Biology:HSD17B10

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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. Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. 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). 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.

Function

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

Structure

Gene

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

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

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. 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.

Interactions

HSD17B10 has been shown to interact with Amyloid precursor protein.

Further reading

• "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. doi:10.1006/bbrc.1996.0961. PMID 8687463. 
• "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. doi:10.1111/j.1742-4658.2005.04911.x. PMID 16176262. 
• "HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids". Molecular Genetics and Metabolism 92 (1–2): 36–42. 2007. doi:10.1016/j.ymgme.2007.06.001. PMID 17618155. 
• "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. doi:10.1016/s0167-4781(96)00171-6. PMID 9061028. 
• "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. doi:10.1074/jbc.273.17.10741. PMID 9553139. 
• "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. doi:10.1073/pnas.95.15.8709. PMID 9671743. Bibcode: 1998PNAS...95.8709M. 
• "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. doi:10.1046/j.1432-1327.1998.2580053.x. PMID 9851691. 
• "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. doi:10.1016/S0014-5793(99)00586-4. PMID 10371197. 
• "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. doi:10.1042/bj3450139. PMID 10600649. 
• Role of type 10 17beta-hydroxysteroid dehydrogenase in the pathogenesis of Alzheimer's disease. 487. 2001. 101–10. doi:10.1007/978-1-4615-1249-3_8. ISBN 978-1-4613-5461-1. 
• "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. doi:10.1016/S0006-8993(01)02497-0. PMID 11430884. 
• "Characterization and localization of human type10 17beta-hydroxysteroid dehydrogenase". European Journal of Biochemistry 268 (18): 4899–907. Sep 2001. doi:10.1046/j.0014-2956.2001.02421.2421.x. PMID 11559359. 
• "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. doi:10.1016/S0169-328X(02)00102-X. PMID 11869808. 
• "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. doi:10.1086/375116. PMID 12696021.