Molecular characterization of the enzyme responsible of the biosynthesis of dendrogenin A and other cholesterol bioactive conjugates – DASYNT2

We have recently discovered in mammals the existence of dendrogenin A (DDA). It is a steroidal alkaloid derived from cholesterol that induces cell differentiation and autophagy. We have shown that this lipid displays tumor suppressor and neurostimulating properties. DDA is an exceptional endogenous molecule, acting at a low dose through a specific mechanism. Based on significant preliminary data, the DASYNT2 project aims to characterize in depth the enzyme responsible of DDA biosynthesis. It also aims to: 1) synthesize other substances derived from cholesterol that could be produced according to an similar metabolic scheme; 2) to evaluate these new conjugates in their potency to modulate cell differentiation, mobility and death; 3) to determine through which mechanisms they would act; and 4) to establish whether or not these molecules are metabolites. Our preliminary data indicate that two new molecules from this series that we have chemically synthesized are bioactive and are metabolites present in mammalian tissues. These compounds are dendrogenin B and a conjugate of cholesterol with glutathione which we have also shown to be produced by DDA synthetase. This new metabolic branch of the cholesterol pathway will probably be at least as important in biology as that of cysteinyl-leukotrienes. This branch of the arachinonic acid metabolism had been identified in the late 1970s and plays a crucial role in the inflammation and pathogenesis of asthma.