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The Marletta Laboratory

Soluble Guanylate Cyclase

People working on this project:
Basak Surmeli, PhD
Eric Underbakke, PhD

The diatomic gas nitric oxide (NO) serves as a unique and important signaling molecule in mammalian physiology. NO is an effective signaling agent for transient paracrine and autocrine signaling because it freely diffuses through membranes and exhibits a short biological half-life. NO signaling controls diverse circulatory and neural processes, including vasodilation, angiogenesis, neurotransmission, myocardial function, and platelet aggregation. Accordingly, disruptions in NO signaling have been linked to heart disease, stroke, and hypertension, and neurodegeneration.

Soluble guanylate cyclase (sGC) is the primary cellular NO receptor. sGC converts GTP to the secondary messenger cGMP. NO produced by the enzyme nitric oxide synthase binds to sGC through a ferrous heme cofactor. Formation of the NO-heme complex initiates a largely uncharacterized conformational change that stimulates cyclase activity several hundred-fold. The burst of cGMP regulates downstream effectors such as phosphodiesterases, ion-gated channels, and cGMP-dependent protein kinases.

NO biologu - Underbakke 

sGC is a heterodimeric hemoprotein composed of two homologous subunits, alpha and beta. NO-induced activation presumably occurs via conformational changes communicated from the sGC heme to the catalytic domains. However, this regulatory mechanism remains poorly understood. We are interested in addressing the following questions regarding the regulation and function of sGC:

  1. How does the binding of NO affect the heme and the local protein environment?
  2. How is NO-binding communicated to the catalytic domains?
  3. How does non-heme NO interaction modulate sGC activity?
  4. How do small molecule effectors and therapeutics rescue sGC activity?
  5. How do nucleotides regulate sGC activity?

Publications (since 2002)

Fernhoff NB, Derbyshire ER, Underbakke ES, Marletta MA. Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide. J Biol Chem. 2012, 287, 43053-62.

Gunn A, Derbyshire ER, Marletta MA, Britt RD. Conformationally distinct five-coordinate heme-NO complexes of soluble guanylate cyclase elucidated by multifrequency electron paramagnetic resonance (EPR). Biochemsitry. 2012, 51, 8384-90.

Surmeli NB, Marletta MA. Insight into the rescue of soluble guanylate cyclase by the activator cinaciguat. Chembiochem 2012, 13, 977-981.

Derbyshire ER, Marletta MA. Structure and Regulation of soluble guanylate cyclase. Annu Rev Biochem. 2012, 81, 533-59.

Derbyshire ER, Winter MB, Ibrahim M, Deng S, Spiro TG, Marletta MA. Probing domain interactions in soluble guanylate cyclase. Biochemistry 2011, 50, 4281-90.

Ibrahim M, Derbyshire ER, Soldatova AV, Marletta MA, Spiro TG. Soluble guanylate cyclase is activated differently by excess NO and by YC-1: resonance raman spectroscopic evidence. Biochemistry 2010, 49, 3815-23.

Derbyshire ER, Deng S, Marletta MA. Incorporation of tyrosine and glutamine residues into the soluble guanylate cyclase heme distal pocket alters NO and O2 binding. J Biol Chem. 2010, 285, 17471-8.

Ibrahim M, Derbyshire ER, Marletta MA, Spiro TG. Probing soluble guanylate cyclase activation by CO and YC-1 using resonance raman spectroscopy. Biochemistry. 2010, 49, 3815-23.

Fernhoff NB, Derbyshire ER, Marletta MA. A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase. Proc Natl Acad Sci USA. 2009, 106, 21602-7.

Derbyshire ER, Fernhoff NB, Deng S, Marletta, MA. Nucleotide regulation of soluble guanylate cyclase substrate specificity. Biochemistry 2009, 48, 7519-24.

Zimmer M, Gray JM, Pokala N, Chang AJ, Karow DS, Marletta MA, Hudson ML, Morton DB, Chronis N, Bargmann Cl. Neurons detect increases and decreases in oxygen levels using distinct guanylate cyclases. Neuron 2009, 61:865-79.

Derbyshire ER, Marletta MA. Biochemistry of soluble guanylate cyclase. Handb. Exp. Pharmacol. 2009, 191, 17-31. Rev.

Derbyshire ER, Gunn A, Ibrahim M, Spiro TG, Britt RD, Marletta MA. Characterization of two different five-coordinate soluble guanylate cyclase ferrous-nitrosyl complexes. Biochemistry 2008, 47, 3892-9.

Derbyshire ER, Marletta MA. Butyl isocyanide as a probe of the activation mechanism of soluble guanylate cyclase: investigating the role of non-heme nitric oxide. J. Biol. Chem. 2007, 282, 35741-8.

Huang SH, Rio DC, Marletta MA. Ligand binding and inhibition of an oxygen-sensitive soluble guanylate cyclase, Gyc-88E, from Drosophila. Biochemistry 2007, 46, 15115-22.

Winger JA, Derbyshire ER, Marletta MA. Dissociation of nitric oxide from soluble guanylate cyclase and heme-nitric oxide/oxygen binding domain constructs. J. Biol. Chem. 2007, 282, 897-907.

Hering KW, Artz JD, Pearson WH, Marletta MA. The design and synthesis of YC-1 analogues as probes for soluble guanylate cyclase. Bioorg Med. Chem. Lett. 2006, 16, 618-21.

Karow DS, Pan D, Davis JH, Behrends S, Mathies RA, Marletta MA. Characterization of functional heme domains from soluble guanylate cyclase. Biochemistry. 2005, 44, 16266-74.

Derbyshire ER, Tran R, Mathies RA, Marletta MA. Characterization of nitrosoalkane binding and activation of soluble guanylate cyclase. Biochemistry. 2005, 44, 16257-65.

Cary SP, Winger JA, Marletta MA. Tonic and acute nitric oxide signaling through soluble guanylate cyclase is mediated by nonheme nitric oxide, ATP, and GTP. Proc. Natl. Acad. Sci. U S A. 2005, 102,13064-9.

Winger JA, Marletta MA. Expression and characterization of the catalytic domains of soluble guanylate cyclase: interaction with the heme domain. Biochemistry. 2005, 44, 4083-90.

Gray JM, Karow DS, Lu H, Chang AJ, Chang JS, Ellis RE, Marletta MA; Bargmann, CI. Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase homologue. Nature. 2004, 430, 317-22.

Ballou DP, Zhao Y, Brandish PE, Marletta MA. Revisiting the kinetics of nitric oxide (NO) binding to soluble guanylate cyclase: the simple NO-binding model is incorrect. Proc. Natl. Acad. Sci. USA 2002, 99, 12097-101.

Artz JD, Schmidt B, McCracken JL, Marletta MA. Effects of nitroglycerin on soluble guanylate cyclase: implications for nitrate tolerance. J. Biol. Chem. 2002, 277, 18253-6.