The structural basis for substrate specificity and inhibition of human S-adenosylmethionine decarboxylase

S-Adenosylmethionine decarboxylase belongs to a small class of amino acid d ecarboxylases that use a covalently bound pyruvate as a prosthetic group. I t is an essential enzyme for polyamine biosynthesis and provides an importa nt target for the design of anti-parasitic and cancer chemotherapeutic agen ts. We have determined the structures of S-adenosylmethionine decarboxylase complexed with the competitive inhibitors methylglyoxal bis(guanylhydrazon e) and 4-amidinoindan-1-one-2 ' -amidinohydrazone as well as the irreversib le inhibitors 5 ' -deoxy-5 '-[N-methyl-N-[(2-aminooxy)ethyl] amino] adenosi ne, 5 ' deoxy-5 '-[N-methyl-N-(3-hydrazinopropyl)amino]adenosine, and the m ethyl ester analogue of S-adenosylmethionine. These structures elucidate re sidues important for substrate binding and show how those residues interact with both covalently and noncovalently bound inhibitors. S-Adenosylmethion ine decarboxylase has a four-layer alpha beta beta alpha sandwich fold with residues from both beta -sheets contributing to substrate and inhibitor bi nding. The side chains of conserved residues Phe7. Phe223, and Glu247 and t he backbone carbonyl of Leu65 play important roles in binding and positioni ng the ligands. The catalytically important residues Cys82, Ser229, and His 243 are positioned near the methionyl group of the substrate. One molecule of putrescine per monomer is observed between the two beta -sheets but far away from the active site. The activating effects of putrescine may be due to conformational changes in the enzyme, to electrostatic effects, or both. The adenosyl moiety of the bound ligand is observed in the unusual syn con formation. The five structures reported here provide a framework for interp retation of S-adenosylmethionine decarboxylase inhibition data and suggest strategies for the development of more potent and more specific inhibitors of S-adenosylmethionine decarboxylase.