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Molecular Basis for Converting (2S)-Methylsuccinyl-CoA Dehydrogenase into an Oxidase

Department of Biochemistry and Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, Karl-von-Frisch-Str. 10, 35043 Marburg, Germany
Molecular Enzymology Group, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
LOEWE Center for Synthetic Microbiology, University of Marburg, 35043 Marburg, Germany
Author to whom correspondence should be addressed.
Molecules 2018, 23(1), 68;
Received: 21 November 2017 / Revised: 18 December 2017 / Accepted: 21 December 2017 / Published: 28 December 2017
(This article belongs to the Special Issue Flavoenzymes)
Although flavoenzymes have been studied in detail, the molecular basis of their dioxygen reactivity is only partially understood. The members of the flavin adenosine dinucleotide (FAD)-dependent acyl-CoA dehydrogenase and acyl-CoA oxidase families catalyze similar reactions and share common structural features. However, both enzyme families feature opposing reaction specificities in respect to dioxygen. Dehydrogenases react with electron transfer flavoproteins as terminal electron acceptors and do not show a considerable reactivity with dioxygen, whereas dioxygen serves as a bona fide substrate for oxidases. We recently engineered (2S)-methylsuccinyl-CoA dehydrogenase towards oxidase activity by rational mutagenesis. Here we characterized the (2S)-methylsuccinyl-CoA dehydrogenase wild-type, as well as the engineered (2S)-methylsuccinyl-CoA oxidase, in detail. Using stopped-flow UV-spectroscopy and liquid chromatography-mass spectrometry (LC-MS) based assays, we explain the molecular base for dioxygen reactivity in the engineered oxidase and show that the increased oxidase function of the engineered enzyme comes at a decreased dehydrogenase activity. Our findings add to the common notion that an increased activity for a specific substrate is achieved at the expense of reaction promiscuity and provide guidelines for rational engineering efforts of acyl-CoA dehydrogenases and oxidases. View Full-Text
Keywords: acyl-CoA dehydrogenase; acyl-CoA oxidase; enzyme engineering; flavin adenine dinucleotide acyl-CoA dehydrogenase; acyl-CoA oxidase; enzyme engineering; flavin adenine dinucleotide
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MDPI and ACS Style

Burgener, S.; Schwander, T.; Romero, E.; Fraaije, M.W.; Erb, T.J. Molecular Basis for Converting (2S)-Methylsuccinyl-CoA Dehydrogenase into an Oxidase. Molecules 2018, 23, 68.

AMA Style

Burgener S, Schwander T, Romero E, Fraaije MW, Erb TJ. Molecular Basis for Converting (2S)-Methylsuccinyl-CoA Dehydrogenase into an Oxidase. Molecules. 2018; 23(1):68.

Chicago/Turabian Style

Burgener, Simon, Thomas Schwander, Elvira Romero, Marco W. Fraaije, and Tobias J. Erb 2018. "Molecular Basis for Converting (2S)-Methylsuccinyl-CoA Dehydrogenase into an Oxidase" Molecules 23, no. 1: 68.

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