Inhibition of aldo-keto reductase family 1 member B10 by unsaturated fatty acids.
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 IC50value of 4.2 μM cis-Unsaturated fatty acids inhibited AKR1B10 more potently, and linoleic, arachidonic, and docosahexaenoic acids showed the lowest IC50values of 1.1 μM. The inhibition by these fatty acids was reversible and kinetically competitive with respect to the substrate, showing the Kivalues 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.
Faculty of Engineering, Gifu University, Gifu, 501-1193, Japan.
Akira
A
Hara
Gifu Pharmaceutical University, Gifu, 501-1196, Japan. Electronic address: sendo@gifu-pu.ac.jp.
Satoshi
S
Endo
Gifu Pharmaceutical University, Gifu, 501-1196, Japan.
Toshiyuki
T
Matsunaga
Gifu Pharmaceutical University, Gifu, 501-1196, Japan.
Midori
M
Soda
Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Ossama
O
El-Kabbani
Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan.
Koji
K
Yashiro
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000074408:Aldo-Keto Reductases; D016718:Arachidonic Acid / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D045744:Cell Line, Tumor; D003600:Cytosol / Q000737:chemistry; D015195:Drug Design; D005231:Fatty Acids, Unsaturated / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D019787:Linoleic Acid / Q000737:chemistry; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000737:chemistry; D012984:Software
D005231:Fatty Acids, Unsaturated; D011994:Recombinant Proteins; D016718:Arachidonic Acid; D002244:Carbon; D019787:Linoleic Acid; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase
AKR1B10; Aldo-keto reductase; Cancer; Inhibitory selectivity; cis-Unsaturated fatty acids