James L. Thomas, Ph.D.
Division of Basic Medical Sciences
Department of Obstetrics & Gynecology
Mercer University School of Medicine
Macon, GA 31207
The steroid metabolizing enzyme, 3beta-hydroxysteroid
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
breast tumors to slow their growth.