ArticleProceedings of the National Academy of Sciences of the United States of America2003
A constitutively activated mutant of human soluble guanylyl cyclase (sGC): implication for the mechanism of sGC activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 62 citations in OpenAlex.
- Role of the Coiled-Coil Domain in Allosteric Activity Regulation in Soluble Guanylate Cyclase.Biochemistry · 2023Article
- Article
- Cellular Factors That Shape the Activity or Function of Nitric Oxide-Stimulated Soluble Guanylyl Cyclase.Cells · 2023Review
- Inactivation of soluble guanylyl cyclase in living cells proceeds without loss of haem and involves heterodimer dissociation as a common step.British journal of pharmacology · 2022Article
- Higher susceptibility to heme oxidation and lower protein stability of the rare αBiochemical pharmacology · 2021Article
- Homogeneous single-label cGMP detection platform for the functional study of nitric oxide-sensitive (soluble) guanylyl cyclases and cGMP-specific phosphodiesterases.Scientific reports · 2020Article
- Article
- Heat shock protein 90 regulates soluble guanylyl cyclase maturation by a dual mechanism.The Journal of biological chemistry · 2019Article
- New conception for the development of hypertension in preeclampsia.Oncotarget · 2016Article
- Constitutive cyclic GMP accumulation in Arabidopsis thaliana compromises systemic acquired resistance induced by an avirulent pathogen by modulating local signals.Scientific reports · 2016Article
- Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension.Clinical genetics · 2016Article
- Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice.Nature communications · 2015Article
- The fibrate gemfibrozil is a NO- and haem-independent activator of soluble guanylyl cyclase: in vitro studies.British journal of pharmacology · 2015Article
- A high-throughput fluorimetric assay for 2-hydroxyglutarate identifies Zaprinast as a glutaminase inhibitor.Cancer discovery · 2014Article
- Structures of soluble guanylate cyclase: implications for regulatory mechanisms and drug development.Biochemical Society transactions · 2014Review
- YC-1 binding to the β subunit of soluble guanylyl cyclase overcomes allosteric inhibition by the α subunit.Biochemistry · 2014Article
- Article
- Role of nitric oxide and cGMP in the modulation of vascular contraction induced by angiotensin II and Bay K8644 during ischemia/reperfusion.Experimental and therapeutic medicine · 2013Article
- Article
- The G-protein regulator LGN modulates the activity of the NO receptor soluble guanylate cyclase.The Biochemical journal · 2012Article
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4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Heterodimeric alphabeta soluble guanylyl cyclase (sGC) is a recognized receptor for nitric oxide (NO) and mediates many of its physiological functions. Although it has been clear that the heme moiety coordinated by His-105 of the beta subunit is crucial for mediating the activation of the enzyme by NO, it is not understood whether the heme moiety plays any role in the function of the enzyme in the absence of NO. Here we analyze the effects of biochemical and genetic removal of heme and its reconstitution on the activity of the enzyme. Detergent-induced loss of heme from the wild-type alphabeta enzyme resulted in several-fold activation of the enzyme. This activation was inhibited after hemin reconstitution. A heme-deficient mutant alphabetaCys-105 with Cys substituted for His-105 was constitutively active with specific activity approaching the activity of the wild-type enzyme activated by NO. However, reconstitution of mutant enzyme with heme and/or DTT treatment significantly inhibited the enzyme. Mutant enzyme reconstituted with ferrous heme was activated by NO and CO alone and showed additive effects between gaseous effectors and the allosteric activator 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine. We propose that the heme moiety through its coordination with His-105 of the beta subunit acts as an endogenous inhibitor of sGC. Disruption of the heme-coordinating bond induced by binding of NO releases the restrictions imposed by this bond and allows the formation of an optimally organized catalytic center in the heterodimer.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.