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J. Biol. Chem., Vol. 283, Issue 17, 11832-11840, April 25, 2008

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Molecular Insights into the Biosynthesis of the F₄₂₀ Coenzyme^*

Farhad Forouhar, Mariam Abashidze, Huimin Xu, Laura L. Grochowski, Jayaraman Seetharaman, Munif Hussain, Alexandre Kuzin, Yang Chen, Weihong Zhou¹, Rong Xiao^¶, Thomas B. Acton^¶, Gaetano T. Montelione^¶, Anne Galinier^||, Robert H. White, and Liang Tong²

From the Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, New York, New York 10027, the Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, ^¶Center for Advanced Biotechnology and Medicine, Northeast Structural Genomics Consortium, Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, and ^||Laboratoire de Chimie Bactérienne, UPR 9043, Institut de Biologie Structurale et Microbiologie, CNRS, 31 Chemin Joseph Aiguier, 13009 Marseille, France

Coenzyme F₄₂₀, a hydride carrier, is found in Archaea and some bacteria and has crucial roles in methanogenesis, antibiotic biosynthesis, DNA repair, and activation of antitubercular compounds. CofD, 2-phospho-L-lactate transferase, catalyzes the last step in the biosynthesis of F₄₂₀-0 (F₄₂₀ without polyglutamate), by transferring the lactyl phosphate moiety of lactyl(2)diphospho-(5')guanosine to 7,8-didemethyl-8-hydroxy-5-deazariboflavin ribitol (Fo). CofD is highly conserved among F₄₂₀-producing organisms, and weak sequence homologs are also found in non-F₄₂₀-producing organisms. This superfamily does not share any recognizable sequence conservation with other proteins. Here we report the first crystal structures of CofD, the free enzyme and two ternary complexes, with Fo and P_i or with Fo and GDP, from Methanosarcina mazei. The active site is located at the C-terminal end of a Rossmann fold core, and three large insertions make significant contributions to the active site and dimer formation. The observed binding modes of Fo and GDP can explain known biochemical properties of CofD and are also supported by our binding assays. The structures provide significant molecular insights into the biosynthesis of the F₄₂₀ coenzyme. Large structural differences in the active site region of the non-F₄₂₀-producing CofD homologs suggest that they catalyze a different biochemical reaction.

Received for publication, December 19, 2007 , and in revised form, January 28, 2008.

The atomic coordinates and structure factors (codes 3CGW, 3C3D, and 3C3E) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Protein Structure Initiative of the National Institutes of Health Grants P50 GM062413 and U54 GM074958, National Science Foundation Grant MCB 0231319, the CNRS, and the French Foundation for Medical Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: College of Life Sciences, Nankai University, Tianjin, 300071, China.

² To whom correspondence should be addressed. E-mail: ltong{at}columbia.edu.

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