scholarly journals Oxygen Binding and Redox Properties of the Heme in Soluble Guanylate Cyclase

2011 ◽  
Vol 286 (18) ◽  
pp. 15678-15687 ◽  
Author(s):  
Ryu Makino ◽  
Sam-yon Park ◽  
Eiji Obayashi ◽  
Tetsutaro Iizuka ◽  
Hiroshi Hori ◽  
...  
Keyword(s):  
High Spin ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Heme Iron ◽  
Redox Properties ◽  
Oxygen Binding ◽  
X Ray ◽  
Midpoint Potential ◽  
Ferrous Heme ◽  
X Ray Absorption

Soluble guanylate cyclase is an NO-sensing hemoprotein that serves as a NO receptor in NO-mediated signaling pathways. It has been believed that this enzyme displays no measurable affinity for O2, thereby enabling the selective NO sensing in aerobic environments. Despite the physiological significance, the reactivity of the enzyme-heme for O2 has not been examined in detail. In this paper we demonstrated that the high spin heme of the ferrous enzyme converted to a low spin oxyheme (Fe2+-O2) when frozen at 77 K in the presence of O2. The ligation of O2 was confirmed by EPR analyses using cobalt-substituted enzyme. The oxy form was produced also under solution conditions at −7 °C, with the extremely low affinity for O2. The low O2 affinity was not caused by a distal steric protein effect and by rupture of the Fe2+-proximal His bond as revealed by extended x-ray absorption fine structure. The midpoint potential of the enzyme-heme was +187 mV, which is the most positive among high spin protoheme-hemoproteins. This observation implies that the electron density of the ferrous heme iron is relatively low by comparison to those of other hemoproteins, presumably due to the weak Fe2+-proximal His bond. Based on our results, we propose that the weak Fe2+-proximal His bond is a key determinant for the low O2 affinity of the heme moiety of soluble guanylate cyclase.

X-ray absorption spectral study of ferric high-spin hemoproteins: XANES evidences for coordination structure of the heme iron

1990 ◽  
Vol 112 (8) ◽  
pp. 2921-2924 ◽  
Author(s):  
Yoshitsugu Shiro ◽  
Fumitoshi Sato ◽  
Tomohiko Suzuki ◽  
Tetsutaro Iizuka ◽  
Tadashi Matsushita ◽  
...  
Keyword(s):  
High Spin ◽  
Spectral Study ◽  
Heme Iron ◽  
Coordination Structure ◽  
X Ray ◽  
X Ray Absorption

scholarly journals L-edge X-ray Absorption Spectroscopy of Non-Heme Iron Sites:  Experimental Determination of Differential Orbital Covalency

2003 ◽  
Vol 125 (42) ◽  
pp. 12894-12906 ◽  
Author(s):  
Erik C. Wasinger ◽  
Frank M. F. de Groot ◽  
Britt Hedman ◽  
Keith O. Hodgson ◽  
Edward I. Solomon
Keyword(s):  
Experimental Determination ◽  
Absorption Spectroscopy ◽  
Heme Iron ◽  
X Ray ◽  
Non Heme Iron ◽  
X Ray Absorption

scholarly journals Fingerprinting Electronic Structure of Heme Iron by Ab Initio Modeling of Metal L-Edge X-ray Absorption Spectra

2018 ◽  
Vol 15 (1) ◽  
pp. 477-489 ◽  
Author(s):  
Meiyuan Guo ◽  
Erik Källman ◽  
Rahul V. Pinjari ◽  
Rafael C. Couto ◽  
Lasse Kragh Sørensen ◽  
...  
Keyword(s):  
Electronic Structure ◽  
Ab Initio ◽  
Absorption Spectra ◽  
Heme Iron ◽  
X Ray ◽  
Ab Initio Modeling ◽  
X Ray Absorption

Abstract 107: Cytochrome B5 Reductase 3 Sensitizes Soluble Guanylate Cyclase to Nitric Oxide in Vascular Smooth Muscle

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Adam C Straub ◽  
Anh T Nguyen ◽  
Mizanur Rahaman ◽  
Stephanie M Mutchler ◽  
Megan Miller ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Cytochrome B5 ◽  
Heme Iron ◽  
Cytochrome B5 Reductase ◽  
Arterial Blood

The inability nitric oxide (NO) to stimulate soluble guanylate cyclase (sGC) has been linked to numerous cardiovascular diseases (CVD) including hypertension. While several studies have defined the importance of sGC expression in the cardiovascular system, the basic mechanisms that regulate sGC activity remain incompletely understood. Here, we report for the first time that sGC heme iron redox state, which is essential for NO-induced sGC activation, is regulated by cytochrome B5 reductase 3 (CyB5R3). Genetic knockdown and pharmacological inhibition of CyB5R3 in primary rat vascular smooth muscle cells resulted in a 60% loss in cGMP production. Conversely, the sGC activator Bay 58-2667, which activates oxidized or heme free sGC, reversed these effects. Consistent with our cell culture work, purified protein studies demonstrate that CyB5R3 can directly reduce oxidized sGC heme iron and sensitize sGC to NO. To test the functional importance of Cyb5R3 activity, we cultured mouse thoracodorsal arteries with a pharmacological inhibitor of Cyb5R3 (ZINC 747) and performed vascular reactivity studies using pressure myography. Arteries treated with ZINC 747 showed decreased responsiveness the NO donor DETA-NONOate but increase sensitivity to Bay 58-2667. We then treated mice with 10mg/kg/day of ZINC 747 using osmotic mini pumps, which caused an increase in mean arterial blood pressure (107.5±3.4 vs 131±13.16) measured via radio telemetry. Lastly, translational studies reveal that the CyB5R3 T116S polymorphism with allele frequency 0.23 only in African Americans is unable to reduce sGC and correlates with increased blood pressure. Considering the defining role of sGC in NO signaling and the fact that the oxidation state of sGC may predict responses to NO therapies and new classes of sGC activator medications, we anticipate that these studies may significantly impact our understanding of biology, precision therapeutics (right drug for the right patient) and pharmacogenetics (T117S SNP based drug selection).

The K edges of the heme iron in the x-ray absorption spectra of native and carboxymethylated cytochrome c

1981 ◽  
Vol 15 (2) ◽  
pp. 179-184 ◽  
Author(s):  
Alfredo Colosimo ◽  
Maurizio Brunori ◽  
Francesco Andreasi ◽  
Settimio Mobilio
Keyword(s):  
Cytochrome C ◽  
Absorption Spectra ◽  
Heme Iron ◽  
X Ray ◽  
X Ray Absorption

scholarly journals Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Benjamin G Horst ◽  
Adam L Yokom ◽  
Daniel J Rosenberg ◽  
Kyle L Morris ◽  
Michal Hammel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Electron Microscopy ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Coiled Coil ◽  
X Ray ◽  
Nitric Oxide Signaling ◽  
Catalytic Domains ◽  
X Ray Scattering ◽  
Cryo Electron Microscopy

Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in mammalian nitric oxide signaling. We determined structures of full-length Manduca sexta sGC in both inactive and active states using cryo-electron microscopy. NO and the sGC-specific stimulator YC-1 induce a 71° rotation of the heme-binding β H-NOX and PAS domains. Repositioning of the β H-NOX domain leads to a straightening of the coiled-coil domains, which, in turn, use the motion to move the catalytic domains into an active conformation. YC-1 binds directly between the β H-NOX domain and the two CC domains. The structural elongation of the particle observed in cryo-EM was corroborated in solution using small angle X-ray scattering (SAXS). These structures delineate the endpoints of the allosteric transition responsible for the major cyclic GMP-dependent physiological effects of NO.

Comparison of the crystal structures and thermochemistry of a novel soluble guanylate cyclase stimulator riociguat and its solvates

2017 ◽  
Vol 73 (5) ◽  
pp. 891-898 ◽  
Author(s):  
Xinbo Zhou ◽  
Xiurong Hu ◽  
Jianming Gu ◽  
Jianrong Zhu
Keyword(s):  
Crystal Structure ◽  
Thermogravimetric Analysis ◽  
Crystal Structures ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Crystal Packing ◽  
X Ray Diffraction ◽  
Scanning Calorimetry ◽  
X Ray ◽  
Soluble Guanylate Cyclase Stimulator

Riociguat (Rio) is the first oral soluble guanylate cyclase stimulator to be approved for pulmonary arterial hypertension. In this study, form (II) of riociguat and three solvates with acetonitrile [form (III)],N,N-dimethylformamide [form (IV)] and ethyl acetate [form (V)] were crystallized. They were identified and characterized by differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction, and their crystal structures were determined by single-crystal X-ray diffraction. No crystal structure has previously been reported for the known form (II) of riociguat. Crystal structure determination of Rio and its new solvates revealed that the dimericR22(14) motif is common in both structures. The crystal packing of solvates adopts channel-like patterns, whereas form (II) of riociguat adopts sheet-like patterns. Strong π–π interactions exist in the above four forms. The conformation of the riociguat in one molecule of 0.5-DMF solvate was found to be significantly different from the conformations found in the other solvates. Desolvation of the three solvates was studied by thermogravimetric analysis and X-ray diffraction, and was shown to transform them into form (I) of riociguat.

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