br Activation of soluble guanylate cyclase The

Activation of soluble guanylate cyclase The molecular steps involved in sGC activation have evolved significantly over the last several years. The key studies are outlined below, but here we provide an overall summary. The activation mechanism of sGC was initially proposed to be relatively simple, where the 5c Fe2+–NO heme complex generated upon NO binding led to fully active enzyme. Detailed kinetic studies on NO binding to the heme and enzyme activity has led to a more complicated mechanism, perhaps in hindsight not unexpected given the pivotal role played by sGC in human physiology. There are two aspects to NO activation of sGC. The first involves the formation the 5c ferrous nitrosyl heme complex, and the most recent evidence is consistent with a distal version of this species (5c Fe2+–NO). sGC treated with 1 equivalent of NO is activated to only ∼15% of maximal activity. Addition of excess NO fully activates sGC and increases the rate at which the 5c Fe2+–NO heme complex forms from the 6c His–Fe2+–NO species. All evidence points towards a second NO binding site for the action of this excess NO as discussed below.
Deactivation of soluble guanylate cyclase
Conclusion The eukaryotic nitric oxide 2-Amino-ATP mg sGC plays a pivotal role in eukaryotic gas signaling and is essential for many physiological processes that affect human health. The biochemical activation and deactivation of sGC has been challenging to understand, partly because of the difficulty in generating large quantities of homogeneous protein, but more so due to the complexity of the activation mechanism of the enzyme. To date, the best supported model of sGC activation and deactivation is outlined in Fig. 8. In this three-activity model, the first molecule of NO binds on the distal side of the heme in the H-NOX domain, resulting in a partially activated enzyme. As the concentration of NO increases to nanomolar levels, NO interacts with the second site on sGC to fully activate the enzyme. As this concentration decreases, NO dissociates from the second site, and returns the enzyme to partial activity.
Conflicts of interest
Acknowledgements B.G.H. and M.A.M. would like to thank the other members of the Marletta lab for fruitful discussions and critical review of this manuscript. B.G.H. was supported in part by a NIH Chemistry-Biology Interface Institutional Training Grant (T32 GM066698).
Introduction Glaucoma is a neurodegenerative disease characterized by progressive degeneration of retinal ganglion cells (RGCs) and subsequent irreversible loss of vision. Over 60.5 million people worldwide are affected by primary open angle glaucoma (POAG) – a figure projected to increase to 79 million in 2020 and 111.8 million by 2040 [1,2]. Glaucoma is often associated with elevated intraocular pressure (IOP), termed ocular hypertension. However, at least a third of patients with glaucomatous vision loss have normotensive IOP (normotensive glaucoma; NTG) [[3], [4], [5], [6]] and disease incidence increases with age, regardless of IOP. This suggests that ocular hypertension is only one mechanism for glaucoma etiology and progression [7]. Despite these indications, ocular hypertension remains the only target of current glaucoma therapeutics. Current strategies to lower IOP include topical application of eye drops and surgical intervention. Unfortunately, successful reduction of IOP via these therapies only serves to slow progression of the disease [8]. Thus, the identification of novel therapeutics that target other disease mechanisms is important for the evolution of glaucoma treatment. Nitric oxide (NO) is an endogenous signaling molecule that is emerging as a novel target for therapeutic lowering of IOP [8]. NO is produced endogenously in various ocular tissues in both the anterior and posterior segments of the eye and is a potent activator of soluble guanylate cyclase (termed GC, formerly known as sGC). Recent evidence implicates the NO-GC-cyclic guanosine monophosphate (NO-GC-cGMP) pathway in both IOP regulation (see section 6.1) and retinal pathophysiology of glaucoma (see section 6). In this review, we will discuss the evidence that the NO-GC-cGMP pathway may contribute to glaucoma pathophysiology as well as its potential as a novel multi-target approach for glaucoma therapeutics.