Structures and functions of human placental aromatase and steroid sulfatase, two key enzymes in estrogen biosynthesis

Cytochrome P450 aromatase (AROM) and steroid sulfatase (STS) are the two key enzymes for the biosynthesis of estrogens in human, and maintenance of the critical balance between androgens and estrogens. Human AROM, an integral membrane protein of the endoplasmic reticulum, is a member of the cytochrome P450 superfamily. It is the only enzyme to catalyze the conversion of androgens with non-aromatic A-rings to estrogens characterized by the aromatic A-ring. Human STS, also an integral membrane protein of the endoplasmic reticulum, is a Ca2+-dependent enzyme that catalyzes the hydrolysis of sulfate esters of estrone and dehydroepiandrosterone to the unconjugated steroids, the precursors of the most potent forms of estrogens and androgens, namely, 17B-estra-diol, 16a,17B-estriol, testosterone and dihydrotestosterone. Expression of these steroidogenic enzymes locally within organs and tissues of the endocrine, reproductive, and central nervous systems is the key for maintaining high levels of the reproductive steroids. The enzymes have been drug targets for the prevention and treatment of diseases associated with steroid hormone excesses, especially in breast, endometrial and prostate malignancies. Both enzymes have been the subjects of vigorous research for the past six decades. In this article, we review the important findings on their structure-function relationships, specifically, the work that began with unravelling of the closely guarded secrets, namely, the 3-D structures, active sites, mechanisms of action, origins of substrate specificity and the basis of membrane integration. Remarkably, these studies were conducted on the enzymes purified in their pristine forms from human placenta, the discarded and their most abundant source. The puri-fication, assay, crystallization, and structure determination methodologies are described. Also reviewed are their functional quaternary organizations, post-translational modifications and the advancements made in the structure-guided inhibitor design efforts. Outstanding questions that still remain open are summarized in closing.