Nucleotide regulation of soluble guanylate cyclase substrate specificity

Biochemistry. 2009 Aug 11;48(31):7519-24. doi: 10.1021/bi900696x.


Soluble guanylate cyclase (sGC) serves as a receptor for the signaling agent nitric oxide (NO). sGC synthesis of cGMP is regulated by NO, GTP, ATP, and allosteric activators such as YC-1. The guanylate cyclase activity and adenylate cyclase activity of full-length sGC and the sGC catalytic domain constructs (alpha1(cat)beta1(cat)) are reported here. ATP is a mixed-type inhibitor of cGMP production for both sGC and alpha1(cat)beta1(cat), indicating that the C-terminus of sGC contains an allosteric nucleotide binding site. YC-1 did not activate alpha1(cat)beta1(cat) or compete with ATP inhibition of cGMP synthesis, which suggests that YC-1 and ATP bind to distinct sites. alpha1(cat)beta1(cat) and NO-stimulated sGC also synthesize cAMP, but this activity is inhibited by ATP via noncompetitive substrate inhibition and by GTP via mixed-type inhibition. Additionally, the adenylate cyclase activity of purified sGC was inhibited by PC12 lysate, suggesting that an intracellular small molecule or protein regulates this activity in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / antagonists & inhibitors
  • Adenosine Triphosphate / chemistry*
  • Adenosine Triphosphate / physiology
  • Adenylyl Cyclases / metabolism
  • Allosteric Regulation / physiology
  • Allosteric Site / physiology
  • Animals
  • Catalytic Domain
  • Guanosine Triphosphate / chemistry*
  • Guanosine Triphosphate / metabolism
  • Guanosine Triphosphate / physiology
  • Guanylate Cyclase / antagonists & inhibitors
  • Guanylate Cyclase / chemistry
  • Guanylate Cyclase / metabolism*
  • PC12 Cells
  • Protein Conformation
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism*
  • Rats
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Soluble Guanylyl Cyclase
  • Substrate Specificity


  • Protein Subunits
  • Receptors, Cytoplasmic and Nuclear
  • Guanosine Triphosphate
  • Adenosine Triphosphate
  • Adenylyl Cyclases
  • adenylyl cyclase 1
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase