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Journal of Biochemistry Advance Access published online on February 8, 2007
Journal of Biochemistry, doi:10.1093/jb/mvm055
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© 2007 The Japanese Biochemical Society

Structure of the Antitumor Enzyme L-Methionine {gamma}-Lyase from Pseudomonas putida at 1.8Å Resolution

Daizou Kudou1, Shintaro Misaki2, Masao Yamashita1, Takashi Tamura1, Tomoaki Takakura3, Takayuki Yoshioka4, Shigeo Yagi5, Robert M Hoffman5, Akio Takimoto3 and Kenji Inagaki1,*

1Department of Biofunctional Chemistry, Graduate School of Natural Science and Technology, Okayama University, Okayama-shi, Okayama 700-8530, Japan
2Diagnostic Division, SHIONOGI & CO., LTD. 2-5-1 Mishima, Settsu, Osaka 566-0022, Japan
3Discovery Research Laboratories, SHIONOGI & CO., LTD. 1-3, Kuise Tarajima 2-chome, Amagasaki, Hyogo 660-0813, Japan
4Pharmaceutical Research & Development Division, SHIONOGI & CO., LTD. 12-4 Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan
5AntiCancer Inc., 7917 Ostrow Street, San Diego, CA 92111, USA

*Corresponding author : Kenji Inagaki Department of Biofunctional Chemistry, Graduate School of Natural Science and Technology, Okayama University, Okayama-shi, Okayama 700-8530, Japan Tel, Fax : +81-86-251-8299 E-mail : kinagaki{at}cc.okayama-u.ac.jp

Received October 2, 2006; Accepted January 30, 2007


  Abstract

L-Methionine {gamma}-lyase (EC 4.4.1.11 [EC] , MGL_Pp) from Pseudomonas putida is a multifunctional enzyme, which belongs to the {gamma}-family of pyridoxal-5’-phosphate (PLP) dependent enzymes. In this report, we demonstrate that the three-dimensional structure of MGL_Pp has been completely solved by the molecular replacement method to an R-factor of 20.4% at 1.8Å resolution. Detailed information of the overall structure of MGL_Pp supplies a clear picture of the substrate- and PLP-binding pockets. Tyr59 and Arg61 of neighboring subunits, which are strongly conserved in other {gamma}-family enzymes, contact the phosphate group of PLP. These residues are important as the main anchor within the active site. Lys240, Asp241 and Arg61 of one partner monomer and Tyr114 and Cys116 of the other partner monomer form a hydrogen-bond network in the MGL active site which is specific for MGLs. It is also suggested that electrostatic interactions at the subunit interface are involved in the stabilization of the structural conformation. The detailed structure will facilitate the development of MGL_Pp as an anti-cancer drug.

Key Words: Methionine {gamma}-lyase, pyridoxal 5’-phosphate, X-ray structure


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