Inhibitory action of polyunsaturated fatty acids on IMP dehydrogenase.
We screened the inhibitor of mouse inosine 5'-monophosphate dehydrogenase (IMPDH) type II from natural compounds, and found that a fatty acid, linoleic acid (C18:2), inhibited IMPDH activity. In the C18:2 fatty acid derivatives, all trans-configuration (i.e., linoelaidic acid), ester form, alcohol form, and addition of the hydroxyl group of linoleic acid had no effect on inhibitory activity. Therefore, both parts of a carboxylic acid and an alkyl chain containing cis-type double bonds of fatty acid might be essential for inhibition. Among the various carbon atom lengths and double bonds of fatty acids examined, the strongest inhibitor was C20:2-fatty acid, eicosadienoic acid, and 50% inhibition was observed at a concentration of 16.1 microM. Eicosadienoic acid induced the inhibition of IMPDH activity and was competitive with respect to IMP (K(i)=3.1 microM). For inhibitory effect, the C20-fatty acids ranked as follows: C20:2>C20:3>C20:1>> C20:4>C20:5, and C20:0 showed no inhibition. The energy-minimized three-dimensional structures of linear-chain C20-fatty acids were calculated, and it was found that a length of 20.7-22.5A and width of 4.7-7.2A in the fatty acid molecular structure was suggested to be important for IMPDH inhibition. Docking simulation of C20-fatty acids and mouse IMPDH type II, which was homology modeled from human IMPDH type II (PDB code: 1NF7), was performed, and the fatty acid could bind to Cys331, which is a amino acid residue of the active site, competitively with IMP. Based on these results, the IMPDH-inhibitory mechanism of fatty acids is discussed.
Mizushina
Yoshiyuki
Y
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan. mizushin@nutr.kobegakuin.ac.jp
Dairaku
Issei
I
Yanaka
Noriyuki
N
Takeuchi
Toshifumi
T
Ishimaru
Chisato
C
Sugawara
Fumio
F
Yoshida
Hiromi
H
Kato
Norihisa
N
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D003545:Cysteine; D004537:Eicosanoic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D019787:Linoleic Acid / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship
D004537:Eicosanoic Acids; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D019787:Linoleic Acid; D007168:IMP Dehydrogenase; D003545:Cysteine