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J. Biol. Chem., Vol. 283, Issue 34, 23161-23168, August 22, 2008

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Biosynthesis of 2-Hydroxyethylphosphonate, an Unexpected Intermediate Common to Multiple Phosphonate Biosynthetic Pathways^*

Zengyi Shao, Joshua A. V. Blodgett, Benjamin T. Circello^¶1, Andrew C. Eliot^||, Ryan Woodyer^**, Gongyong Li, Wilfred A. van der Donk^¶¶, William W. Metcalf^¶¶¶2, and Huimin Zhao^¶¶3

From the Departments of Chemical and Biomolecular Engineering and Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, the Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, the ^¶Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, ^||Dupont Central Research and Development, Wilmington, Delaware 19880, ^**zuChem Inc., Peoria, Illinois 61604, the R&D Department, Shanghai Chemspec Corporation, No. 3, Lane 1273, TongPu Road, Shanghai 200333, China, and the ^¶¶Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Phosphonic acids encompass a common yet chemically diverse class of natural products that often possess potent biological activities. Here we report that, despite the significant structural differences among many of these compounds, their biosynthetic routes contain an unexpected common intermediate, 2-hydroxyethyl-phosphonate, which is synthesized from phosphonoacetaldehyde by a distinct family of metal-dependent alcohol dehydrogenases (ADHs). Although the sequence identity of the ADH family members is relatively low (34–37%), in vitro biochemical characterization of the homologs involved in biosynthesis of the antibiotics fosfomycin, phosphinothricin tripeptide, and dehydrophos (formerly A53868) unequivocally confirms their enzymatic activities. These unique ADHs have exquisite substrate specificity, unusual metal requirements, and an unprecedented monomeric quaternary structure. Further, sequence analysis shows that these ADHs form a monophyletic group along with additional family members encoded by putative phosphonate biosynthetic gene clusters. Thus, the reduction of phosphonoacetaldehyde to hydroxyethyl-phosphonate may represent a common step in the biosynthesis of many phosphonate natural products, a finding that lends insight into the evolution of phosphonate biosynthetic pathways and the chemical structures of new C–P containing secondary metabolites.

Received for publication, March 5, 2008 , and in revised form, May 27, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM059334, GM067725, and GM077596 through the NIGMS. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental information, four supplemental figures, and one supplemental table.

¹ BTC was supported by a National Institutes of Health Chemistry-Biology Interface Training Program (GM070421).

² To whom correspondence may be addressed: Dept. of Microbiology, University of Illinois at Urbana-Champaign, B103 CLSL, 601 S. Goodwin Ave., Urbana, IL 61801. Tel.: 217-244-1943; Fax: 217-244-6697; E-mail: metcalf{at}uiuc.edu. ³ To whom correspondence may be addressed: Dept. of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL 61801. Tel.: 217-333-2631; Fax: 217-333-5052; E-mail: zhao5{at}uiuc.edu.

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