title: YC-1 activation of human soluble guanylyl cyclase has both heme-dependent and heme-independent components.
abstract: YC-1 [3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole] is an allosteric activator of soluble guanylyl cyclase (sGC). YC-1 increases the catalytic rate of the enzyme and sensitizes the enzyme toward its gaseous activators nitric oxide or carbon monoxide. In other studies the administration of YC-1 to experimental animals resulted in the inhibition of the platelet-rich thrombosis and a decrease of the mean arterial pressure, which correlated with increased cGMP levels. However, details of YC-1 interaction with sGC and enzyme activation are incomplete. Although evidence in the literature indicates that YC-1 activation of sGC is strictly heme-dependent, this report presents evidence for both heme-dependent and heme-independent activation of sGC by YC-1. The oxidation of the sGC heme by 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one completely inhibited the response to NO, but only partially attenuated activation by YC-1. We also observed activation by YC-1 of a mutant sGC, which lacks heme. These findings indicate that YC-1 activation of sGC can occur independently of heme, but that activation is substantially increased when the heme moiety is present in the enzyme.
authors.affiliation: Department of Integrative Biology and Pharmacology, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: E
authors.initials: E
authors.lastname: Martin
authors.forename: Y C
authors.initials: YC
authors.lastname: Lee
authors.forename: F
authors.initials: F
authors.lastname: Murad
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010084:Oxidation-Reduction; D011810:Quinoxalines / Q000494:pharmacology; D012995:Solubility
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D017931:DNA Primers; D020536:Enzyme Activators; D007191:Indazoles; D010069:Oxadiazoles; D011810:Quinoxalines; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D006418:Heme; D006162:Guanylate Cyclase