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Background and Signicance No Chemistry Chemical Tools and Techniques Future Directions for the Field of No Signaling
University of
Nitric oxide (NO) is an essential signaling molecule for many eukaryotic organisms. NO is produced in vivo by the enzyme nitric oxide synthase (NOS) from the amino acid L-arginine. The apolar gas readily diffuses across cell membranes, where it binds to the heme of soluble guanylate cyclase (sGC), the principle NO receptor. Once activated, sGC converts GTP to cGMP at a rate that is several-hundred fold above the basal level. This NO/cGMP signaling cascade modulates several physiologic processes including vasodilation, platelet aggregation, and neurotransmission. Although the cGMP-dependent affects of NO remain active areas of research, additional cGMP-independent responses to NO also are being investigated. Endogenous levels of NO can modulate protein function by S-nitrosation, a covalent modication that has been implicated in the transcriptional regulation of genes involved in the immune response and in apoptosis.
In biologic systems, nitric oxide (NO) functions as both a critical cytotoxic agent and an essential signaling molecule. The toxicity of the diatomic gas has long been accepted; however, nitric oxide was not known to be a physiologically relevant signaling molecule until it was identied as the endothelium-derived relaxing factor (EDRF) (reviewed in Reference 1). Since this discovery, the enzymatic synthesis of NO and the signaling pathways that it regulates have been the focus of many studies. In higher eukaryotes, nitric oxide synthase (NOS) produces NO from L-arginine (reviewed in References 24). Despite several years of research, the NOS catalytic mechanism remains a topic of investigation, but commonly it is accepted that NO is essential for several physiologic processes. Many signaling responses that NO modulates are mediated by the NO-induced activation of the heme protein soluble guanylate cyclase (sGC). NO binds to sGC at a diffusion-controlled rate and leads to a severalhundred-fold increase in the synthesis of the second messenger cGMP from GTP (5, 6). Other diatomic gases either do not bind (dioxygen) or do not activate sGC signicantly (carbon monoxide). This characteristic provides selectivity and efciency for NO even in an aerobic environment, which is critical because of the high reactivity of NO. The NOS/sGC pathway is important for maintaining homeostasis, and many diseases have been linked to the dysfunction in NO signaling (reviewed in Reference 7). Studies on cGMP-dependent NO responses continue to expand, and other roles for the gas are emerging in both prokaryotic and eukaryotic organisms. In higher eukaryotes, protein S -nitrosation, an oxidative modication of cysteine residues, is
implicated in an increasing number of cGMP-independent signaling systems (reviewed in Reference 8), whereas in bacteria, a class of potential heme-based NO sensors recently has been identied and proposed to participate in two-component signal transduction pathways (9).
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Generator cell
Target cell
L-Arg + O2
a1 b1 NO Mg2+ sGC
GTP
NOS
cGMP + PPi
SNO
Figure 1 Nitric oxide signal transduction pathway. NO synthesized by NOS diffuses across cell membranes to a target cell. NO activates sGC, which leads to an increase in cGMP synthesis. The oxidation products of NO also can react with protein thiols, which leads to protein S-nitrosation.
(13, 14), which are present at 0.2 and 1.7 mM, respectively, in vivo (15). The efcient binding of NO by sGC allows for the rapid production of cGMP, which then binds to phosphodiesterases (PDE), ion-gated channels, and cGMP-dependent protein kinases (cGK) to regulate several physiologic functions including vasodilation, platelet aggregation, and neurotransmission (1618). The amplitude and duration of these cGMP effects are regulated additionally by the activity of PDE, the enzyme that hydrolyzes cGMP (reviewed in Reference 19). The importance of this signaling pathway has been demonstrated in mouse models in which the triple NOS knockouts exhibit characteristics consistent with nephrogenic diabetes insipidus (20). Knockouts of the sGC 1 subunit exhibit elevated blood pressure, reduced heart rate, and dysfunction in gastrointestinal contractility (21), and studies on mice decient of the sGC 1 subunit indicate that the protein is essential for NO-mediated pulmonary vasodilation (22). Additionally, several diseases have been linked to defects in the NO signaling pathway. Independent of cGMP production by sGC, NO also can affect biologic processes by covalently modifying and/or oxidizing proteins. Here, we summarize the best-characterized physiologic responses to NO.
cGMP-dependent signaling
NO is important for the function of the cardiovascular system and is critical for blood pressure regulation. In vascular smooth muscle cells, cGMP can bind to and activate cGK, specically the type I and I isoforms. These isoforms are splice variants of the same gene that has different sensitivities to cGMP. During activation, cGK phosphorylates the large conductance Ca2+ -activated K+ channel (23) and IRAG (IP3 receptor associated cGMP kinase substrate) (24), which are involved in the regulation of extracellular Ca2+ entry and intracellular Ca2+ release, respectively. The release of Ca2+ into the cytosol leads to smooth muscle contraction by the activation of a myosin 2
light chain kinase (MLCK) that phosphorylates the myosin light chain (MLC) (reviewed in Reference 25). Smooth muscle contraction also is regulated by myosin light chain phosphatase (MLCP), the protein that dephosphorylates MLC. cGKI phosphorylates and inhibits Rho A, a GTPase that activates Rho kinase. Rho kinase inhibits the activity of MLCP, and therefore the cGMP-dependent inhibition of Rho A contributes to smooth muscle relaxation (26). Vasodilation also is modulated by PDE5, a major cGMP-hydrolyzing PDE. This protein is important for inducing relaxation under low Ca2+ conditions and has become an important drug target because the inhibition of PDE5 leads to increased levels of cGMP after NO-induced sGC stimulation (19). sGC activation also is important for the immune response. Human platelets generate cGMP after NO activation of sGC, which leads to the inhibition of platelet activation or aggregation. This effect is mediated primarily by cGMP activation of cGKI. Many targets for activated cGKI have been proposed, including the vasodilator stimulated phosphoprotein (VASP). Phosphorylation of VASP correlates with the binding of brinogen to glycoprotein IIb/IIIa, expression of P-selectin, and platelet adhesion (reviewed in References 16 and 27). Small molecule sGC activators (2830) have been shown to inhibit platelets and are potential antithrombic agents that could be used to treat cardiovascular diseases.
cGMP-independent signaling
The oxidative addition of NO to a thiol, termed S -nitrosation, is a posttranslational modication that can modulate protein function. With high concentrations of NO, this modication can alter protein function indiscriminately; however, only a limited number of proteins are S -nitrosated in vivo (8). This selectivity of nitrosothiol formation suggests that a mechanism of regulation of SNO formation and/or decay exists; however, the details of this regulation are unknown.
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The S -nitrosation of proteins has been implicated in regulating apoptosis, protein expression, and tissue oxygenation (3133). For example, low levels of NO can inhibit apoptosis via the S -nitrosation of caspase proteases, which contain a cysteine residue that is essential for catalytic activity (33). Furthermore, this process may be regulated by the protein thioredoxin, the primary intracellular oxidoreductase that may function as a nitrosotransferase (34). S -nitrosation also inhibits the DNA binding activity of NF-kB transcription factors, which effects protein expression (31), and S -nitrosohemoglobin has been implicated in the regulation of blood ow and tissue oxygenation (reviewed in References 32 and 35). Interestingly, both NOS and sGC have been shown to be S -nitrosated by low levels of NO (3638). In NOS, this nitrosation occurs at zinc tetrathiolate cysteines that are critical for maintaining a functional dimer. Modication of these cysteines leads to the formation of inactive monomers, which could be a means of regulating NO production in vivo (37). S -nitrosation of sGC results in the inhibition of NO-stimulated activity (38). This mechanism of desensitization may account for the clinical condition known as NO tolerance, which is an ongoing problem in the treatment of heart disease.
No Chemistry
NOS
Mammalian NOS is a P-450-like enzyme that catalyzes the oxidation of L-arginine to L-citrulline and NO. This process is a two-step reaction that leads to a ve-electron oxidation of L-arginine. The enzyme requires NADPH and O2 as substrates for both reaction steps, and iron protoporphyrin IX (heme), FMN, FAD, and tetrahydrobiopterin (H4 B) as protein-bound cofactors. NOS is active as a homodimer and contains an N-terminal oxygenase (or heme) domain, a C-terminal avoprotein reductase domain, and a central calmodulin binding region
(4) (Fig. 2a). The heme domain of NOS (NOSheme ) can be isolated, and it binds heme, H4 B, and L-arginine. This domain is functional if provided with reducing equivalents such as sodium dithionite (39, 40). The crystal structures of eNOSheme (41) and iNOSheme (42) show how substrate and cofactors bind within the active site and identify residues that are important for H4 B binding and dimerization, including a zinc tetrathiolate at the bottom of the dimer interface that stabilizes subunit binding and is involved in maintaining the integrity of the H4 B binding site (43). The reductase domain binds to NADPH, FMN, and FAD and provides electrons to the heme active site for catalysis, a process that is controlled by Ca2+ /calmodulin binding. In the rst step, L-arginine is hydroxylated to form N -hydroxy-L-arginine (NHA) (Fig. 2b). This reaction mechanism is analogous to those catalyzed by cyctochrome P-450s, which involves a proposed high-valent oxo-iron intermediate that could transfer an activated oxygen species to a substrate. In the second reaction step, the 3-electron oxidation of NHA produces L-citrulline and NO. It has been proposed that this step involves the attack of a ferric peroxide intermediate on the guanido carbon; however, experimental evidence is not sufcient to distinguish between this and other proposed mechanisms (reviewed in Reference 2). The most controversial questions about the NOS mechanism concern the source of the electrons in each reaction step and cofactor stoichiometry. NO can have a short half-life in aqueous solution, which may seem problematic for it to reach its intracellular target. A second-order dependence exists on NO autoxidation shown in the rate law below (reviewed in Reference 44).
= k [NO]2 [O2 ]
Consequently, at nanomolar signaling concentrations, the lifetime of NO is sufcient for it to reach sGC. The end-products of NO decomposition are nitrite (NO2 ) and nitrate (NO3 ). NO and reaction intermediates along the decomposition pathway can react with several intracellular molecules, but reactions
Figure 2 Nitric oxide synthase. (a). Domain architecture of NOS. The heme domain binds Zn2+ (gray box), heme (gray parallelogram), and H4 B (white box). The reductase domain binds FMN, FAD, and NADPH (white boxes). CaM (white box) is between the heme domain and the reductase domain. (b). Two-step reaction scheme for NO synthesis by NOS. WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.
with heme cofactors and cysteines are the most relevant to its function as a signaling agent and also contribute to its toxicity.
a1 b1 NO His Basal
Figure 3 Soluble guanylate cyclase. (a). Domain architecture of sGC. sGC consists of two homologous subunits, 1 and 1. Each subunit contains an N-terminal H-NOX domain, a central predicted PAS-like region, and a C-terminal catalytic domain. Heme (gray parallelogram) binds to the H-NOX domain on the 1 subunit. (b). NO activation of sGC. NO binds to the sGC heme, which leads to the formation of a 5-coordinate ferrous nitrosyl complex and activates the protein several-hundred fold above the basal level.
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bound was reported recently (54, 55). This structure shows that a distal pocket tyrosine interacts with bound O2 though an H-bond. Whereas the crystal structure of the O2, excluding H-NOX from Nostoc sp., shows that no hydrogen bond donor exists in the distal heme pocket (53), sequence analysis predicts that polar residues capable of interacting with O2 are absent in sGC. Mutagenesis studies that introduced a Tyr into the distal pocket of the 1 H-NOX domain produced a protein that was capable of binding O2 (58); however, the same mutation in full-length sGC did not facilitate O2 binding (59, 60). This nding indicates that the presence of a distal pocket Tyr may be involved in stabilizing FeII O2 complexes in H-NOX proteins, but other factors are involved in ligand discrimination in sGC. The size and overall polarity of the heme distal pocket and the strength of the proximal FeHis bond have been proposed as mechanisms of discriminating against O2 binding (57). The crystal structures of the H-NOX proteins also have facilitated the study of sGC activation. Specically, the differential pivoting and bending in the H-NOX heme during NO or CO binding may account for the varying degree of activation induced by the two ligands (200-fold versus 4-fold, respectively) (53). However, details about how movement in the H-NOX domains affect the catalytic domain may remain unresolved until the full-length structure is elucidated.
precursor in this pathway (62, 63), that L-citrulline was an additional product (63), and that L-arginine conversion to L-citrulline was coupled with NO formation (64). Chromatographic methods to separate substrate from product, radioimmunoassays (RIA), or enzyme-linked immunosorbent assays (ELISA) can be used for the sensitive detection of reaction products and/or substrate. Reaction stoichiometry, turnover number (k cat ), and K M for substrate can be determined. Additionally, reaction intermediates and possible transition states can be investigated by rapid quench methods, design of rational based inhibitors, and isotope exchange experiments.
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electron (65, 72). The application of EPR to the structural study of metalloproteins and electron transfer systems has expanded because of the development of pulsed-EPR techniques and high-eld/high-frequency spectrometers coupled with advances in rapid-freeze quench systems. Typically, EPR experiments are performed around 9 GHz (X-band), but studies also are done at 2 GHz (L-band), 4 GHz (S-band), 24 GHz (K-band), and 35 GHz (Q-band) frequencies (72). EPR studies with sGC conrmed that the nitric oxide radical was binding to the heme moiety and that the sGC FeII NO complex was 5-coordinate (73). EPR also provided the rst direct evidence that the H3 B radical is formed during the NOS reaction and supports the involvement of the cofactor in the electron transfer mechanism (40).
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See Also
Enzyme Kinetics Hemes in Biology Post-Translational Modications to Regulate Protein Function Signal Cascades, Protein Interaction Networks in Spectroscopic Techniques: Proteins
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