The molecular mechanism of heme loss from oxidized soluble guanylate cyclase induced by conformational change

Pan, Jie; Zhang, Xiaoxue; Yuan, Hong; Xu, Qiming; Zhang, Huijuan; Zhou, Yajun; Huang, Zhong‐Xian; Tan, Xiangshi

doi:10.1016/j.bbapap.2016.02.012

Cited by 11 publications

(11 citation statements)

References 56 publications

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“…sGC is a key signal-transduction enzyme in the cardiovascular system, and many cardiovascular diseases, such as hypertension, pulmonary hypertension, heart failure, chronic kidney disease, and erectile dysfunction, are associated with dysfunction of the NO/sGC/cGMP-signaling pathway (Kemp-Harper and Feil 2008;Schulz et al 2008;Stasch et al 2011;Klinger and Kadowitz 2017). NO/sGC/cGMP signaling can be impaired in a variety of ways: increased ROS production by NADPH-oxidases and uncoupled NO-synthases, scavenging of NO via the reaction of NO and O 2À to form peroxynitrite, and oxidation of sGC to its NO-insensitive Fe 3+ state and subsequent loss of the NO binding site on the prosthetic heme group (Stasch and Hobbs 2009;Stasch et al 2011;Pan et al 2016). Oxidative stress ultimately results in a reduced bioavailability of NO.…”

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confidence: 99%

Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

132

149

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When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.

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mentioning

confidence: 99%

Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

132

149

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“…For the emission spectrum of FlAsH-EDT 2 has good overlap with α and β absorbance bands of the heme, the FlAsH-EDT 2 is a good probe to study the conformational change induced by NO binding based on the energy transfer between heme and FlAsH-EDT 2 . Previous work has been confirmed that the replacement of the residues (TC) and the FlAsH-EDT 2 would not affect the heme microenviroment and heme binding in the sGC β1 variants [sGC β1(1-385)- 386 TC 391 , sGC β1(1-385)- 243 TC 248 and sGC β1(1-619)- 243 TC 248 insect ] 31 .…”

Section: Resultsmentioning

confidence: 90%

“…11 . The plasmids [sGC β1(1-385)- 386 TC 391 , sGC β1(1-385)- 243 TC 248 and sGC β1(1-619)- 243 TC 248 insect ], which were introduced with a small tetracysteine (TC: CCPGCC), have been constructed as described before 31 . The construction of the plasmid of sGC β1(1-619)- 386 TC 391 insect was the same as the sGC β1(1-619)- 243 TC 248 insect .…”

Section: Methodsmentioning

confidence: 99%

“…The truncated sGC β1(1-385) variants [sGC β1(1-385)- 386 TC 391 and sGC β1(1-385)- 243 TC 248 ] were expressed in E. coli . and purified as described before 31 . The protein concentration was estimated by the Soret peak using the pyridinehemochromagen assay.…”

Section: Methodsmentioning

confidence: 99%

“…For example, to generate sGC α1(1-690)-CFP insect & β1(1-619)-YFP insect , Sf9 cells were co-transfected with sGC α1(1-690)-CFP insect and β1(1-619)-YFP insect viruses. The following purification processes were performed in a glove-box under high pure nitrogen as described before 31 . The recombinant proteins expressed in sf9 cells were obtained without heme group, and the heme reconstitution was performed as previously 5 .…”

Section: Methodsmentioning

confidence: 99%

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Probing the Molecular Mechanism of Human Soluble Guanylate Cyclase Activation by NO in vitro and in vivo

Pan

Yuan

Zhang

et al. 2017

Sci Rep

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Soluble guanylate cyclase (sGC) is a heme-containing metalloprotein in NO-sGC-cGMP signaling. NO binds to the heme of sGC to catalyze the synthesis of the second messenger cGMP, which plays a critical role in several physiological processes. However, the molecular mechanism for sGC to mediate the NO signaling remains unclear. Here fluorophore FlAsH-EDT 2 and fluorescent proteins were employed to study the NO-induced sGC activation. The diatomic gas nitric oxide (NO) is an essential signaling molecule in biology. NO signaling controls several physiological processes including vasodilation, neurotransmission and platelet aggregation [1][2][3][4][5] . Soluble guanylate cyclase (sGC) is a primary receptor of NO 6 . When activated, sGC catalyzes the conversion of substrate GTP to cGMP. cGMP, as a second messenger, triggers the downstream signaling cascades, including ion-gated channels, phosphodiesterases (PDEs) and cGMP-dependent protein kinases. Impairment of the NO-sGC-cGMP signaling has been linked to heart disease, hypertension, stroke, neurodegeneration and erectile dysfunction 7,8 . Therefore, sGC is a therapeutic drug target for treating diseases by improving the NO-sGC-cGMP signaling 9,10 .The isoform α1β1 is ubiquitously distributed in cytosolic fractions of tissues, while α2β1 is mainly in brain. The most commonly studied and predominant sGC isoform is a Heme-containing heterodimeric enzyme composed of α1 and β1 subunits. Each subunit contains four domains: an N-terminal heme-NO/O 2 -binding (H-NOX) domain, a Per/Arnt/Sim (PAS) domain, a helical (CC) domain and a C-terminal catalytic domain 1 . However, the crystal structure of the human sGC holo-enzyme remains unknown, although one human sGC domain structure (catalytic domain) and homologies of other domains have been characterized by crystallography [11][12][13][14][15] . The H-NOX domain of β1 subunit binds heme through His105 and senses NO 11,16 , but the corresponding domain (pseudo-H-NOX) of α1 subunit does not bind heme and its function remains unclear. Both the PAS and CC domains of α1 and β1 subunits are involved in the heterodimer formation, cyclase activation regulation and signaling transmission 13,15,17,18 . The C-terminal catalytic domain constitutes the active site formed at the interface between α1 and β1 subunits 14,19 . Recently, the higher-order domain architecture of the sGC heterodimer have been reconstructed through diverse approaches, including small-angle X-ray scattering (SAXS), Hydrogen/ deuterium exchange mass spectrometry (HDX-MS), and single-particle electron microscopy [20][21][22] . These studies

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Recent Developments for the Treatment of Glaucoma

Adams

Papillon

2020

Topics in Medicinal Chemistry

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The molecular mechanism of heme loss from oxidized soluble guanylate cyclase induced by conformational change

Cited by 11 publications

References 56 publications

Soluble Guanylate Cyclase Stimulators and Activators

Soluble Guanylate Cyclase Stimulators and Activators

Probing the Molecular Mechanism of Human Soluble Guanylate Cyclase Activation by NO in vitro and in vivo

Recent Developments for the Treatment of Glaucoma

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