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    • br Conclusion and perspectives Guanylyl cyclases are

    2021-12-15


    Conclusion and perspectives Guanylyl cyclases are ubiquitous enzymes that regulate critical functions in bacteria to humans. In mammals there are seven mGCs and activators of all members have now been identified. Mutations in the genes that encode mGCs or pathologic activation of these enzymes or their activators are associated with diseases of the cardiovascular, skeletal, intestinal or visual systems. Understanding the regulation of mGCs is important because several family members are drug targets. For example, GC-A is the target of two drugs (Carperitide and Nesiritide) approved for the treatment of congestive heart failure as well as a new chimeric natriuretic peptide called CD-NP that had favorable therapeutic effects in a recent clinical study [124], [125]. GC-B is the target for drugs in development for the treatment of skeletal diseases and glaucoma, and GC-C is the target of linaclotide, a drug that is currently in phase III clinical trials for the treatment of chronic constipation and irritable bowel syndrome. A novel, yet untested, approach to activating these receptors is to target the allosteric ATP binding site with small, cell-permeable ATP analogs. Alternatively, blocking GC-C activity with competitive or mixed inhibitors as was recently demonstrated for GC-A and GC-B may lead to a viable drug for the treatment or prevention of heat-stable enterotoxin infection [126].
    Acknowledgments
    Nitric oxide (NO) and NO synthases
    Oxidative/nitrative stress in obstructive airway diseases Reactive oxygen species (ROS) are unstable molecules with an unpaired electron that can be generated endogenously by mitochondrial electron transport during respiration or during activation of inflammatory cells, and exogenously by cigarette smoke or air pollutants. These small reactive signaling molecules can oxidize proteins, lipids or DNA, leading to cell dysfunction and cell death. Also reactive nitrogen species (RNS), such as the highly pro-inflammatory molecule peroxynitrite, can cause tissue injury in various organs. Normally, they are counterbalanced by antioxidants and rapidly removed from the body. An imbalance between ROS/RNS and antioxidants leads to oxidative/nitrative stress [33], [34], [35]. Both oxidative and nitrative stress have been linked with inflammatory, obstructive airway diseases, including gallic acid and COPD [36], [37]. Activated inflammatory cells such as macrophages and neutrophils produce increased levels of NO and ROS (superoxide () and hydrogen radical ()) (Fig. 1). NO rapidly reacts with to form the pro-inflammatory molecule peroxynitrite. Peroxynitrite alters the function of proteins by nitration of tyrosine residues. Currently, 3-nitrotyrosine is measured as a footprint of peroxynitrite release. Using a new noninvasive technique, Osoata et al. were able to measure peroxynitrite in exhaled breath condensate [38]. The levels of peroxynitrite were significantly higher in patients with COPD compared with smokers and healthy controls [38].
    Soluble guanylyl cyclase Both transmembrane and soluble forms of guanylyl cyclases exist. The transmembrane, particulate GC (pGC) acts as a receptor for hormones such as atrial, brain (B-type) and C-type natriuretic peptides. For further information on this transmembrane form of GC, we refer the reader to an excellent review [39]. Soluble GC (sGC) is an intracellular receptor for gaseous ligands (NO and to a minor extent CO) and is able to associate with the plasma membrane through protein–protein interactions in a Ca2+-dependent manner [40]. sGC is a heterodimer, consisting of an α-subunit and a β-subunit. There are 2 forms of the α-subunit (α1 and α2) and of the β-subunit (β1 and β2), but only α1β1 and α2β1 are active. α1β1 and α2β1 are equally present in the brain, while α1β1 is the most prevalent form in other tissues such as the lung [41]. Both forms have a similar catalytic rate and sensitivity towards NO. The C-terminal catalytic domains of both isoforms are required to form a catalytic active centre. The β-subunit has an amino-terminal heme-binding domain. A heme moiety that interacts with the heme-binding domain, is essential for the sensing of NO, increasing the cGMP production from GTP [42]. The heme moiety is a large heterocyclic organic ring with a central metal ion (Fe). sGC is activated by nanomolar concentrations of NO in the presence of the reduced Fe2+ (ferrous) heme moiety, while oxidized, Fe3+ (ferric) heme is insensitive to NO (Fig. 2). Moreover, the oxidized heme rapidly released from the protein, resulting in the exposure of an ubiquitination site on the protein moiety, which leads to ubiquitination and proteolytic degradation of the enzyme. Similar to oxidized heme, heme-deficient sGC is unresponsive to NO. Oxidation is induced by exogenous molecules, such as ODQ (1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one), and by endogenous molecules, including reactive oxygen species (ROS) and reactive nitrogen species (RNS) [40].