4cql
Crystal structure of heterotetrameric human ketoacyl reductase complexed with NAD
Structural highlights
FunctionDHB8_HUMAN NAD-dependent 17-beta-hydroxysteroid dehydrogenase with highest activity towards estradiol. Has very low activity towards testosterone. The heteroteramer with CBR4 has NADH-dependent 3-ketoacyl-acyl carrier protein reductase activity. May play a role in biosynthesis of fatty acids in mitochondria.[1] [2] Publication Abstract from PubMedMitochondrial 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 alpha2beta2-assembly composed of 17beta-hydroxysteroid dehydrogenase type-8 (HSD17B8, alpha-subunit) and carbonyl reductase type-4 (CBR4, beta-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 beta-oxidation pathway. Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase.,Venkatesan R, Sah-Teli SK, Awoniyi LO, Jiang G, Prus P, Kastaniotis AJ, Hiltunen JK, Wierenga RK, Chen Z Nat Commun. 2014 Sep 9;5:4805. doi: 10.1038/ncomms5805. PMID:25203508[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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