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Literature summary extracted from

  • Stuehr, D.J.; Misra, S.; Dai, Y.; Ghosh, A.
    Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase (2021), J. Biol. Chem., 296, 100336.
    View publication on PubMed

Activating Compound

EC Number Activating Compound Comment Organism Structure
4.6.1.2 BAY 41-2272 also termed BAY 41, Riociguat or IWP-051, a small molecule sGC agonist that activates only the mature ferrous sGC heterodimer. The ligand binding does not require the help of Hsp90 Mammalia
4.6.1.2 BAY 58-2667 BAY 58, a small molecule sGC agonist that activates only the heme-free or heme-oxidized forms of sGC. The ligand binding does not require the help of Hsp90 Mammalia
4.6.1.2 BAY 60-2270 also termed BAY 60 or Cinaciguat, a small molecule sGC agonist that activates only the heme-free or heme-oxidized forms of sGC. The ligand binding does not require the help of Hsp90 Mammalia
4.6.1.2 Hsp90 promotes heme insertion into apo-sGCbeta. Heme insertion by cytosolic chaperone Hsp90 is part of the maturation process of the sGC heterodimer, detailed overview. Heme insertion triggers Hsp90 dissociation from sGCbeta1, and this allows it to bind an sGCalpha1 subunit to form the mature sGC heterodimer. Hsp90 binding forces aposGCbeta to adopt a more extended conformation compared with when it is on its own in solution or when it is in the heterodimer. Hsp90 stabilizes a structurally open conformation of apo-sGCbeta to enable heme insertion Mammalia
4.6.1.2 NO NO binding to the ferrous heme of sGCbeta breaks the proximal His-heme iron bond, initiating a series of structural changes that project through the heterodimer CC domains to the catalytic domains, resulting in an increased cGMP synthesis activity. If the sGC heme becomes oxidized to the ferric state, it is no longer activated by NO and is also more prone to dissociate from the sGC. Thus, to function in NO-cGMP signaling cascades, sGCbeta must acquire heme, form a heterodimer with sGCalpha, and maintain its heme in the ferrous state. The ligand binding does not require the help of Hsp90 Mammalia

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
4.6.1.2 soluble
-
 Mammalia
-
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
4.6.1.2 GTP Mammalia
-
 3',5'-cyclic GMP + diphosphate
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
4.6.1.2 Mammalia
-
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
4.6.1.2 additional information enzyme sGC maturation involves posttranslational heme insertion into the apo-sGCbeta subunit, followed by binding of sGCbeta to sGCalpha to form the sGC heterodimer. Heme insertion triggers cytosolic chaperone Hsp90 dissociation from sGCbeta1, and this allows it to bind an sGCalpha1 subunit to form the mature sGC heterodimer Mammalia

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
4.6.1.2 GTP
-
 Mammalia 3',5'-cyclic GMP + diphosphate
-
 ?

Subunits

EC Number Subunits Comment Organism
4.6.1.2 heterodimer enzyme sGC maturation involves posttranslational heme insertion into the apo-sGCbeta subunit, followed by binding of sGCbeta to sGCalpha to form the sGC heterodimer. The heterodimer interface primarily consists of surface contacts formed between the respective Per-Arnt-Sim (PAS) domains, the coiled-coil (CC) domains, and catalytic domains of the respective subunits. In addition, cross-subunit interactions between different domains can form that likely further stabilize and modify the heterodimer structure. Only the ferrous heme-containing sGCalphabeta heterodimer can respond to NO to catalyze cGMP formation. GAPDH delivers heme, which is inserted into the aposGCbeta1 in an ATP-driven, Hsp90-dependent process. Heme insertion triggers Hsp90 dissociation from sGCbeta1, and this allows it to bind an sGCalpha1 subunit to form the mature sGC heterodimer. Maturation process of the sGC heterodimer, detailed overview. Apo-sGCbeta interacts with Hsp90 and sGCalpha on a mutually exclusive basis. This allows cells to maximize formation of heme-containing functional sGC heterodimers while minimizing formation of heme-free nonfunctional sGC heterodimers Mammalia

Synonyms

EC Number Synonyms Comment Organism
4.6.1.2 sGC
-
 Mammalia
4.6.1.2 soluble guanylyl cyclase
-
 Mammalia

Cofactor

EC Number Cofactor Comment Organism Structure
4.6.1.2 heme NO binding to the ferrous heme of sGCbeta breaks the proximal His-heme iron bond, initiating a series of structural changes that project through the heterodimer CC domains to the catalytic domains, resulting in an increased cGMP synthesis activity. If the sGC heme becomes oxidized to the ferric state, it is no longer activated by NO and is also more prone to dissociate from the sGC. Thus, to function in NO-cGMP signaling cascades, sGCbeta must acquire heme, form a heterodimer with sGCalpha, and maintain its heme in the ferrous state. Heme insertion by cytosolic chaperone Hsp90 as part of the maturation process of the sGC heterodimer, detailed overview. Heme insertion triggers Hsp90 dissociation from sGCbeta1, and this allows it to bind an sGCalpha1 subunit to form the mature sGC heterodimer Mammalia

General Information

EC Number General Information Comment Organism
4.6.1.2 malfunction heme oxidation may be an important mechanism of sGC inactivation. Heme loss is also widely invoked to explain the accumulation of inactive sGC. Consecutive Hsp90 association and dissociation events prevent the formation of heme-free nonfunctional sGC heterodimers, while simultaneously ensuring that heme-replete and functional sGC heterodimers form in cells. Enzyme sGC inactivation and recovery mechanisms, overview Mammalia
4.6.1.2 additional information only the ferrous heme-containing sGCalphabeta heterodimer can respond to NO to catalyze cGMP formation Mammalia
4.6.1.2 physiological function soluble guanylate cyclase (sGC) is a heme-containing heterodimeric enzyme that generates many molecules of cGMP in response to its ligand nitric oxide (NO). sGC thereby acts as an amplifier in NO-driven biological signaling cascades. sGC helps regulate the cardiovascular, neuronal, and gastrointestinal systems through its cGMP production. Enzyme regulation mechanism, overview. sGC activator compounds like BAY 60 can bind within immature apo-sGCbeta1 and drive maturation to the sGC heterodimer independent of Hsp90, GAPDH, or heme. Apo-sGCbeta interacts with Hsp90 and sGCalpha on a mutually exclusive basis. This allows cells to maximize formation of heme-containing functional sGC heterodimers while minimizing formation of heme-free nonfunctional sGC heterodimers Mammalia