Leukotriene Synthesis Inhibitors in a FLAP

Science's STKE  31 Jul 2007:
Vol. 2007, Issue 397, pp. tw275
DOI: 10.1126/stke.3972007tw275

Leukotrienes are bioactive lipid metabolites involved in respiratory and cardiovascular diseases. They are synthesized from arachidonic acid by the enzyme 5-lipoxygenase, and the integral membrane protein 5-lipoxygenase–activating protein (FLAP) plays an essential role in their biosynthesis. Ferguson et al. describe the crystal structure of human FLAP in complex with two different leukotriene biosynthesis inhibitors. The structures suggest how the inhibitors prevent arachidonic acid from binding to FLAP, from which it is likely transferred to 5-lipoxygenase. The structural data provide a basis for the development of drugs targeted against FLAP that would inhibit leukotriene biosynthesis.

A. D. Ferguson, B. M. McKeever, S. Xu, D. Wisniewski, D. K. Miller, T.-T. Yamin, R. H. Spencer, L. Chu, F. Ujjainwalla, B. R. Cunningham, J. F. Evans, J. W. Becker, Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein. Science 317, 510-512 (2007). [Abstract] [Full Text]