ATP allosterically activates the human 5-lipoxygenase molecular mechanism of arachidonic acid and 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid

Biochemistry. 2014 Jul 15;53(27):4407-19. doi: 10.1021/bi401621d. Epub 2014 Jul 2.


5-Lipoxygenase (5-LOX) reacts with arachidonic acid (AA) to first generate 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid [5(S)-HpETE] and then an epoxide from 5(S)-HpETE to form leukotriene A4, from a single polyunsaturated fatty acid. This work investigates the kinetic mechanism of these two processes and the role of ATP in their activation. Specifically, it was determined that epoxidation of 5(S)-HpETE (dehydration of the hydroperoxide) has a rate of substrate capture (Vmax/Km) significantly lower than that of AA hydroperoxidation (oxidation of AA to form the hydroperoxide); however, hyperbolic kinetic parameters for ATP activation indicate a similar activation for AA and 5(S)-HpETE. Solvent isotope effect results for both hydroperoxidation and epoxidation indicate that a specific step in its molecular mechanism is changed, possibly because of a lowering of the dependence of the rate-limiting step on hydrogen atom abstraction and an increase in the dependency on hydrogen bond rearrangement. Therefore, changes in ATP concentration in the cell could affect the production of 5-LOX products, such as leukotrienes and lipoxins, and thus have wide implications for the regulation of cellular inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / chemistry*
  • Allosteric Regulation
  • Arachidonate 5-Lipoxygenase / chemistry*
  • Arachidonic Acid / chemistry*
  • Calcium / chemistry
  • Enzyme Activation
  • Epoxy Compounds / chemistry
  • Humans
  • Leukotriene A4 / chemistry
  • Leukotrienes / chemistry*
  • Peroxides / chemistry
  • Stereoisomerism
  • Viscosity


  • Epoxy Compounds
  • Leukotriene A4
  • Leukotrienes
  • Peroxides
  • Arachidonic Acid
  • arachidonic acid 5-hydroperoxide
  • Adenosine Triphosphate
  • Arachidonate 5-Lipoxygenase
  • Calcium