The effects of nitroxyl (HNO) on soluble guanylate cyclase activity: interactions at ferrous heme and cysteine thiols.
It has been previously proposed that nitric oxide (NO) is the only biologically relevant nitrogen oxide capable of activating the enzyme soluble guanylate cyclase (sGC). However, recent reports implicate HNO as another possible activator of sGC. Herein, we examine the affect of HNO donors on the activity of purified bovine lung sGC and find that, indeed, HNO is capable of activating this enzyme. Like NO, HNO activation appears to occur via interaction with the regulatory ferrous heme on sGC. Somewhat unexpectedly, HNO does not activate the ferric form of the enzyme. Finally, HNO-mediated cysteine thiol modification appears to also affect enzyme activity leading to inhibition. Thus, sGC activity can be regulated by HNO via interactions at both the regulatory heme and cysteine thiols.
Miller
Thomas W
TW
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095.
Cherney
Melisa M
MM
the Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706.
Lee
Andrea J
AJ
the Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706.
Francoleon
Nestor E
NE
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095.
Farmer
Patrick J
PJ
the Department of Chemistry, University of California, Irvine, California 92697.
King
S Bruce
SB
the Department of Chemistry, Wake Forest University, Winston Salem, North Carolina 27109.
Hobbs
Adrian J
AJ
Department of Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, United Kingdom.
Miranda
Katrina M
KM
the Department of Chemistry, University of Arizona, Tucson, Arizona 85721.
Burstyn
Judith N
JN
the Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706.
Fukuto
Jon M
JM
the Department of Chemistry, Sonoma State University, Rohnert Park, California 94928-3609.
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D003545:Cysteine / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000378:metabolism*; D006418:Heme / Q000737:chemistry*; D007501:Iron / Q000737:chemistry; D008168:Lung / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D009569:Nitric Oxide / Q000737:chemistry; D009589:Nitrogen Oxides / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D014665:Vasodilator Agents / Q000494:pharmacology
D009589:Nitrogen Oxides; D018160:Receptors, Cytoplasmic and Nuclear; D013438:Sulfhydryl Compounds; D014665:Vasodilator Agents; D009569:Nitric Oxide; D006418:Heme; D007501:Iron; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C039900:nitroxyl; D003545:Cysteine