1I72

HUMAN S-ADENOSYLMETHIONINE DECARBOXYLASE WITH COVALENTLY BOUND PYRUVOYL GROUP AND COVALENTLY BOUND 5'-DEOXY-5'-[N-METHYL-N-(2-AMINOOXYETHYL) AMINO]ADENOSINE

1I72 の概要

• エントリーDOI: 10.2210/pdb1i72/pdb
• 関連するPDBエントリー: 1I79 1I7B 1I7C 1I7M 1JEN
• 分子名称: S-ADENOSYLMETHIONINE DECARBOXYLASE BETA CHAIN, S-ADENOSYLMETHIONINE DECARBOXYLASE ALPHA CHAIN, 5'-DEOXY-5'-[N-METHYL-N-(2-AMINOOXYETHYL) AMINO]ADENOSINE, ... (5 entities in total)
• 機能のキーワード: spermidine biosynthesis, lyase, decarboxylase, pyruvate, s-adenosylmethionine, sandwich, allosteric enzyme, pyruvoyl
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38794.04

構造登録者

Tolbert, W.D.,Ekstrom, J.L.,Mathews, I.I.,Secrist III, J.A.,Pegg, A.E.,Ealick, S.E. (登録日: 2001-03-07, 公開日: 2001-08-22, 最終更新日: 2024-10-16)

主引用文献

Tolbert, W.D.,Ekstrom, J.L.,Mathews, I.I.,Secrist III, J.A.,Kapoor, P.,Pegg, A.E.,Ealick, S.E.
The structural basis for substrate specificity and inhibition of human S-adenosylmethionine decarboxylase.
Biochemistry, 40:9484-9494, 2001

PubMed Abstract: 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.

PubMed: 11583147
DOI: 10.1021/bi010735w

実験手法

X-RAY DIFFRACTION (2 Å)