S-ADENOSYLMETHIONINE DECARBOXYLASE AS AN ENZYME TARGET FOR THERAPY

The polyamine biosynthetic pathway has attracted much interest as a therapeutic target. Many studies have shown the potential value of inhibitors of the first enzyme in the biosynthetic pathway, ornithine decarboxylase, which forms putrescine. In order to convert putrescine into the polyamines, spermidine and spermine, the aminopropyl donor, decarboxylated S-adenosylmethionine, is needed. Therefore, S-adenosylmethionine decarboxylase (AdoMetDC, EC 4.1.1.50) is essential for polyamine synthesis. Early studies of the inhibition of this enzyme were carried out with compounds such as methylglyoxal bis(guanylhydrazone) that lack specificity and also lack potency since they are competitive inhibitors whose effects are overcome by a compensatory increase in the amount of the target enzyme. Recently, powerful irreversible inhibitors of AdoMetDC have become available including 5'-{[(Z)-4-amino-2-butenyl]methylamino}-5'-deoxyadenosine, an enzyme activated inhibitor and 5'-deoxy-5'-[(3-hydrazinopropyl)methylamino]adenosine which binds to the active site and forms a covalent bond with the pyruvate prosthetic group. This review describes the current state of knowledge of the structure and properties of AdoMetDC, the available inhibitors of this enzyme, their mechanism of action and their effects on polyamines and on the growth of tumors and protozoan parasites. These effects indicate that AdoMetDC inhibitors may be of therapeutic value either alone or in combination with ornithine decarboxylase inhibitors and that further trials of these compounds should be considered.