Activation of soluble guanylate cyclase by carbon monoxide and nitric oxide: a mechanistic model.
Soluble guanylate cyclase (GC) from bovine lung is activated 4-fold by carbon monoxide (CO) and 400-fold by nitric oxide (NO). Spectroscopic and kinetic data for ligation of CO and NO with GC are summarized and compared with similar data for myoglobin (Mb), hemoglobin (Hb), and heme model compounds. Kinetic, thermodynamic, and structural data form a basis on which to construct a model for the manner in which the two ligands affect protein structure near the heme for heme proteins in general and for GC in particular. The most significant datum is that although association rates of ligands with GC are similar to those with Mb and Hb, their dissociation rates are dramatically faster. This suggests a delicate balance between five- and six-coordinate heme iron in both NO and CO complexes. Based on these and other data, a model for GC activation is proposed: The first step is formation of a six-coordinate species concomitant with tertiary and quaternary structural changes in protein structure and about a 4-fold increase in enzyme activity. In the second step, applicable to NO, the bond from iron to the proximal histidine ruptures, leading to additional relaxation in the quaternary and tertiary structure and a further 100-fold increase in activity. This is the main event in activation, available to NO and possibly other activators or combinations of activators. It is proposed, finally, that the proximal base freed in step 2, or some other protein base suitably positioned as a result of structural changes following ligation, may provide a center for nucleophilic substitution catalyzing the reaction GTP --> cGMP. An example is provided for a similar reaction in a derivatized protoheme model compound. The reaction mechanism attempts to rationalize the relative enzymatic activities of GC, heme-deficient GC, GC-CO, and GC-NO on a common basis and makes predictions for new activators that may be discovered in the future.
Sharma
V S
VS
Department of Medicine and Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, 92093-0652, USA.
Magde
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D002248:Carbon Monoxide / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D006418:Heme; D007700:Kinetics; D008956:Models, Chemical; D008962:Models, Theoretical; D009211:Myoglobin / Q000737:chemistry / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D012995:Solubility; D013057:Spectrum Analysis / Q000379:methods; D013816:Thermodynamics
D009211:Myoglobin; D009569:Nitric Oxide; D006418:Heme; D002248:Carbon Monoxide; D006162:Guanylate Cyclase