Nitric Oxide Synthases Overview
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Questions and Answers

What role does tetrahydrobiopterin play in nitric oxide synthesis by nitric oxide synthase (NOS)?

  • It acts as an electron donor to the oxy-ferrous complex of NOS. (correct)
  • It is necessary for substrate binding to NOS.
  • It prevents the production of superoxide by NOS.
  • It is only required for cytochrome P450 enzymes.

    • What could be a consequence of NOS activity in the absence of substrate and tetrahydrobiopterin?

  • Increased production of nitric oxide.
  • Formation of destructive reactive oxygen species. (correct)
  • Enhanced signaling through cyclic GMP pathways.
  • Substrate binding to the heme group of NOS.

    • Which of the following is NOT a major isoform of nitric oxide synthase?

  • Cytosolic NOS (cNOS) (correct)
  • Neuronal NOS (nNOS)
  • Inducible NOS (iNOS)
  • Endothelial NOS (eNOS)

    • How does nitric oxide (NO) influence soluble guanylate cyclase activity?

    <p>It destabilizes the heme-histidine bond to activate the enzyme.</p> Signup and view all the answers

    What physiological functions are mediated by cyclic GMP?

    <p>Signal transduction in various tissues.</p> Signup and view all the answers

    What role does calmodulin play in the activation of nitric oxide synthases (NOSs)?

    <p>It binds to NOSs, facilitating electron transfer.</p> Signup and view all the answers

    Where is neuronal nitric oxide synthase (nNOS) primarily localized?

    <p>In the skeletal muscle and neurons.</p> Signup and view all the answers

    Which of the following statements about the formation of reduced oxygen species by NOS is correct?

    <p>It can occur even in the absence of substrate.</p> Signup and view all the answers

    What is the primary source of nitric oxide (NO) during its synthesis?

    <p>Guanidino group of arginine</p> Signup and view all the answers

    What happens to the heme reduction rate when calmodulin is not bound to NOSs?

    <p>Heme reduction occurs very slowly.</p> Signup and view all the answers

    What is the effect of calcium influx on neuronal nitric oxide synthase (nNOS)?

    <p>It activates the enzyme without transcriptional induction.</p> Signup and view all the answers

    Which of the following is a key difference between nitric oxide synthases (NOSs) and cytochromes P450?

    <p>Binding of substrate alters the heme's reduction potential in P450s.</p> Signup and view all the answers

    What is produced if the second electron is transferred to the heme before superoxide is released?

    <p>Hydrogen peroxide</p> Signup and view all the answers

    What is the primary function of phosphodiesterases (PDEs) with respect to cGMP levels?

    <p>Hydrolyze cGMP to 5'–nucleotides</p> Signup and view all the answers

    Which PDE does Sildenafil specifically inhibit to treat erectile dysfunction?

    <p>PDE5</p> Signup and view all the answers

    Why is the selectivity of Sildenafil for PDE5 over PDE3 significant?

    <p>It prevents increased incidence of cardiac arrhythmias.</p> Signup and view all the answers

    What is a notable side effect associated with Sildenafil due to its action on PDE6?

    <p>Blue-green tint in vision</p> Signup and view all the answers

    What potential risk arises from combining Sildenafil with nitrates?

    <p>Potentially fatal hypotension</p> Signup and view all the answers

    What are the metabolic pathways that Sildenafil is primarily processed through?

    <p>CYP2C9 and CYP3A4</p> Signup and view all the answers

    What physiological response does Sildenafil preserve by inhibiting PDE5?

    <p>Prolonged vasodilatory signals</p> Signup and view all the answers

    What is the effect of Sildenafil on blood pressure?

    <p>Mild and clinically insignificant reduction</p> Signup and view all the answers

    What is the primary role of NOSII in the immune response?

    <p>To destroy engulfed pathogens</p> Signup and view all the answers

    Which cell types primarily express NOSII?

    <p>Activated neutrophils and macrophages</p> Signup and view all the answers

    What induces the expression of NOSII?

    <p>Cytokines and endotoxins</p> Signup and view all the answers

    How does the amount of nitric oxide produced by NOSII compare to that produced by NOSI and NOSIII?

    <p>NOSII produces significantly more nitric oxide than NOSI and NOSIII</p> Signup and view all the answers

    What kind of pathogens does NOSII primarily help eliminate?

    <p>Intracellular pathogens and tumor cells</p> Signup and view all the answers

    What type of protein is inhibited by the nitric oxide produced by NOSII?

    <p>Metal-containing heme proteins</p> Signup and view all the answers

    In which of the following conditions is NOSII known to be active?

    <p>Rheumatoid arthritis and asthma</p> Signup and view all the answers

    What is one potential negative effect of NOSII activity in chronic inflammation?

    <p>Exacerbation of inflammatory conditions</p> Signup and view all the answers

    What is a significant consequence of excessive nitric oxide (NO) production in septic shock?

    <p>Massive systemic vasodilation</p> Signup and view all the answers

    Why is hypotension in septic shock patients often resistant to conventional vasoconstrictor drugs?

    <p>Due to overproduction of nitric oxide</p> Signup and view all the answers

    Which therapeutic intervention has been investigated for septic shock treatment?

    <p>Nitric oxide synthase inhibitors</p> Signup and view all the answers

    What effect does nitric oxide (NO) have on systemic vascular resistance in septic shock treatment?

    <p>It decreases systemic vascular resistance</p> Signup and view all the answers

    What role does NO play that could be beneficial in septic shock despite its adverse effects?

    <p>Acts as an antiplatelet agent</p> Signup and view all the answers

    What is the estimated mortality rate associated with septic shock?

    <p>50%-70%</p> Signup and view all the answers

    Which nitric oxide synthase is primarily expressed in vascular endothelial cells?

    <p>NOSIII</p> Signup and view all the answers

    What mechanism does nitric oxide (NO) use to induce hypotension?

    <p>Activation of guanylate cyclase</p> Signup and view all the answers

    Study Notes

    Nitric Oxide Synthases (NOS)

    • NOS enzymes catalyze the conversion of L-arginine to nitric oxide (NO) and citrulline.
    • The reaction is initiated by calmodulin binding, which activates the enzyme.
    • Electrons are donated by NADPH, passing through FAD and FMN before reducing the heme iron.
    • Oxygen binds to the ferrous heme iron, and two oxygen molecules are consumed in the reaction.

    NOS Reaction Cycle

    • Arginine is first oxidized to N-hydroxy-L-arginine.
    • N-hydroxy-L-arginine is then oxidized to NO and citrulline.
    • The source of NO is the guanidino group of arginine.
    • The reaction requires 1.5 molecules of NADPH.
    • Carbon monoxide inhibits NOS activity.

    Regulation of NOS activity

    • Calmodulin binds to NOS in the presence of calcium, activating the enzyme.
    • Without calmodulin, heme reduction and electron transfer are slow.
    • Calmodulin binding causes a conformational change, promoting electron transfer.

    Reactive Oxygen Species (ROS) Production

    • In the absence of substrate, NOS can produce superoxide and hydrogen peroxide.
    • Superoxide is formed by autoxidation of the oxy-ferrous complex.
    • Hydrogen peroxide results from the decay of the peroxy-ferrous complex.
    • These ROS can contribute to inflammation and disease.

    Tetrahydrobiopterin (BH4) Cofactor

    • BH4 is essential for NO synthesis by NOS, but not by cytochrome P450 enzymes.
    • BH4 donates an electron to the oxy-ferrous complex, accelerating heme reduction.
    • Without BH4, NOS produces superoxide.

    NOS Isoforms

    • Three major NOS isoforms exist: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS).
    • nNOS is found in neurons and skeletal muscle.
    • iNOS is primarily found in immune cells like macrophages and neutrophils.
    • eNOS is localized in vascular endothelial cells.

    Physiological Functions of NO

    • Many of NO's functions are mediated through activation of soluble guanylate cyclase (sGC).
    • sGC converts GTP to cGMP, a second messenger involved in signal transduction.
    • NO binds to the heme of sGC, activating the enzyme.

    Neuronal NOS (nNOS)

    • nNOS is constitutively expressed and activated by calcium influx.
    • It serves as a neurotransmitter in the nervous system.
    • In skeletal muscle, nNOS contributes to muscle contraction.

    Inducible NOS (iNOS)

    • iNOS is induced by inflammatory cytokines like IFN-gamma, IL-1, TNF-alpha, and LPS.
    • It is activated under basal conditions and produces high levels of NO.
    • NO generated by iNOS has cytotoxic effects, targeting metal-containing proteins and causing DNA damage.

    Endothelial NOS (eNOS)

    • eNOS is constitutively expressed in endothelial cells and activated by calcium influx.
    • It produces low levels of NO, which acts as a vasodilator, inhibits platelet and leukocyte adhesion, and counteracts angiotensin II vasoconstriction.

    Therapeutic Manipulation of cGMP Levels

    • cGMP levels are influenced by sGC activity and phosphodiesterase (PDE) degradation.
    • PDE inhibitors prolong the effects of cGMP.

    Sildenafil (Viagra)

    • Sildenafil is a potent inhibitor of PDE5, primarily found in the corpus cavernosum.
    • It enhances cGMP levels, promoting vasodilation and erectile function.
    • Sildenafil is contraindicated in patients using nitrates due to the risk of severe hypotension.

    Nitric Oxide Overproduction in Septic Shock

    • Overproduction of NO by iNOS contributes to septic shock, causing vasodilation and hypotension.
    • NOS inhibitors can increase blood pressure, but they may exacerbate organ dysfunction.

    Summary of NOS Functions

    • nNOS: neuronal signaling and muscle contraction
    • iNOS: immune defense and inflammation
    • eNOS: vasodilation, antithrombotic and anti-inflammatory effects

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    Description

    Explore the intricate mechanisms of Nitric Oxide Synthases (NOS) in this quiz. Learn about the conversion of L-arginine to nitric oxide, including key steps in the reaction cycle and regulation of NOS activity. This quiz also delves into the role of reactive oxygen species and the influence of calmodulin on NOS function.

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