title: How might 12 (R) HETE cause the inhibition of Na,K-ATPase?
abstract: OBJECTIVE
  12 (R) hydroxy 5,8,10,14-eicosatetraenoic acid [12 (R) HETE] is a potent inhibitor of Na,K-ATPase. This study was an attempt to determine how the eicosanoid might inhibit the enzyme by using molecular modeling.
  
  
  METHODS
  Models were generated using the program HyperChem 2.0 for Windows. Models of 12 (R) HETE, 12 (S) HETE (the "S" isomer of 12 (R) HETE), and 8 (R) hydroxy-hexadecatrienoic acid [8 (R) HHDTrE, a catabolic isomer of 12 (R) HETE] were formed and docked with phosphatidyl choline and the H3-H4 peptide of the alpha-subunit of Na,K-ATPase. In addition, models of 12 (R) HETE, and related compounds, were formed and complexed with calcium, and then docked with phosphatidyl choline. The energies of stabilization were calculated for each optimal docking.
  
  
  RESULTS
  Optimal steric fitting and calculated energies of stabilization indicated that 12 (R) HETE and 8 (R) HHDTrE had the best fits when bound to the fatty acid portions of phosphatidyl choline. However, when Ca-HETE complexes were modeled, it was found that they formed even more stable complexes when bound to phosphatidyl choline. Calculated energies of 12 (S) HETE, whether complexed to calcium or not, were less favorable than the other HETE compounds.
  
  
  CONCLUSIONS
  The results of the study indicate that plasma membrane lipids rather than Na,K-ATPase itself are more likely to be bound by 12 (R) HETE and its related compounds. Moreover, it was found that the calcium complexes of 12 (R) HETE and 8 (R) HHDTrE are even more likely to dock with plasma membrane lipids. This suggests that such complexes may be able to transport calcium into the cell and make it available for the inhibition of Na, K-ATPase at the enzyme's sodium binding site.
authors.affiliation: Vision Science Research Center, School of Optometry, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. davwhik@vision.vsrc.uab.edu
authors.forename: D R
authors.initials: DR
authors.lastname: Whikehart
authors.forename: H F
authors.initials: HF
authors.lastname: Edelhauser
authors.forename: W D
authors.initials: WD
authors.lastname: Woods
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000737:chemistry* / Q000494:pharmacology; D002118:Calcium / Q000737:chemistry; D002462:Cell Membrane / Q000737:chemistry; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D010713:Phosphatidylcholines / Q000737:chemistry; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D010713:Phosphatidylcholines; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium