Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Mizushina, Y. et al.

Yoshiyuki Mizushina, Issei Dairaku, Noriyuki Yanaka, Toshifumi Takeuchi, Chisato Ishimaru, Fumio Sugawara, Hiromi Yoshida, Norihisa Kato,

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.[1]

References

Inhibitory action of polyunsaturated fatty acids on IMP dehydrogenase. Mizushina, Y., Dairaku, I., Yanaka, N., Takeuchi, T., Ishimaru, C., Sugawara, F., Yoshida, H., Kato, N. Biochimie (2007) [Pubmed]

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