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

Rajaram Venkatesan (), Shiv K. Sah-Teli, Luqman O. Awoniyi, Guangyu Jiang, Piotr Prus, Alexander J. Kastaniotis, J. Kalervo Hiltunen, Rik K. Wierenga and Zhijun Chen ()
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Rajaram Venkatesan: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu
Shiv K. Sah-Teli: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu
Luqman O. Awoniyi: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu
Guangyu Jiang: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu
Piotr Prus: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu
Alexander J. Kastaniotis: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu
J. Kalervo Hiltunen: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu
Rik K. Wierenga: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu
Zhijun Chen: State Key Laboratory of Supramolecular Structure and Materials, Jilin University

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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 α2β2-assembly composed of 17β-hydroxysteroid dehydrogenase type-8 (HSD17B8, α-subunit) and carbonyl reductase type-4 (CBR4, β-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 β-oxidation pathway.

Date: 2014
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DOI: 10.1038/ncomms5805

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