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Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10) is the HSD17B10 gene product playing an appreciable role in cognitive functions. It is the main hub of exercise-upregulated mitochondrial proteins and is involved in a variety of metabolic pathways including neurosteroid metabolism to regulate allopregnanolone homeostasis. Deacetylation of 17β-HSD10 by sirtuins helps regulate its catalytic activities. 17β-HSD10 may also play a critical role in the control of mitochondrial structure, morphology and dynamics by acting as a member of the Parkin/PINK1 pathway, and by binding to cyclophilin D to open mitochondrial permeability pore. 17β-HSD10 also serves as a component of RNase P necessary for mitochondrial tRNA maturation. This dehydrogenase can bind with the Aβ peptide thereby enhancing neurotoxicity to brain cells. Even in the absence of Aβ, its quantitative and qualitative variations can result in neurodegeneration. Since elevated levels of 17β-HSD10 were found in brain cells of Alzheimer's disease (AD) patients and mouse AD models, it is considered to be a key factor in AD pathogenesis. Since data underlying Aβ-binding-alcohol dehydrogenase (ABAD) were not secured from reported experiments, ABAD appears to be a fabricated alternative term for the HSD17B10 gene product. Results of this study would encourage researchers to solve the question why elevated levels of 17β-HSD10 are present in brains of AD patients and mouse AD models. Searching specific inhibitors of 17β-HSD10 may find candidates to reduce senile neurodegeneration and open new approaches for the treatment of AD. [ABSTRACT FROM AUTHOR]

Mutations in the HSD17B10 gene were identified in two previously described mentally retarded males. A point mutation c.776G>C was found from a survivor (SV), whereas a potent mutation, c.419C>T, was identified in another deceased case (SF) with undetectable hydroxysteroid (17[beta]) dehydrogenase 10 (HSD10) activity. Protein levels of mutant HSD10(R130C) in patient SF and HSD10(E249Q) in patient SV were about half that of HSD10 in normal controls. The E249Q mutation appears to affect HSD10 subunit interactions, resulting in an allosteric regulatory enzyme. For catalyzing the oxidation of allopregnanolone by [NAD.sup.+] the Hill coefficient of the mutant enzyme is [approximately equal to] 1.3. HSD10(E249Q) was unable to catalyze the dehydrogenation of 2-methyl-3-hydroxybutyryl-CoA and the oxidation of allopregnanolone, a positive modulator of the [gamma]-aminobutyric acid type A receptor, at low substrate concentrations. Neurosteroid homeostasis is critical for normal cognitive development, and there is increasing evidence that a blockade of isoleucine catabolism alone does not commonly cause developmental disabilities. The results support the theory that an imbalance in neurosteroid metabolism could be a major cause of the neurological handicap associated with hydroxysteroid (17[beta]) dehydrogenase 10 deficiency. developmental disabilities | HSD10 deficiency | hydroxyacyl-CoA dehydrogenase

Glusuper139 of the alpha-subunit of multienzyme complex of fatty acid oxidation from Escherichia coli has been determined as the catalytic residue of enoyl-CoA hydratase. A mechanism for the hydration of 2-trans-enoyl-CoA, catalyzed by the gamma-carboxyl groups of conserved glutamate residues of enoyl-CoA hydratases, is proposed based on kinetic data and structural information. The gamma-carboxyl group of glutamate-119 of the alpha-subunit of the E.coli fatty acid oxidation complex is shwon to act as a catalytic base of enoyl-CoA hydratase.

Every conserved acidic residue in the dehydrogenase functional domain in Escherichia coli except for those in the NAD-binding motif was replaced with alanine to determine the roles of acidic residues in the dehydrogenase catalysis. Findings showed that Asp524 and Asp542 have very little involvement in dehydrogenase catalysis. On the other hand, the alpha/Glu462 -> Ala mutant complex exhibited a greater than 160-fold reduction in the k(sub cat) of the dehydrogenase in the forward direction without a significant change of the K(sub m) for the substrate.

Histidine amino acid at the 450th position (His(super 450)) of L-3-hydroxyacyl coenzyme A dehydrogenase is essential for the dehydrogenase activity of fatty acid oxidation multienzyme complexes in Escherichia coli. Substitution of His(super 450) by Gln or Ala inactivates the dehydrogenase activity of the complexes. This is due to a large increase in the transition state's free energy. However, catalytic activity of the complexes is unaffected. Substitution of Gly(super 322) with Ala has no effect on the activity of the multienzyme complex.