Mechanism of action of MK-401 against Fasciola hepatica: inhibition of phosphoglycerate kinase.
The effect of MK-401 (4-amino-6-trichloroethenyl 1,3-benzenedisulfonamide) on Fasciola hepatica phosphoglycerate kinase (EC 2.7.2.3) was investigated. MK-401 was a competitive inhibitor of both 3-phosphoglycerate and ATP and had a Ki of 0.29 mM. ATP, 1,3-diphosphoglycerate and MK-401 protected the Fasciola enzyme from inhibition by N-ethylmaleimide. Analogues of MK-401 with different substituents at the 6 position (R = Cl, CF3, C2 F3, C3 F7) were competitive inhibitors of both 3-phosphoglycerate and ATP and a good correlation between the Ki and in vivo activity of these analogues was observed.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D004163:Diphosphoglyceric Acids / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D005210:Fasciola hepatica / Q000201:enzymology*; D005988:Glyceric Acids / Q000494:pharmacology; D007700:Kinetics; D010735:Phosphoglycerate Kinase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013424:Sulfanilamides / Q000494:pharmacology*
D004163:Diphosphoglyceric Acids; D005988:Glyceric Acids; D013424:Sulfanilamides; C015891:glycerate 1,3-biphosphate; C005156:3-phosphoglycerate; D000255:Adenosine Triphosphate; D010735:Phosphoglycerate Kinase; C015675:clorsulon; D005033:Ethylmaleimide