Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme oxygenase (HO) converts heme to carbon monoxide (CO) and biliverdin IX. CO is a weak activator of soluble guanylyl cyclase (SGC), the enzyme that catalyzes the conversion of GTP to the second messenger cGMP. HO overexpression has recently been shown to inhibit production of cGMP by SGC in vivo. The aim of the present study was to investigate a possible influence of biliverdin IX on SGC activity. Using recombinant alpha(1)/beta(1) isoform of SGC, we show an inhibitory effect of biliverdin IX in the micromolar range both on basal and NO stimulated guanylyl cyclase activity. Bilirubin IX which differs from biliverdin IX in two hydrogen atoms had no effect. Biliverdin IX reduced maximal guanylyl cyclase activity (V(max) values) while it had no effect on the K(M) values indicating unchanged affinity towards the substrate GTP. Concentration response experiments using the NO donor, 2,2-diethyl-1-nitroso-oxyhydrazine (DEA/NO), showed that enzyme activities at maximal DEA/NO concentration were reduced by biliverdin IX. The affinity of the NO-donor, DEA/NO, towards SGC was significantly reduced in the presence of biliverdin IX. Biliverdin IX lowered enzyme activity at maximal activator concentrations of YC-1 and protoporphyrin IX (PPIX) while it had no significant effect on the EC(50) values of these two NO independent activators. The inhibitory effect of biliverdin IX on PPIX activated enzyme activity is not shared by ODQ, which indicates that the inhibitory mechanism of biliverdin IX is different from ODQ.
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PMID:Biliverdin IX is an endogenous inhibitor of soluble guanylyl cyclase. 1210 11

Reactive oxygen species (ROS) increase the contractile response of airway smooth muscle (ASM). Heme oxygenase (HO) catabolizes heme to the powerful antioxidant bilirubin. Because HO is expressed in the airways, we investigated its effects on ASM contractility and ROS production in guinea pig trachea. HO expression was higher in the epithelium than in tracheal smooth muscle. Incubation of tracheal rings (TR) with the HO inhibitor tin protoporphyrin (SnPP IX) or the HO substrate hemin increased and decreased, respectively, ASM contractile response to carbamylcholine. The effect of hemin was reversed by SnPP and mimicked by the antioxidants superoxide dismutase (SOD) and catalase. Hemin significantly reduced the effect of carbamylcholine in rings treated with the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), compared with ODQ-treated rings without hemin incubation, suggesting that the CO-guanosine 3',5'-cyclic monophosphate pathway was not involved in the control of tracheal reactivity. SnPP and hemin increased and decreased ROS production by TR by 18 and 38%, respectively. Bilirubin (100 pM) significantly decreased TR contractility and ROS production. Hemin, bilirubin, and SOD/catalase decreased phosphorylation of the contractile protein myosin light chain, whereas SnPP significantly augmented it. These data suggest that modulation of the redox status by HO and, moreover, by bilirubin modulates ASM contractility by modulating levels of phosphorylated myosin light chain.
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PMID:Heme oxygenase modulates oxidant-signaled airway smooth muscle contractility: role of bilirubin. 1216 79

The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via post-translational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK(Ca) channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK(Ca) channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidant-generating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress.
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PMID:Cerebroprotective functions of HO-2. 1828 71