title: Mode of inhibition of brain Na+,K+-ATPase by agelasidines and agelasines from a sea sponge.
abstract: The Na+,K+-ATPase from brain or kidney and sarcoplasmic reticulum (SR) Ca2+-ATPase were inhibited potently by agelasidine C (Agd-C) and agelasine B (Ags-B), the bioactive principles of sea sponge, while Agd-C and Ags-B exerted less potent inhibition of heart Na+,K+-ATPase. The ionized moiety in Agd-C and the long nonpolar side chains in Ags-B play important roles in their inhibitory action. The inhibition of Na+,K+-ATPase by Agd-C or Ags-B was virtually reversed by diluting with the inhibitor-free solution. Kinetic analysis of the inhibitory effects of Agd-C and Ags-B indicates that the inhibition of pig brain Na+,K+-ATPase is parabolic and noncompetitive with respect to ATP. This may indicate that the inhibition of Na+,K+-ATPase results from the binding of two molecules of Agd-C or Ags-B to one enzyme. The sigmoidal behavior (n = 1.3-1.4) in the K+ activation curve for Na+,K+-ATPase was strikingly intensified (n = 2.1) by Agd-C, whereas it was almost eliminated (n = 1.1) by Ags-B. These results suggest that the cooperative interaction between K+-binding sites on the enzyme was dramatically altered.
authors.affiliation: Mitsubishi-Kasei Institute of Life Sciences, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: H M
authors.initials: HM
authors.lastname: Wu
authors.forename: J
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Ohizumi
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D004285:Dogs; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D009206:Myocardium / Q000201:enzymology; D009281:Naphthalenes; D011161:Porifera; D011687:Purines / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D006146:Guanidines; D009281:Naphthalenes; D011687:Purines; C054174:agelasine B; C054173:agelasidine C; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase