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An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration |
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| Author: | Rahman, M. Tanvir1; Koski, M. Kristian2; Panecka-Hofman, Joanna3,4; |
| Organizations: |
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 |
| Format: | article |
| Version: | published version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 1.8 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe2023071390600 |
| Language: | English |
| Published: |
Springer Nature,
2023
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| Publish Date: | 2023-07-13 |
| Description: |
AbstractMitochondrial 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. see all
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| Series: |
Nature communications |
| ISSN: | 2041-1723 |
| ISSN-E: | 2041-1723 |
| ISSN-L: | 2041-1723 |
| Volume: | 14 |
| Issue: | 1 |
| Article number: | 619 |
| DOI: | 10.1038/s41467-023-36358-7 |
| OADOI: | https://oadoi.org/10.1038/s41467-023-36358-7 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
1182 Biochemistry, cell and molecular biology |
| Subjects: | |
| Funding: |
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 |
| Detailed Information: |
314925 (Academy of Finland Funding decision) |
| Copyright information: |
© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
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https://creativecommons.org/licenses/by/4.0/ |