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.[5][6][7][8][9] Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined.[10] 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).[11] 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.[12][13]
17beta-hydroxysteroid dehydrogenase 10 is a member of the short-chain dehydrogenase/reductase superfamily.[14] This homotetrameric mitochondrial multifunctional enzyme catalyzes the oxidation of neuroactive steroids and the degradation of isoleucine.[15] This enzyme is capable of binding to other peptides, such as estrogen receptor α, amyloid-β, and tRNAmethyltransferase 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.[13]
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.[10] The molecular weight of 17β-HSD10 that is composed of four identical subunits is 108 kDa; each subunit consists of 261 amino acid residues.[16] 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,[17] ERAB is actually identical to 17β-HSD10 that is localized in mitochondria but not ER.[7]
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).[10] 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.[15][18][19] 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.[13] The discovery of this enzyme's true function has opened a new therapeutic avenue for treating AD.
^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. PMID21708223. S2CID8608312.
^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. PMID15860413. S2CID53221489.
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. PMID8687463.
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. PMID17618155.
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 (BBA) - Gene Structure and Expression. 1350 (3): 317–24. doi:10.1016/s0167-4781(96)00171-6. PMID9061028.
Yang SY, He XY (2001). "Role of Type 10 17ß-Hydroxysteroid Dehydrogenase in the Pathogenesis of Alzheimer's Disease". Neuropathology and Genetics of Dementia. Advances in Experimental Medicine and Biology. Vol. 487. pp. 101–10. doi:10.1007/978-1-4615-1249-3_8. ISBN978-1-4613-5461-1. PMID11403151.
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. PMID11430884. S2CID22800813.
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. PMID11869808.
1so8: Abeta-bound human ABAD structure [also known as 3-hydroxyacyl-CoA dehydrogenase type II (Type II HADH), Endoplasmic reticulum-associated amyloid beta-peptide binding protein (ERAB)]
1u7t: Crystal Structure of ABAD/HSD10 with a Bound Inhibitor
2o23: The structure of wild-type human HADH2 (17beta-hydroxysteroid dehydrogenase type 10) bound to NAD+ at 1.2 A
![1so8: Abeta-bound human ABAD structure [also known as 3-hydroxyacyl-CoA dehydrogenase type II (Type II HADH), Endoplasmic reticulum-associated amyloid beta-peptide binding protein (ERAB)]](/wiki/File:PDB_1so8_EBI.jpg)
