'''HUMAN S-ADENOSYLMETHIONINE DECARBOXYLASE WITH COVALENTLY BOUND PYRUVOYL GROUP AND COVALENTLY BOUND 5'-DEOXY-5'-[(3-HYDRAZINOPROPYL)METHYLAMINO]ADENOSINE'''
===HUMAN S-ADENOSYLMETHIONINE DECARBOXYLASE WITH COVALENTLY BOUND PYRUVOYL GROUP AND COVALENTLY BOUND 5'-DEOXY-5'-[(3-HYDRAZINOPROPYL)METHYLAMINO]ADENOSINE===
==Overview==
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S-Adenosylmethionine decarboxylase belongs to a small class of amino acid decarboxylases that use a covalently bound pyruvate as a prosthetic group. It is an essential enzyme for polyamine biosynthesis and provides an important target for the design of anti-parasitic and cancer chemotherapeutic agents. We have determined the structures of S-adenosylmethionine decarboxylase complexed with the competitive inhibitors methylglyoxal bis(guanylhydrazone) and 4-amidinoindan-1-one-2'-amidinohydrazone as well as the irreversible inhibitors 5'-deoxy-5'-[N-methyl-N-[(2-aminooxy)ethyl]amino]adenosine, 5'-deoxy-5'-[N-methyl-N-(3-hydrazinopropyl)amino]adenosine, and the methyl ester analogue of S-adenosylmethionine. These structures elucidate residues important for substrate binding and show how those residues interact with both covalently and noncovalently bound inhibitors. S-Adenosylmethionine decarboxylase has a four-layer alphabeta betaalpha sandwich fold with residues from both beta-sheets contributing to substrate and inhibitor binding. The side chains of conserved residues Phe7, Phe223, and Glu247 and the backbone carbonyl of Leu65 play important roles in binding and positioning the ligands. The catalytically important residues Cys82, Ser229, and His243 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 conformation. The five structures reported here provide a framework for interpretation of S-adenosylmethionine decarboxylase inhibition data and suggest strategies for the development of more potent and more specific inhibitors of S-adenosylmethionine decarboxylase.
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==About this Structure==
==About this Structure==
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[[Category: Sandwich]]
[[Category: Sandwich]]
[[Category: Spermidine biosynthesis]]
[[Category: Spermidine biosynthesis]]
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Revision as of 10:31, 1 July 2008
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HUMAN S-ADENOSYLMETHIONINE DECARBOXYLASE WITH COVALENTLY BOUND PYRUVOYL GROUP AND COVALENTLY BOUND 5'-DEOXY-5'-[(3-HYDRAZINOPROPYL)METHYLAMINO]ADENOSINEHUMAN S-ADENOSYLMETHIONINE DECARBOXYLASE WITH COVALENTLY BOUND PYRUVOYL GROUP AND COVALENTLY BOUND 5'-DEOXY-5'-[(3-HYDRAZINOPROPYL)METHYLAMINO]ADENOSINE
1I79 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
The structural basis for substrate specificity and inhibition of human S-adenosylmethionine decarboxylase., Tolbert WD, Ekstrom JL, Mathews II, Secrist JA 3rd, Kapoor P, Pegg AE, Ealick SE, Biochemistry. 2001 Aug 14;40(32):9484-94. PMID:11583147
