James L. Thomas, Ph.D.

The objective of my research is to define the reaction mechanisms of human 3beta-hydroxysteroid dehydrogenase/isomerase by relating structure to function. 3beta-HSD/isomerase is the "gateway" enzyme in all steroidogenic tissues because the precursor steroids- pregnenolone, dehydroepiandrosterone (DHEA) and 17alpha-hydroxypregnenolone- must be converted by this enzyme to ultimately become the active steroid hormones- progesterone, estradiol, testosterone, cortisol and aldosterone. Two genes express the enzyme in a tissue-specific manner in humans. One gene expresses the type 1 3beta-HSD/isomerase in placenta, mammary gland and breast tumors. The other gene expresses the type 2 3beta-HSD/isomerase in the adrenals and gonads. There are key differences in kinetics of substrate utilization and inhibition by the two isoenzymes. In my ongoing studies, mutagenesis of targeted amino acids in the enzyme based on structural data determine key structure/function relationships and evaluate why the two isoenzymes exhibit kinetic differences. After the structural basis for these differences are determined, a pharmacological intervention can be devised to selectively inhibit the type 1 enzyme that is expressed in placenta to control the timing of labor as well as in breast tumors to slow their growth.