Crystal structure of archaeal ketopantoate reductase complexed with coenzyme a and 2‐oxopantoate provides structural insights into feedback regulation |
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| Authors: | Yoshiki Aikawa Yuichi Nishitani Hiroya Tomita Haruyuki Atomi Kunio Miki |
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| Affiliation: | 1. Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo‐Ku, Kyoto, Japan;2. Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo‐Ku, Kyoto, Japan;3. JST, Chiyoda‐Ku, Tokyo, Japan |
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| Abstract: | Coenzyme A (CoA) plays essential roles in a variety of metabolic pathways in all three domains of life. The biosynthesis pathway of CoA is strictly regulated by feedback inhibition. In bacteria and eukaryotes, pantothenate kinase is the target of feedback inhibition by CoA. Recent biochemical studies have identified ketopantoate reductase (KPR), which catalyzes the NAD(P)H‐dependent reduction of 2‐oxopantoate to pantoate, as a target of the feedback inhibition by CoA in archaea. However, the mechanism for recognition of CoA by KPR is still unknown. Here we report the crystal structure of KPR from Thermococcus kodakarensis in complex with CoA and 2‐oxopantoate. CoA occupies the binding site of NAD(P)H, explaining the competitive inhibition by CoA. Our structure reveals a disulfide bond between CoA and Cys84 that indicates an irreversible inhibition upon binding of CoA. The structure also suggests the cooperative binding of CoA and 2‐oxopantoate that triggers a conformational closure and seems to facilitate the disulfide bond formation. Our findings provide novel insights into the mechanism that regulates biosynthesis of CoA in archaea. Proteins 2016; 84:374–382. © 2016 Wiley Periodicals, Inc. |
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| Keywords: | feedback inhibition competitive inhibition conformational closure irreversible binding hyperthermophilic archaea |
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