . 10741–6 . Apr 1998 . 9553139 . 10.1074/jbc.273.17.10741 . free .
• Miller AP, Willard HF . Chromosomal basis of X chromosome inactivation: identification of a multigene domain in Xp11.21-p11.22 that escapes X inactivation . Proceedings of the National Academy of Sciences of the United States of America . 95 . 15 . 8709–14 . Jul 1998 . 9671743 . 21141 . 10.1073/pnas.95.15.8709 . 1998PNAS...95.8709M . free .
• Hansis C, Jähner D, Spiess AN, Boettcher K, Ivell R . 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 . European Journal of Biochemistry . 258 . 1 . 53–60 . Nov 1998 . 9851691 . 10.1046/j.1432-1327.1998.2580053.x . free .
• Oppermann UC, Salim S, Tjernberg LO, Terenius L, Jörnvall H . 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 . FEBS Letters . 451 . 3 . 238–42 . May 1999 . 10371197 . 10.1016/S0014-5793(99)00586-4 . free .
• He XY, Yang YZ, Schulz H, Yang SY . Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase . The Biochemical Journal . 345 . 1 . 139–43 . Jan 2000 . 10600649 . 1220740 . 10.1042/bj3450139 .
• Book: Yang SY, He XY . Neuropathology and Genetics of Dementia . Role of Type 10 17ß-Hydroxysteroid Dehydrogenase in the Pathogenesis of Alzheimer's Disease . Advances in Experimental Medicine and Biology . 487 . 101–10 . 2001 . 11403151 . 10.1007/978-1-4615-1249-3_8 . 978-1-4613-5461-1 .
• Frackowiak J, Mazur-Kolecka B, Kaczmarski W, Dickson D . Deposition of Alzheimer's vascular amyloid-beta is associated with decreased expression of brain L-3-hydroxyacyl-coenzyme A dehydrogenase (ERAB) . Brain Research . 907 . 1–2 . 44–53 . Jul 2001 . 11430884 . 10.1016/S0006-8993(01)02497-0 . 22800813 .
• He XY, Merz G, Yang YZ, Mehta P, Schulz H, Yang SY . Characterization and localization of human type10 17beta-hydroxysteroid dehydrogenase . European Journal of Biochemistry . 268 . 18 . 4899–907 . Sep 2001 . 11559359 . 10.1046/j.0014-2956.2001.02421.2421.x . free .
• He XY, Wen GY, Merz G, Lin D, Yang YZ, Mehta P, Schulz H, Yang SY . Abundant type 10 17 beta-hydroxysteroid dehydrogenase in the hippocampus of mouse Alzheimer's disease model . Brain Research. Molecular Brain Research . 99 . 1 . 46–53 . Feb 2002 . 11869808 . 10.1016/S0169-328X(02)00102-X .
• Ofman R, Ruiter JP, Feenstra M, Duran M, Poll-The BT, Zschocke J, Ensenauer R, Lehnert W, Sass JO, Sperl W, Wanders RJ . 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene . American Journal of Human Genetics . 72 . 5 . 1300–7 . May 2003 . 12696021 . 1180283 . 10.1086/375116 .

Notes and References

1. Marques AT, Antunes A, Fernandes PA, Ramos MJ . Comparative evolutionary genomics of the HADH2 gene encoding Abeta-binding alcohol dehydrogenase/17beta-hydroxysteroid dehydrogenase type 10 (ABAD/HSD10) . BMC Genomics . 7 . 202 . Sep 2006 . 16899120 . 1559703 . 10.1186/1471-2164-7-202 . free .
2. Yang SY, He XY, Miller D . Hydroxysteroid (17β) dehydrogenase X in human health and disease . Molecular and Cellular Endocrinology . 343 . 1–2 . 1–6 . Aug 2011 . 21708223 . 10.1016/j.mce.2011.06.011 . 8608312 .
3. He XY, Merz G, Mehta P, Schulz H, Yang SY . Human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase is a single-domain multifunctional enzyme. Characterization of a novel 17beta-hydroxysteroid dehydrogenase . The Journal of Biological Chemistry . 274 . 21 . 15014–9 . May 1999 . 10329704 . 10.1074/jbc.274.21.15014 . free .
4. Persson B, Kallberg Y, Bray JE, Bruford E, Dellaporta SL, Favia AD, Duarte RG, Jörnvall H, Kavanagh KL, Kedishvili N, Kisiela M, Maser E, Mindnich R, Orchard S, Penning TM, Thornton JM, Adamski J, Oppermann U . The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative . Chemico-Biological Interactions . 178 . 1–3 . 94–8 . Mar 2009 . 19027726 . 2896744 . 10.1016/j.cbi.2008.10.040 . 2009CBI...178...94P .
5. Holzmann J, Frank P, Löffler E, Bennett KL, Gerner C, Rossmanith W . RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme . Cell . 135 . 3 . 462–74 . Oct 2008 . 18984158 . 10.1016/j.cell.2008.09.013 . free .
6. Web site: Entrez Gene: HSD17B10 hydroxysteroid (17-beta) dehydrogenase 10.
7. He XY, Yang YZ, Schulz H, Yang SY . Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase . The Biochemical Journal . 345 . 139–43 . Jan 2000 . 10600649 . 10.1042/bj3450139 . 1 . 1220740.
8. Yan SD, 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 . An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease . Nature . 389 . 6652 . 689–95 . Oct 1997 . 9338779 . 10.1038/39522 . 1997Natur.389..689D . 4343238 .
9. Yang SY, He XY, Isaacs C, Dobkin C, Miller D, Philipp M . Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders . The Journal of Steroid Biochemistry and Molecular Biology . 143 . 460–72 . Sep 2014 . 25007702 . 10.1016/j.jsbmb.2014.07.001 . free .
10. Yang SY, He XY, Schulz H . Multiple functions of type 10 17beta-hydroxysteroid dehydrogenase . Trends in Endocrinology and Metabolism . 16 . 4 . 167–75 . 2005 . 15860413 . 10.1016/j.tem.2005.03.006 . 53221489 .
11. Yang SY, He XY, Olpin SE, Sutton VR, McMenamin J, Philipp M, Denman RB, Malik M . Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism . Proceedings of the National Academy of Sciences of the United States of America . 106 . 35 . 14820–4 . Sep 2009 . 19706438 . 2728107 . 10.1073/pnas.0902377106 . 2009PNAS..10614820Y . free .
12. He XY, Schulz H, Yang SY . A human brain L-3-hydroxyacyl-coenzyme A dehydrogenase is identical to an amyloid beta-peptide-binding protein involved in Alzheimer's disease . The Journal of Biological Chemistry . 273 . 17 . 10741–6 . Apr 1998 . 9553139 . 10.1074/jbc.273.17.10741. free .
13. Beyreuther K, Masters CL . Alzheimer's disease. The ins and outs of amyloid-beta . Nature . 389 . 6652 . 677–8 . Oct 1997 . 9338775 . 10.1038/39479 . 1997Natur.389..677B . free .
14. Seaver LH, He XY, Abe K, Cowan T, Enns GM, Sweetman L, Philipp M, Lee S, Malik M, Yang SY . A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability . PLOS ONE . 6 . 11 . e27348 . November 2011 . 22132097 . 3222643 . 10.1371/journal.pone.0027348 . 2011PLoSO...627348S . free .
15. Lenski C, Kooy RF, Reyniers E, Loessner D, Wanders RJ, Winnepenninckx B, Hellebrand H, Engert S, Schwartz CE, Meindl A, Ramser J . The reduced expression of the HADH2 protein causes X-linked mental retardation, choreoathetosis, and abnormal behavior . American Journal of Human Genetics . 80 . 2 . 372–7 . Feb 2007 . 17236142 . 1785340 . 10.1086/511527 .