Human Keto Acyl Reductase

Function

The mitochondrial fatty acid synthesis (mtFAS) pathway generates precursors for mitochondrally generated alpha-lipoic acids. Defeciency of mtFAS leads to respiratory chain degects and mitochondrial dysfunction. The mtFAS has four enzymatic steps, catalyzed by four different enzymes. Ketoacyl acyl-carrier-protein (ACP) reductase (KAR) catalyzes the second step of mtFAS pathway, where 3-ketoacyl-ACP is reduced to 3R-hydroxyacyl-ACP utilizing NADPH as cofactor. KAR is a heterotetrameric complex made from two different polypeptides: 17β-hydroxysteroid dehydrogenase type 8 (HSD17B8 or KE6, α-subunit) and carbonyl reductase type 4 (CBR4 or SDR45C1, β-subunit)9. ^[1]

Disease

Deficiency of the KAR or mtFAS pathway leads to respiratory chain defects and mitochondrial dysfunction in eukaryotes.

Relevance

All other mtFAS enzymes identified so far are encoded by a single gene while KAR complex is encoded by two different genes HSD17B8 and CBR4.Both subunits complement each other to form a stable quaternary structure as seen in the crystal structure. Further, the functional studies suggest that CBR4 is the functional subunit of KAR. Whereas, HSD17B8 works as a scaffold protein to facilitate the function and stability of KAR. HSD17B8 may works as an auxiliary fatty acid beta oxidation enzymes for the oxidation of 3R-hydroxyacyl-CoA metabolites.

Structural highlights

Crystal structure of human mitochondrial heteroterameric KAR is solved at 2.34 Å. The co-factors NAD is selectively bound to the HSD17B8 subunits whereas NADP is bound to the CBR4 subunits. Both NAD and NADP are stabilized by several conserved hydrogen bonding interactions in their respective binding sites. The Asp42, Arg12 and Arg 34 are the crucial residues for co-factor recognition. Acetate ion is also bound near NAD, which identifies the fatty acyl chain binding pocket. Ser 135, Tyr148 and Lys152 in CBR4 subunit are the catalytic triad residues involved in the catalysis. ^[2]

are bound to the each subunit. is bound in HSD17B8 subunit. is bound to the CBR4 subunit. is bound near the NAD bindig site. is also bound in the structure.

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