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J. Biol. Chem., Vol. 282, Issue 47, 34159-34166, November 23, 2007

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10-Formyltetrahydrofolate Dehydrogenase Requires a 4'-Phosphopantetheine Prosthetic Group for Catalysis^*

Henry Donato¹, Natalia I. Krupenko¹, Yaroslav Tsybovsky, and Sergey A. Krupenko²

From the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425 and the Department of Chemistry and Biochemistry, College of Charleston, Charleston, South Carolina 29424

10-Formyltetrahydrofolate dehydrogenase (FDH) consists of two independent catalytic domains, N- and C-terminal, connected by a 100-amino acid residue linker (intermediate domain). Our previous studies on structural organization and enzymatic properties of rat FDH suggest that the overall enzyme reaction, i.e. NADP⁺-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO₂, consists of two steps: (i) hydrolytic cleavage of the formyl group in the N-terminal catalytic domain, followed by (ii) NADP⁺-dependent oxidation of the formyl group to CO₂ in the C-terminal aldehyde dehydrogenase domain. In this mechanism, it was not clear how the formyl group is transferred between the two catalytic domains after the first step. This study demonstrates that the intermediate domain functions similarly to an acyl carrier protein. A 4'-phosphopantetheine swinging arm bound through a phosphoester bond to Ser³⁵⁴ of the intermediate domain transfers the formyl group between the catalytic domains of FDH. Thus, our study defines the intermediate domain of FDH as a novel carrier protein and provides the previously lacking component of the FDH catalytic mechanism.

Received for publication, September 11, 2007 , and in revised form, September 17, 2007.

^* This work was supported by National Institutes of Health Grant DK54388. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425. Tel.: 843-792-0845; Fax: 843-792-8565; E-mail: krupenko{at}musc.edu.

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