4CQM

Crystal structure of heterotetrameric human ketoacyl reductase complexed with NAD and NADP

Summary for 4CQM

• Entry DOI: 10.2210/pdb4cqm/pdb
• Related: 4CQL
• Descriptor: ESTRADIOL 17-BETA-DEHYDROGENASE 8, CARBONYL REDUCTASE FAMILY MEMBER 4, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (8 entities in total)
• Functional Keywords: oxidoreductase, kar, ketoacyl reductase, 3-ketoacyl-acp reductase, ke6, hsd8, 17-beta hydroxysteroid dehydrogenase, hsd17b8, 3r-hydroxyacyl-coa dehydrogenase, cbr4, carbobyl reductase type4, nad, nadh, nadp, nadph, hetero tetramer
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Mitochondrion matrix: Q92506 Q8N4T8 Q92506
• Total number of polymer chains: 16
• Total formula weight: 439364.52

Authors

Venkatesan, R.,SahTeli, S.K.,Awoniyi, L.O.,Jiang, G.,Prus, P.,Kastoniotis, A.J.,Hiltunen, J.K.,Wierenga, R.K.,Chen, Z. (deposition date: 2014-02-19, release date: 2014-09-10, Last modification date: 2024-11-13)

Primary citation

Venkatesan, R.,Sah-Teli, S.K.,Awoniyi, L.O.,Jiang, G.,Prus, P.,Kastaniotis, A.J.,Hiltunen, J.K.,Wierenga, R.K.,Chen, Z.
Insights Into Mitochondrial Fatty Acid Synthesis from the Structure of Heterotetrameric 3-Ketoacyl-Acp Reductase/3R-Hydroxyacyl-Coa Dehydrogenase.
Nat.Commun., 5:4805-, 2014

PubMed 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.

PubMed: 25203508
DOI: 10.1038/NCOMMS5805

Experimental method

X-RAY DIFFRACTION (2.339 Å)