Characterization of a new branch in the cholesterol pathway centered on cholesterol-5,6-epoxides: the story of dendrogenins and oncosterone discoveries

Abstract: The 20th century was marked by the characterization of the human genome, transcriptome and proteome. The elucidation of the human metabolome is still in its infancy but remains an extraordinary challenge for the future. This is mainly because it requires specific analytical methods dedicated to different structural classes and subclasses of metabolites that display very different physico-chemical properties. The sterolome constitutes a subdivision of the lipidome, which is in expansion. Apart from steroids (defining the steroidome), the sterolome includes cholesterol and its steroidal precursors, plant and other living organisms sterols, bile acids, and oxysterols in their free or conjugated forms. Oxysterols are mono- or poly-oxygenation products of sterols known to exist in free form or as conjugates with fatty acids, sulfate, or glucides. The characterization of known sterols is still ongoing and revealed very specific structure-dependent biological properties suggesting that each oxysterol may have a specific biological function in a given physiological context. The identification of new bioactive sterol metabolites remains a very challenging but important objective for the future. We have developed a targeted and rational approach to identify new bioactive oxysterols. We have designed the chemical structure of new putative bioactive sterol metabolites. We have: 1) chemically synthesized them, 2) developed specific analytical methods to confirm their existence as endogenous metabolites in mammals, 3) characterized their biological properties, 4) identified their cognate receptors, 5) identified their biosynthesis enzymes, 6) and studied the deregulation of their metabolism in cancers. In this paper, the author will expand on the 5,6-EC metabolic branch that was uncovered, and led to the discoveries of the oncometabolite and tumor promoter oncosterone and of the tumor suppressor metabolite dendrogenin A, both involved in the control of carcinogenesis.