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Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase

DOI: 10.1038/ncomms5805 DOI Help
PMID: 25203508 PMID Help

Authors: Rajaram Venkatesan (Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Finland) , Shiv K. Sah-teli (Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Finland) , Luqman O. Awoniyi (Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Finland) , Guangyu Jiang (Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Finland) , Piotr Prus (Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Finland) , Alexander J. Kastaniotis (Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Finland) , J. Kalervo Hiltunen (Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Finland) , Rik K. Wierenga (Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Finland) , Zhijun Chen (State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun, China)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 5 , PAGES 4805

State: Published (Approved)
Published: September 2014
Diamond Proposal Number(s): 8030

Abstract: Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory growth in yeast and mammalian embryonic survival. The human 3-ketoacyl-acyl carrier protein (ACP) reductase (KAR) of mtFAS is a heterotetrameric á2â2-assembly composed of 17â-hydroxysteroid dehydrogenase type-8 (HSD17B8, á-subunit) and carbonyl reductase type-4 (CBR4, â-subunit). Here we provide a structural explanation for the stability of the heterotetramer from the crystal structure with NAD(+) and NADP(+) bound to the HSD17B8 and CBR4 subunits, respectively, and show that the catalytic activity of the NADPH- and ACP-dependent CBR4 subunit is crucial for a functional HsKAR. Therefore, mtFAS is NADPH- and ACP dependent, employing the 3R-hydroxyacyl-ACP intermediate. HSD17B8 assists in the formation of the competent HsKAR assembly. The intrinsic NAD(+)- and CoA-dependent activity of the HSD17B8 subunit on the 3R-hydroxyacyl-CoA intermediates may indicate a role for this subunit in routing 3R-hydroxyacyl-CoA esters, potentially arising from the metabolism of unsaturated fatty acids, into the mitochondrial â-oxidation pathway.

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Other Facilities: ESRF, Grenoble

Added On: 01/10/2014 13:35

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