Soluble guanylate cyclase is activated differently by excess NO and by YC-1: resonance Raman spectroscopic evidence.
Modulation of soluble guanylate cyclase (sGC) activity by nitric oxide (NO) involves two distinct steps. Low-level activation of sGC is achieved by the stoichiometric binding of NO (1-NO) to the heme cofactor, while much higher activation is achieved by the binding of additional NO (xsNO) at a non-heme site. Addition of the allosteric activator YC-1 to the 1-NO form leads to activity comparable to that of the xsNO state. In this study, the mechanisms of sGC activation were investigated using electronic absorption and resonance Raman (RR) spectroscopic methods. RR spectroscopy confirmed that the 1-NO form contains five-coordinate NO-heme and showed that the addition of NO to the 1-NO form has no significant effect on the spectrum. In contrast, addition of YC-1 to either the 1-NO or xsNO forms alters the RR spectrum significantly, indicating a protein-induced change in the heme geometry. This change in the heme geometry was also observed when BAY 41-2272 was added to the xsNO form. Bands assigned to bending and stretching motions of the vinyl and propionate substituents undergo changes in intensity in a pattern suggesting altered tilting of the pyrrole rings to which they are attached. In addition, the N-O stretching frequency increases, with no change in the Fe-NO stretching frequency, an effect modeled via DFT calculations as resulting from a small opening of the Fe-N-O angle. These spectral differences demonstrate different mechanisms of activation by synthetic activators, such as YC-1 and BAY 41-2272, and excess NO.
Ibrahim
Mohammed
M
Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
Derbyshire
Emily R
ER
Soldatova
Alexandra V
AV
Marletta
Michael A
MA
Spiro
Thomas G
TG
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D018360:Crystallography, X-Ray; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D007191:Indazoles / Q000494:pharmacology*; D009569:Nitric Oxide / Q000737:chemistry / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D013056:Spectrophotometry, Ultraviolet; D013059:Spectrum Analysis, Raman
D020536:Enzyme Activators; D007191:Indazoles; D018160:Receptors, Cytoplasmic and Nuclear; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
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