Inhibition of aldo-keto reductase family 1 member B10 by unsaturated fatty acids

• Published in: Archives of biochemistry and biophysics 2016-11, Vol.609, p.69-76
• Main Authors: Hara, Akira, Endo, Satoshi, Matsunaga, Toshiyuki, Soda, Midori, El-Kabbani, Ossama, Yashiro, Koji
• Format: Article
• Language: English
• Subjects: AKR1B10; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - chemistry; Aldo-keto reductase; Arachidonic Acid - chemistry; Cancer; Carbon - chemistry; Cell Line, Tumor; cis-Unsaturated fatty acids; Cytosol - chemistry; Drug Design; Fatty Acids, Unsaturated - chemistry; Humans; Inhibitory selectivity; Kinetics; Linoleic Acid - chemistry; Molecular Docking Simulation; Mutagenesis, Site-Directed; Recombinant Proteins - chemistry; Software
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2016.09.010

A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, is a cytosolic NADPH-dependent reductase toward various carbonyl compounds including reactive aldehydes, and is normally expressed in intestines. The enzyme is overexpressed in several extraintestinal cancers, and suggested as a potential target for cancer treatment. We found that saturated and cis-unsaturated fatty acids inhibit AKR1B10. Among the saturated fatty acids, myristic acid was the most potent, showing the IC50 value of 4.2 μM cis-Unsaturated fatty acids inhibited AKR1B10 more potently, and linoleic, arachidonic, and docosahexaenoic acids showed the lowest IC50 values of 1.1 μM. The inhibition by these fatty acids was reversible and kinetically competitive with respect to the substrate, showing the Ki values of 0.24–1.1 μM. These fatty acids, except for α-linoleic acid, were much less inhibitory to structurally similar aldose reductase. Site-directed mutagenesis study suggested that the fatty acids interact with several active site residues of AKR1B10, of which Gln114, Val301 and Gln303 are responsible for the inhibitory selectivity. Linoleic and arachidonic acids also effectively inhibited AKR1B10-mediated 4-oxo-2-nonenal metabolism in HCT-15 cells. Thus, the cis-unsaturated fatty acids may be used as an adjuvant therapy for treatment of cancers that up-regulate AKR1B10. [Display omitted] •AKR1B10 is potently inhibited by cis-unsaturated fatty acids (18:1 to 22:6).•This inhibition is kinetically competitive, showing Ki values of 0.24–1.1 μM.•The fatty acids show low or no inhibition for AKR1B1 and AKR1A1.•Residues responsible for the inhibitory selectivity are identified.•Linoleic and arachidonic acids inhibit cellular metabolism by AKR1B10.