Tanvir Rahman, M., Kristian Koski, M., Panecka-Hofman, J. et al. An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration. Nat Commun 14, 619 (2023). https://doi.org/10.1038/s41467-023-36358-7
An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration
|Author:||Rahman, M. Tanvir1; Koski, M. Kristian2; Panecka-Hofman, Joanna3,4;|
1Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
2Biocenter Oulu, University of Oulu, Oulu, Finland
3Faculty of Physics, University of Warsaw, Warsaw, Poland
4Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany
5Faculty of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany
6Zentrum für Molekulare Biologie (ZMBH), DKFZ-ZMBH Alliance and Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany
|Online Access:||PDF Full Text (PDF, 1.8 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2023071390600
|Publish Date:|| 2023-07-13
Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory function. MtFAS generates the octanoic acid precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. The structurally well-characterized component of mtFAS, human 2E-enoyl-ACP reductase (MECR) rescues respiratory growth and lipoylation defects of a Saccharomyces cerevisiae Δetr1 strain lacking native mtFAS enoyl reductase. To address the role of longer products of mtFAS, we employed in silico molecular simulations to design a MECR variant with a shortened substrate binding cavity. Our in vitro and in vivo analyses indicate that the MECR G165Q variant allows synthesis of octanoyl groups but not long chain fatty acids, confirming the validity of our computational approach to engineer substrate length specificity. Furthermore, our data imply that restoring lipoylation in mtFAS deficient yeast strains is not sufficient to support respiration and that long chain acyl-ACPs generated by mtFAS are required for mitochondrial function.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work was supported by grants from the Academy of Finland [314925, A.J.K], the Sigrid Juselius Foundation (J.K.H, A.J.K, K.J.A), the Mary and Georg C. Ehrnrooth Foundation [202100005, K.J.A], Jane and Aatos Erkko Foundation (A.J.K) and Finnish Cultural Foundation [00220849, M.T.R.].
|Academy of Finland Grant Number:||
314925 (Academy of Finland Funding decision)
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