Soluble guanylyl cyclase: Molecular basis for ligand selectivity and action in vitro and in vivo

Abstract

Nitric oxide (NO), carbon monoxide (CO), oxygen (O2), hydrogen sulfide (H2S) are gaseous molecules that play important roles in the physiology and pathophysiology of eukaryotes. Tissue concentrations of these physiologically relevant gases vary remarkable from nM range for NO to high μM range of O2. Various hemoproteins play a significant role in sensing and transducing cellular signals encoded by gaseous molecules or in transporting them. Soluble guanylyl cyclase (sGC) is a hemoprotein that plays vital roles in a wide range of physiological functions and combines the functions of gaseous sensor and signal transducer. sGC uniquely evolved to sense low non-toxic levels of NO and respond to elevated NO levels by increasing its catalytic ability to generate the secondary signaling messenger cyclic guanosine monophosphate (cGMP). This review discusses sGC’s gaseous ligand selectivity and the molecular basis for sGC function as high-affinity and selectivity NO receptor. The effects of other gaseous molecules and small molecules of cellular origin on sGC’s function are also discussed.

A heme pocket aromatic quadrupole modulates gas binding to cytochrome c′-β: Implications for NO sensors

“…This process also selectively boosts heme–NO affinity by virtue of the fact that 5cNO sGC complexes exhibit much lower k off values (≤0.12 s −1 ) than the 6cNO precursor (27 s −1 ) ( 17 , 42 , 43 ). Interestingly, spectroscopic and kinetic measurements suggest that sGC can form 5cNO complexes on either heme face, with a proximal 5cNO species generated with excess NO ( 44 ), and a distal 5cNO species with stoichiometric NO ( 42 ) (a condition more akin to the physiological environment) ( 45 ). Furthermore, the distal 5cNO species has a much higher k off value (0.12 s −1 ) than that of the proximal 5cNO species (6 × 10 −4 s −1 ) ( 42 , 43 ).…”

The H-NOX protein structure adapts to different mechanisms in sensors interacting with nitric oxide

“…In human sGC it culminates with 100% population of 5c-NO heme whatever the temperature despite the same tertiary fold, but with the presence of a second NO binding site. 72 The molecular mechanism of bacterial H-NOXs depart from that of sGC, but the isolated heme domain of the latter discloses changed properties close to other H-NOXs. 34 Such adaptation for different reactivities of homologous proteins was also found in cytochromes from a methanotroph bacterium.…”

Gaseous inhibition of the transsulfuration pathway by cystathionine β-synthase

“…29 Relative to another heme signalling protein which binds both CO and NO, soluble guanylate cyclase (sGC), these equilibrium dissociation constants are slightly lower for CO (K D = 260 mM for sGC), and many orders of magnitude higher for NO (K D = 53 nM-850 pM for sGC). 30 The above dissociation constants for hCBS do not take into account the fact that it is a homodimer, with binding to the heme group in one chain potentially being able to affect the binding strength in the other chain. While there is evidence of such allosteric effects for bonding of CO, with different K D1 and K D2 being reported, 25,26,29 we have not attempted to model these effects here.…”