HSD17B10

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 alcohol dehydrogenase.

Structure

Gene

The Human HSD17B10 gene has 6 exons residing 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.

References

References

1. (Sep 2006). "Comparative evolutionary genomics of the HADH2 gene encoding Abeta-binding alcohol dehydrogenase/17beta-hydroxysteroid dehydrogenase type 10 (ABAD/HSD10)". BMC Genomics.
2. (Aug 2011). "Hydroxysteroid (17β) dehydrogenase X in human health and disease". Molecular and Cellular Endocrinology.
3. (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.
4. (Mar 2009). "The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative". Chemico-Biological Interactions.
5. (Oct 2008). "RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme". Cell.
6. "Entrez Gene: HSD17B10 hydroxysteroid (17-beta) dehydrogenase 10".
7. (Jan 2000). "Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase". The Biochemical Journal.
8. (Oct 1997). "An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease". Nature.
9. (Sep 2014). "Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders". The Journal of Steroid Biochemistry and Molecular Biology.
10. (2005). "Multiple functions of type 10 17beta-hydroxysteroid dehydrogenase". Trends in Endocrinology and Metabolism.
11. (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.
12. (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.
13. (Oct 1997). "Alzheimer's disease. The ins and outs of amyloid-beta". Nature.
14. (November 2011). "A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability". PLOS ONE.
15. (Feb 2007). "The reduced expression of the HADH2 protein causes X-linked mental retardation, choreoathetosis, and abnormal behavior". American Journal of Human Genetics.