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

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

  • Nat Commun. 2014 Sep 9;5:4805. doi: 10.1038/ncomms5805.
Rajaram Venkatesan 1,  Shiv K Sah-Teli 1,  Luqman O Awoniyi 1,  Guangyu Jiang 1,  Piotr Prus 1,  Alexander J Kastaniotis 1,  J Kalervo Hiltunen 2,  Rik K Wierenga 1,  Zhijun Chen 3
Affiliations

Affiliations

  • 1 Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, PO Box 5400, Oulu FI-90014, Finland.
  • 2 1] Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, PO Box 5400, Oulu FI-90014, Finland [2] State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun 130012, China.
  • 3 State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun 130012, China.
PMID: 25203508 DOI: 10.1038/ncomms5805
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.

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