HSD17B10

HSD17B10
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1SO8, 1U7T, 2O23
Identifiers
Aliases	HSD17B10, 17b-HSD10, ABAD, CAMR, DUPXp11.22, ERAB, HADH2, HCD2, MHBD, MRPP2, MRX17, MRX31, MRXS10, SCHAD, SDR5C1, hydroxysteroid (17-beta) dehydrogenase 10, hydroxysteroid 17-beta dehydrogenase 10
External IDs	MGI: 1333871 HomoloGene: 68403 GeneCards: HSD17B10
EC number	1.1.1.51
Gene ontology Molecular function • testosterone dehydrogenase [NAD(P) activity] • estradiol 17-beta-dehydrogenase activity • 3-hydroxy-2-methylbutyryl-CoA dehydrogenase activity • acetoacetyl-CoA reductase activity • NAD binding • beta-amyloid binding • steroid binding • protein binding • identical protein binding • oxidoreductase activity • poly(A) RNA binding • cholate 7-alpha-dehydrogenase activity • estrogen receptor binding • 3-hydroxyacyl-CoA dehydrogenase activity Cellular component • cytoplasm • plasma membrane • mitochondrial matrix • mitochondrion Biological process • Leydig cell differentiation • lipid metabolic process • branched-chain amino acid catabolic process • cell aging • mitochondrial tRNA processing • protein homotetramerization • oxidation-reduction process • mitochondrial tRNA methylation • tRNA processing Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3028	15108
Ensembl	ENSG00000072506	ENSMUSG00000025260
UniProt	Q99714	O08756
RefSeq (mRNA)	NM_004493 NM_001037811	NM_016763
RefSeq (protein)	NP_001032900.1 NP_004484.1	n/a
Location (UCSC)	Chr X: 53.43 – 53.43 Mb	Chr X: 152 – 152 Mb
PubMed search	[1]	[2]
Wikidata

View/Edit Human

View/Edit Mouse

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.^{[3][4][5][6][7]} Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined.^[8] Human HSD10 cDNA was cloned from brain (NM_004493), and the resulting protein, a homotetramer, was first characterized as a short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD).^[9] 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.^[10][11]

Function

17beta-hydroxysteroid dehydrogenase 10 is a member of the short-chain dehydrogenase/reductase superfamily.^[12] This homotetrameric mitochondrial multifunctional enzyme catalyzes the oxidation of neuroactive steroids and the degradation of isoleucine.^[13] 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 an alcohol dehydrogenase.^[11]

Structure

Gene

Human HSD17B10 gene has 6 exons resides on the X chromosome at p11.22.^[8]

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.^[8] The molecular weight of 17β-HSD10 that is composed of four identical subunits is 108 kDa; each subunit consists of 261 amino acid residues.^[14] 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,^[15] ERAB is actually identical to 17β-HSD10 that is localized in mitochondria but not ER.^[5]

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).^[8] 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.^[13][16][17] 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.^[11] 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.^[10]

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. Marques AT, Antunes A, Fernandes PA, Ramos MJ (Sep 2006). "Comparative evolutionary genomics of the HADH2 gene encoding Abeta-binding alcohol dehydrogenase/17beta-hydroxysteroid dehydrogenase type 10 (ABAD/HSD10)". BMC Genomics. 7: 202. doi:10.1186/1471-2164-7-202. PMC 1559703. PMID 16899120.
4. Yang SY, He XY, Miller D (Aug 2011). "Hydroxysteroid (17β) dehydrogenase X in human health and disease". Molecular and Cellular Endocrinology. 343 (1-2): 1–6. doi:10.1016/j.mce.2011.06.011. PMID 21708223.
5. He XY, Merz G, Mehta P, Schulz H, Yang SY (May 1999). "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. doi:10.1074/jbc.274.21.15014. PMID 10329704.
6. 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 (Mar 2009). "The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative". Chemico-Biological Interactions. 178 (1-3): 94–8. doi:10.1016/j.cbi.2008.10.040. PMC 2896744. PMID 19027726.
7. Holzmann J, Frank P, Löffler E, Bennett KL, Gerner C, Rossmanith W (Oct 2008). "RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme". Cell. 135 (3): 462–74. doi:10.1016/j.cell.2008.09.013. PMID 18984158.
8. "Entrez Gene: HSD17B10 hydroxysteroid (17-beta) dehydrogenase 10".
9. He XY, Yang YZ, Schulz H, Yang SY (Jan 2000). "Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase". The Biochemical Journal. 345 (1): 139–43. doi:10.1042/bj3450139. PMC 1220740. PMID 10600649.
10. 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 (Oct 1997). "An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease". Nature. 389 (6652): 689–95. doi:10.1038/39522. PMID 9338779.
11. Yang SY, He XY, Isaacs C, Dobkin C, Miller D, Philipp M (Sep 2014). "Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders". The Journal of Steroid Biochemistry and Molecular Biology. 143: 460–72. doi:10.1016/j.jsbmb.2014.07.001. PMID 25007702.
12. Yang SY, He XY, Schulz H (2005). "Multiple functions of type 10 17beta-hydroxysteroid dehydrogenase". Trends in Endocrinology and Metabolism. 16 (4): 167–75. doi:10.1016/j.tem.2005.03.006. PMID 15860413.
13. Yang SY, He XY, Olpin SE, Sutton VR, McMenamin J, Philipp M, Denman RB, Malik M (Sep 2009). "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. doi:10.1073/pnas.0902377106. PMC 2728107. PMID 19706438.
14. He XY, Schulz H, Yang SY (Apr 1998). "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. doi:10.1074/jbc.273.17.10741. PMID 9553139.
15. Beyreuther K, Masters CL (Oct 1997). "Alzheimer's disease. The ins and outs of amyloid-beta". Nature. 389 (6652): 677–8. doi:10.1038/39479. PMID 9338775.
16. Seaver LH, He XY, Abe K, Cowan T, Enns GM, Sweetman L, Philipp M, Lee S, Malik M, Yang SY (November 2011). "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. doi:10.1371/journal.pone.0027348. PMC 3222643. PMID 22132097.
17. Lenski C, Kooy RF, Reyniers E, Loessner D, Wanders RJ, Winnepenninckx B, Hellebrand H, Engert S, Schwartz CE, Meindl A, Ramser J (Feb 2007). "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. doi:10.1086/511527. PMC 1785340. PMID 17236142.

Further reading

• Vredendaal PJ, van den Berg IE, Malingré HE, Stroobants AK, Olde Weghuis DE, Berger R (Jun 1996). "Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence". Biochemical and Biophysical Research Communications. 223 (3): 718–23. doi:10.1006/bbrc.1996.0961. PMID 8687463.
• Yang SY, He XY, Schulz H (Oct 2005). "3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease". The FEBS Journal. 272 (19): 4874–83. doi:10.1111/j.1742-4658.2005.04911.x. PMID 16176262.
• Yang SY, He XY, Miller D (2007). "HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids". Molecular Genetics and Metabolism. 92 (1-2): 36–42. doi:10.1016/j.ymgme.2007.06.001. PMID 17618155.
• Furuta S, Kobayashi A, Miyazawa S, Hashimoto T (Feb 1997). "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. 1350 (3): 317–24. doi:10.1016/s0167-4781(96)00171-6. PMID 9061028.
• He XY, Schulz H, Yang SY (Apr 1998). "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. doi:10.1074/jbc.273.17.10741. PMID 9553139.
• Miller AP, Willard HF (Jul 1998). "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. doi:10.1073/pnas.95.15.8709. PMC 21141. PMID 9671743.
• Hansis C, Jähner D, Spiess AN, Boettcher K, Ivell R (Nov 1998). "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 / FEBS. 258 (1): 53–60. doi:10.1046/j.1432-1327.1998.2580053.x. PMID 9851691.
• Oppermann UC, Salim S, Tjernberg LO, Terenius L, Jörnvall H (May 1999). "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. doi:10.1016/S0014-5793(99)00586-4. PMID 10371197.
• He XY, Yang YZ, Schulz H, Yang SY (Jan 2000). "Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase". The Biochemical Journal. 345 (1): 139–43. doi:10.1042/bj3450139. PMC 1220740. PMID 10600649.
• Yang SY, He XY (2001). "Role of type 10 17beta-hydroxysteroid dehydrogenase in the pathogenesis of Alzheimer's disease". Advances in Experimental Medicine and Biology. 487: 101–10. doi:10.1007/978-1-4615-1249-3_8. PMID 11403151.
• Frackowiak J, Mazur-Kolecka B, Kaczmarski W, Dickson D (Jul 2001). "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. doi:10.1016/S0006-8993(01)02497-0. PMID 11430884.
• He XY, Merz G, Yang YZ, Mehta P, Schulz H, Yang SY (Sep 2001). "Characterization and localization of human type10 17beta-hydroxysteroid dehydrogenase". European Journal of Biochemistry / FEBS. 268 (18): 4899–907. doi:10.1046/j.0014-2956.2001.02421.2421.x. PMID 11559359.
• He XY, Wen GY, Merz G, Lin D, Yang YZ, Mehta P, Schulz H, Yang SY (Feb 2002). "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. doi:10.1016/S0169-328X(02)00102-X. PMID 11869808.
• Ofman R, Ruiter JP, Feenstra M, Duran M, Poll-The BT, Zschocke J, Ensenauer R, Lehnert W, Sass JO, Sperl W, Wanders RJ (May 2003). "2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene". American Journal of Human Genetics. 72 (5): 1300–7. doi:10.1086/375116. PMC 1180283. PMID 12696021.