The mechanisms by which latanoprost free acid inhibits human carbonic anhydrase I and II.
Latanoprost, a prostaglandin F2 alpha analogue, has been shown to be an effective ocular hypotensive agent when used alone on ocular hypertensive or open angle glaucoma patients. Carbonic anhydrase (CA) inhibitors are also used to reduce ocular hypertension by decreasing aqueous humor secretion, and are given in combination with prostaglandin F2 alpha analogue. It has been shown that prostaglandin F2 alpha, Minprostin F2 alpha, has been shown to increase the carbonic anhydrase (CA) activity and blood pressure. However, the effects of latanoprost on CA have not been clarified. Therefore, we studied the effects of latanoprost free acid on human carbonic anhydrase (HCA) I and II using the stopped flow method. Latanoprost free acid inhibited the hydration activity of HCA I or II by a noncompetitive mechanism. The inhibition constants (Ki) of latanoprost free acid for HCA I and II were 0.22 and 2.3 mM, respectively. Therefore, latanoprost free acid is a weak inhibitor of HCA I or II. AutoDock simulation of the latanoprost free acid-HCA I or II complex showed that the carboxylic moiety of latanoprost free acid, which is located at the end of the molecule, binds to the zinc ion of the active site by stretching of the chain of latanoprost free acid through the narrow and deep active site cavity of HCA I or II. In the active site cavity of HCA I or II, one side is hydrophilic and the other is hydrophobic. AutoDock simulation results clearly showed that latanoprost free acids lie down on the hydrophobic sides of the active site cavities in HCA I and II. The noncompetitive inhibition mechanism and the binding mode of latanoprost free acid indicate that the behavior of latanoprost free acid is very similar to that of simple anions.
Sugimoto
Ayako
A
Department of Pharmaceutical Services, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. suzy@hiroshima-u.ac.jp
Ikeda
Hiroaki
H
Tsukamoto
Hidetoshi
H
Kihira
Kenji
K
Takeda
Chiho
C
Hirose
Junzo
J
Hata
Toshiyuki
T
Baba
Eiko
E
Ono
Yukio
Y
D000465:Algorithms; D002245:Carbon Dioxide / Q000378:metabolism; D024401:Carbonic Anhydrase I / Q000378:metabolism*; D024402:Carbonic Anhydrase II / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors; D006801:Humans; D007700:Kinetics; D000077338:Latanoprost; D008958:Models, Molecular; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology*
D002257:Carbonic Anhydrase Inhibitors; D011461:Prostaglandins F, Synthetic; D002245:Carbon Dioxide; D000077338:Latanoprost; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II