title: On the activation of soluble guanylyl cyclase by nitric oxide.
abstract: Soluble guanylyl cyclase (sGC) is the major cellular receptor for the intercellular messenger nitric oxide (NO) and mediates a wide range of physiological effects through elevation of intracellular cGMP levels. Critical to our understanding of how NO signals are decoded by receptive cells and translated into a useful physiological response is an appreciation of the molecular and kinetic details of the mechanism by which NO activates sGC. It is known that NO binds to a haem prosthetic group on the receptor and triggers a conformational change that increases the catalysis of cGMP synthesis by several hundred-fold. The haem is covalently attached to sGC at His-105 of the beta1 subunit, and it was thought previously that activation of sGC by NO occurs in two steps: binding of NO to the haem to form a biliganded state and then rupture of the bond to His-105 triggering an increase in catalytic activity. A recent investigation of the kinetics of sGC activation [Zhao, Y., Brandish, P. E., Ballou, D. P. & Marletta, M. A. (1999) Proc. Natl. Acad. Sci. USA, 96, 14753-14758], however, proposed an additional mechanism by which NO regulates sGC activity, namely, by influencing the rate of cleavage of the His-105 bond. The existence of a second (unidentified) NO-binding site on the enzyme was hypothesized and suggested to be fundamental to cellular NO-signal transduction. Here, we show that it is unnecessary to postulate any such additional mechanism because the results obtained are predicted by the simpler model of sGC activation with a single NO-binding event.
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6AU, United Kingdom. tbellam@nimr.mrc.ac.uk
authors.forename: Tomas C
authors.initials: TC
authors.lastname: Bellamy
authors.forename: John
authors.initials: J
authors.lastname: Wood
authors.forename: John
authors.initials: J
authors.lastname: Garthwaite
mesh_terms: D001665:Binding Sites; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase; D006418:Heme / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D009569:Nitric Oxide / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP