Human Brain Short Chain l-3-Hydroxyacyl Coenzyme A Dehydrogenase Is a Single-domain Multifunctional Enzyme

Abstract

Human brain short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) was found to catalyze the oxidation of 17β-estradiol and dihydroandrosterone as well as alcohols. Mitochondria have been demonstrated to be the proper location of this NAD+-dependent dehydrogenase in cells, although its primary structure is identical to an amyloid β-peptide binding protein reportedly associated with the endoplasmic reticulum (ERAB). This fatty acid β- oxidation enzyme was identified as a novel 17β-hydroxysteroid dehydrogenase responsible for the inactivation of sex steroid hormones. The catalytic rate constant of the purified enzyme was estimated to be 0.66 min-1 with apparent K(m) values of 43 and 50 μM for 17β-estradiol and NAD+, respectively. The catalytic efficiency of this enzyme for the oxidation of 17β-estradiol was comparable with that of peroxisomal 17β-hydroxysteroid dehydrogenase type 4. As a result, the human SCHAD gene product, a single- domain multifunctional enzyme, appears to function in two different pathways of lipid metabolism. Because the catalytic functions of human brain short chain L-3-hydroxyacyl-CoA dehydrogenase could weaken the protective effects of estrogen and generate aldehydes in neurons, it is proposed that a high concentration of this enzyme in brain is a potential risk factor for Alzheimer's disease.