Introduction

The biosyntheses of the essential polyamines spermidine and spermine are dependent on the activity of S-adenosylmethionine decarboxylase (AdoMetDC; EC 4.1.1.50). AdoMetDC catalyzes the conversion of 5-adenosylmethionine (AdoMet) to S-adenosyl-5'-(3-methylthiopropylamine), otherwise known as decarboxylated AdoMet (dcAdoMet), which in turn donates its aminopropyl group to either putrescine for the synthesis of spermidine, or spermidine for the synthesis of spermine. The latter two reactions are catalyzed by the transferase enzymes, spermidine synthase and spermine synthase, respectively. In Saccharomyces cerevisiae, a null mutation in the SPE2 gene, encoding AdoMetDC, conveys an absolute requirement for spermidine or spermine for growth (1), and mouse blastocysts lacking a functional copy of the AdoMetDC gene die at the early stage of gastrulation unless supplied with spermidine (2). As well as being the substrate for AdoMetDC, AdoMet is involved in many other essential biochemical processes in cells and is regarded as the major methyl donor in reactions catalyzed by methyltrans-ferases. However, dcAdoMet is unable to fulfil these other functions, so AdoMetDC activity commits AdoMet to a role in polyamine biosynthesis.

AdoMetDC is synthesized as an inactive proenzyme (~38 kDa in humans) that undergoes an autocatalytic cleavage reaction to form the a and P subunits (~31 and ~7 kDa, respectively in humans) and the covalently bound pyruvoyl cofactor of the mature enzyme. In the decarboxylation reaction, the pyruvoyl group forms a Schiff base with AdoMet, providing an electron sink that facilitates removal of the a-carboxylate group. The negatively charged a-carbon of the substrate is then reprotonated, and Schiff base hydrolysis results in release of the product, dcAdoMet (Fig. 1). The most likely candidate for the role of proton donor in this reaction is the Cys-82 residue, because a C82A mutant protein has much reduced enzyme activity and exhibits a high incidence of incorrect protonation of the pyruvoyl group (3).

Recent elucidations of the crystal structures of the human wild-type and mutated AdoMetDCs have provided profound insight into the evolution, activity, and regulation

From: Polyamine Cell Signaling: Physiology Pharmacology and Cancer Research Edited by: J.-Y. Wang and R. A. Casero, Jr. © Humana Press Inc., Totowa, NJ

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