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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxyacyl CoA Dehydrogenases / metabolism
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Reductase / metabolism
  • Bacterial Proteins / metabolism
  • Crystallography, X-Ray
  • Enzyme Assays
  • Escherichia coli Proteins / metabolism*
  • Fatty Acids / biosynthesis*
  • Humans
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism*
  • Mycobacterium tuberculosis / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / metabolism*
  • Oxidoreductases / metabolism*
  • Protein Structure, Quaternary*
  • Proteins / metabolism*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • Bacterial Proteins
  • Escherichia coli Proteins
  • Fatty Acids
  • HSD17B8 protein, human
  • Mitochondrial Proteins
  • Proteins
  • Saccharomyces cerevisiae Proteins
  • Oxidoreductases
  • 3-Hydroxyacyl CoA Dehydrogenases
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Reductase
  • CBR4 protein, human
  • NAD(P)H Dehydrogenase (Quinone)

Associated data

  • PDB/4CQL
  • PDB/4CQM