Biomedical subjects

Xue-Ying He

Publications and source records attributed to Xue-Ying He.

5 recordsLinked to original sources

PubMed2005

Intracellular oxidation of allopregnanolone by human brain type 10 17beta-hydroxysteroid dehydrogenase.

Allopregnanolone is a positive allosteric modulator of GABAA receptors, generated by the reduction of 5alpha-dihydroprogesterone (5alpha-DHP) in astrocytes. This neuroactive steroid can be inactivated by its 3alpha-oxidation to yield 5alpha-DHP. It was found that 5alpha-DHP levels in HEK293 cells expressing type 10 17beta-hydroxysteroid dehydrogenase (17beta-HSD10), but not its catalytic inactive mutant, increased significantly as allopregnanolone was added to culture media. The results demonstrate that mitochondrial 17beta-HSD10 effectively catalyzes the intracellular oxidation of allopregnanolone. Moreover, brain astrocytes contain a moderate level of 17beta-HSD10, which is elevated in activated astrocytes of brains with Alzheimer type pathology, including sporadic Alzheimer's disease (AD) and Down's syndrome with AD. The distribution of 17beta-HSD10 was found not to parallel that of 3alpha-HSD3. Cerebral cortex has the lowest level of 17beta-HSD10; whereas the hippocampus, hypothalamus, and amygdala possess relatively higher levels of this enzyme. The catalysis of 17beta-HSD10 appears to be essential for maintaining normal functions of GABAergic neurons. The elevated level of 17beta-HSD10 in activated astrocytes is a new feature found in brains of people with AD, and it may have important impact on AD pathogenesis.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed2005

Type 10 17beta-hydroxysteroid dehydrogenase catalyzing the oxidation of steroid modulators of gamma-aminobutyric acid type A receptors.

The steroids allopregnanolone and allotetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) are positive allosteric modulators of GABA(A) receptors, generated by the reduction of 5alpha-dihydroprogesterone (5alpha-DHP) and 5alpha-DHDOC, respectively, under the catalysis of human type 3 3alpha-hydroxysteroid dehydrogenase (HSD). However, brain enzymes catalyzing the conversion of such tetrahydrosteroids back to the corresponding 5alpha-dihydrosteroids remain to be identified. Characterization of human type 10 17beta-HSD provides a new insight into its importance for the oxidation of steroid modulators of GABA(A) receptors. The apparent catalytic efficiency (k(cat)/K(m)) of this enzyme for the oxidation of allopregnanolone and 3alpha,5alpha-THDOC are 432 and 1381 min(-1) mM(-1), respectively. This enzyme has negligible 3-ketosteroid reductase activity for 5alpha-DHP and 5alpha-DHDOC even in an acidic environment. Immunoreactivity against 17beta-HSD10 was found in a number of neuronal populations. Taken together, evidence suggests that 17beta-HSD10 is the brain enzyme capable of catalyzing the oxidation of steroid modulators of GABA(A) receptors.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed2005

3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease.

3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. HAD has a preference for medium chain substrates, whereas short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) acts on a wide spectrum of substrates, including steroids, cholic acids, and fatty acids, with a preference for short chain methyl-branched acyl-CoAs. Therefore, HAD should not be referred to as SCHAD. SCHAD is not a member of the HAD family, but instead, belongs to the short chain dehydrogenase/reductase superfamily. Previously reported cases of SCHAD deficiency are due to an inherited HAD deficiency. SCHAD, also known as 17beta-hydroxysteroid dehydrogenase type 10, is important in brain development and aging. Abnormal levels of SCHAD in certain brain regions may contribute to the pathogenesis of some neural disorders. The human SCHAD gene and its protein product, SCHAD, are potential targets for intervention in conditions, such as Alzheimer's disease, Parkinson's disease, and an X-linked mental retardation, that may arise from the impaired degradation of branched chain fatty acid and isoleucine.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed2003

Oxidative 3alpha-hydroxysteroid dehydrogenase activity of human type 10 17beta-hydroxysteroid dehydrogenase.

In vitro enzyme assays have demonstrated that human type 10 17beta-hydroxysteroid dehydrogenase (17beta-HSD10) catalyzes the oxidation of 5alpha-androstane-3alpha,17beta-diol (adiol), an almost inactive androgen, to dihydrotestosterone (DHT) rather than androsterone or androstanedione. To further investigate the role of this steroid-metabolizing enzyme in intact cells, we produced stable transfectants expressing 17beta-HSD10 or its catalytically inactive Y168F mutant in human embryonic kidney (HEK) 293 cells. It was found that DHT levels in HEK 293 cells expressing 17beta-HSD10, but not its catalytically inactive mutant, will dramatically increase if adiol is added to culture media. Moreover, certain malignant prostatic epithelial cells have more 17beta-HSD10 than normal controls, and can generate DHT, the most potent androgen, from adiol. This event might promote prostate cancer growth. Analysis of the 17beta-HSD10 sequence shows that this enzyme does not have any ER retention signal or transmembrane segments and has not originated by divergence from a retinol dehydrogenase. The data suggest that the unique mitochondrial location of this HSD [Eur. J. Biochem. 268 (2001) 4899] does not prevent it from oxidizing the 3alpha-hydroxyl group of a C19 sterol in living cells. The experimental results lead to the conclusion that mitochondrial 17beta-HSD10 plays a significant part in a non-classical androgen synthesis pathway along with microsomal retinol dehydrogenases.

17-Hydroxysteroid Dehydrogenases↗

PubMedDate not supplied

Multiple functions of type 10 17beta-hydroxysteroid dehydrogenase.

Human 17beta-hydroxysteroid dehydrogenase type 10 (17beta-HSD10) is a mitochondrial enzyme encoded by the SCHAD gene, which escapes chromosome X inactivation. 17Beta-HSD10/SCHAD mutations cause a spectrum of clinical conditions, from mild mental retardation to progressive infantile neurodegeneration. 17Beta-HSD10/SCHAD is essential for the metabolism of isoleucine and branched-chain fatty acids. It can inactivate 17beta-estradiol and steroid modulators of GABA(A) receptors, and convert 5alpha-androstanediol into 5alpha-dihydrotestosterone (DHT). Certain malignant prostatic epithelial cells contain high levels of 17beta-HSD10, generating 5alpha-DHT in the absence of testosterone. 17Beta-HSD10 has an affinity for amyloid-beta peptide, and might be linked to the mitochondrial dysfunction seen in Alzheimer's disease. This versatile enzyme might provide a new drug target for neuronal excitability control and for intervention in Alzheimer's disease and certain cancers.

17-Hydroxysteroid Dehydrogenases↗