Nitric oxide in cellular adaptation and disease

Figures

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  Fig. 1. Structural Diversity among NOS Enzyme Isoforms. The well-conserved protein domain structure of the NOS enzymes is depicted, both common and isoform-specific motifs are shown. Larger boxes indicate the oxygenase and reductase domains that perform the important enzymatic functions, while smaller boxes indicate the simplified positions of a variety of various functional motifs, although in some cases these are distributed in a more complex manner on the actual protein structure. Both the flexible hinge domains between the flavin binding sites in the reductase domain (R-Hinge) and the hinge between the oxidase and reductase domains (OR-Hinge) regulate the flow of electrons between domains, and thus enzymatic activity. Important differences between a number of NOS isoforms are indicated by arrow boxes. Isoform specific localization is directed by multiple motifs, including acylation (palmitoylation, myristoylation) and protein:protein interactions via the PDZ domain. The autoinhibitory (AID) and Akt phosphorylation sites confer regulatory constraint by cellular signaling pathways on NOS1 and NOS3 enzymatic activity, their absence contributes to the constitutive activity of NOS2.…

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  Fig. 2. Conserved Catalytic Mechanism of NOS enzymes. The catalytic mechanism of NOS enzymes is shown superimposed on the protein modular domains where the activity occurs. The role of prosthetic groups in promoting electron flow is emphasized. Electrons are derived from NADPH, then transferred to FAD, and then FMN, before being transferred ultimately to the oxidase domain of the other protein chain in the NOS homodimer (shown here happening within a monomer for simplicity). Calcium promotes the binding of calmodulin (CaM) to the OR-Hinge, inducing a structural rearrangement that allows electron transfer. The autoinhibitory (AID) loop lies within the FMN binding domain of NOS1 and NOS3, it can dislodge CaM in the absence of Ca2+ and terminate enzymatic activity. When the reaction is “coupled”, the Heme/BH4 complex transfers electrons to molecular oxygen and promotes two distinct oxygenation reactions that convert 1)l-Arginine to N-hydroxyarginine (NOHA), and finally to 2)l-citrulline and NO. Loss of substrates or BH4 can cause “uncoupling”, or release of superoxide.

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  Fig. 3. Diverse physiologic contexts and roles for Nitric Oxide Synthases in mammals. NO plays important roles in a wide range of tissues, where it exerts important regulation on physiological processes that are critical for tissue function. When NO signaling is dysregulated, these central tissue processes can become pathophysiological, causing acute or chronic disease. These vignettes illustrate a more general role for NO in adaptation to changes in the organism's need for each of the tissue-specific functions.