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

• Published in: Nature communications 2014-09, Vol.5 (1), p.4805-4805, Article 4805
• Main Authors: Venkatesan, Rajaram, Sah-Teli, Shiv K., Awoniyi, Luqman O., Jiang, Guangyu, Prus, Piotr, Kastaniotis, Alexander J., Hiltunen, J. Kalervo, Wierenga, Rik K., Chen, Zhijun
• Format: Article
• Language: English
• Subjects: 3-Hydroxyacyl CoA Dehydrogenases - metabolism; 3-Oxoacyl-(Acyl-Carrier-Protein) Reductase - metabolism; 38/23; 38/70; 38/77; 631/443/319; 631/45/287/1183; 631/45/535; 82/103; 82/16; 82/29; 82/80; 82/83; Bacterial Proteins - metabolism; Catalysis; Crystal structure; Crystallography, X-Ray; Data collection; Dehydrogenases; Enzyme Assays; Enzymes; Escherichia coli Proteins - metabolism; Fatty acids; Fatty Acids - biosynthesis; Humanities and Social Sciences; Humans; Metabolism; Metabolites; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; multidisciplinary; Mycobacterium tuberculosis - metabolism; NAD(P)H Dehydrogenase (Quinone) - metabolism; Oxidation; Oxidoreductases - metabolism; Physiology; Protein Structure, Quaternary; Proteins; Proteins - metabolism; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5805

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 α 2 β 2 -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 Hs KAR. Therefore, mtFAS is NADPH- and ACP dependent, employing the 3R-hydroxyacyl-ACP intermediate. HSD17B8 assists in the formation of the competent Hs KAR 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. 3-Ketoacyl-ACP reductase is required for mitochondrial fatty acid synthesis. Venkatesan et al. present structures of this enzyme, show that the β-subunit is involved in fatty acid synthesis and propose a role for the α-subunit in routing unsaturated fatty acids into β-oxidation.