Mechanism and Catalytic Site Atlas

S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical regulatory enzyme in the polyamine synthetic pathway, and has been the subject of biochemical studies spanning several decades. AdoMetDC is a target for drug design against cancer, parasitic infection, and a variety of hyperproliferative disorders and has several intriguing biochemical features such as an unusual self-cleavage reaction, a covalently bound reactive pyruvoyl group, allosteric activation, and high in vivo degradation rates.

AdoMetDC catalyses the removal of the carboxylate group from S-adenosylmethionine (AdoMet) to form (5-deoxy-5-adenosyl)(3-aminopropyl) methylsulfonium salt (dcAdoMet), which is committed to act as the n-propylamine group donor for the synthesis of the polyamines spermidine and spermine from the diamine putrescine. These polyamines have been shown to be involved in the initiation and maintenance of proliferative states, and are crucial for cell growth and differentiation. AdoMetDC is a control point within the polyamine pathway, and its activity is highly regulated during the cell cycle via multiple mechanisms. Deregulation of this pathway has been associated with several types of cancers. The unusual catalytic mechanism of AdoMetDC involves a covalently bound pyruvoyl group instead of the cofactor pyridoxal-5-phosphate (PLP). This pyruvoyl group is generated in a post-translation modification internal serinolysis reaction.