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

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Listed:
  • 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
    State Key Laboratory of Supramolecular Structure and Materials, Jilin University)

  • 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)

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.

Suggested Citation

  • Rajaram Venkatesan & Shiv K. Sah-Teli & Luqman O. Awoniyi & Guangyu Jiang & Piotr Prus & Alexander J. Kastaniotis & J. Kalervo Hiltunen & Rik K. Wierenga & Zhijun Chen, 2014. "Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5805
    DOI: 10.1038/ncomms5805
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