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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1072.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Amino Acid Differences in the Deduced 5-Lipoxygenase Sequence of CAST Atherosclerosis-Resistance Mice Confer Impaired Activity When Introduced Into the Human Ortholog

Hartmut Kuhn; Monika Anton; Christa Gerth; Andreas Habenicht

From the Institute of Biochemistry (H.K., M.A., C.G.), Humboldt University Medical School Charité, Berlin and Institute for Vascular Medicine (A.H.), Friedrich-Schiller-University of Jena, Germany.

Correspondence to Dr Hartmut Kuhn, Institute of Biochemistry, University Clinics Charité, Humboldt University, Monbijoustr. 2, 10117 Berlin, F.R. Germany. E-mail hartmut.kuehn{at}charite.de

Objectives— The mouse strain CON6, which was generated by breeding athero-resistant CAST mice into an athero-susceptible B6 background, exhibits almost complete resistance to atherosclerosis. An athero-resistance gene cluster has been localized at the central region of chromosome 6, and among the candidate genes of this locus, the 5-lipoxygenase has attracted particular attention because of its involvement in the biosynthesis of proinflammatory leukotrienes. Comparison of 5-lipoxygenase genomic sequences of B6 and CON6 mice indicated 2 conserved amino acid exchanges in the CON6 animals, but the functional impact of these mutations has not been defined.

Methods and Results— We analyzed the functionality of these amino acid exchanges relative to essential catalytic properties (specific activity, substrate affinity, and reaction specificity) and found that these mutations confer an impaired lipoxygenase and leukotriene A₄-synthase activity when introduced into the human enzyme. In contrast, substrate affinity, enantiomer selectivity, and positional specificity remained unchanged.

Conclusions— These data are consistent with the possibility that naturally occurring conservative mutations in the coding region of the murine 5-lipoxygenase gene can significantly affect enzyme activity and that this loss of function may be involved in CAST/CON6 athero-resistance.

Key Words: eicosanoids • leukotrienes • inflammation • mutation • atherogenesis

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