Role of steroid sulfates in the regulation of steroid hormone biosynthesis

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De novo steroid hormone biosynthesis is realized via a cascade of reactions with participation of six cytochromes P450. CYP11A1 is playing a central role, since it is catalyzing the initial reaction, the side-chain cleavage of cholesterol to pregnenolone. CYP17 is the enzyme catalyzing the formation of essential intermediates for the biosynthesis of sexual hormones. The effect of sulfated steroids and of intermediates and end products of the steroid biosynthesis pathway onto these cytochromes P450 is poorly or not studied but of high interest, especially since many steroid hormones occur in much higher concentrations as esters compared with the free forms. The aim of our project is to investigate the effect of these compounds on the activities of CYP11A1 and CYP17 in reconstituted in vitro systems. It will be studied whether sulfated steroids could serve as substrates or inhibitors of these enzymes. In addition, their effect on protein-protein interactions will be investigated. Finally, using recombinant COS-1 cell cultures co-expressing the CYP11A1 and CYP17 systems, steroid sulfate carriers such as SOAT, steroid sulfotransferases or StS, the effect of the different pathways (steroid biosynthesis, steroid sulfonation, steroid sulfate hydrolysis) on steroid hormone biosynthesis will be investigated in a cellular system.