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    Nitric Oxide

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    Ganesh V Gaonkar
    Nitric oxide supplements are a category of supplements that includes L-citrulline and L-arginine. Researchers have performed multiple clinical trials related to nitric oxide supplements and their effectiveness, often with mixed results.

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    Nitric Oxide

    Uploaded by

    Ganesh V Gaonkar
    91 views20 pages
    Nitric oxide supplements are a category of supplements that includes L-citrulline and L-arginine. Researchers have performed multiple clinical trials related to nitric oxide supplements and their effectiveness, often with mixed results.

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    Nitric oxide supplements are a category of supplements that includes L-citrulline and L-arginine. Researchers have performed multiple clinical trials related to nitric oxide supplements and their effectiveness, often with mixed results.

    Copyright:

    © All Rights Reserved
    91 views20 pages

    Nitric Oxide

    Uploaded by

    Ganesh V Gaonkar
    Nitric oxide supplements are a category of supplements that includes L-citrulline and L-arginine. Researchers have performed multiple clinical trials related to nitric oxide supplements and their effectiveness, often with mixed results.

    Copyright:

    © All Rights Reserved
    of 20

    NITRIC

    OXIDE
    DISCOVERY OF NITRIC
    OXIDE

    Robert Furchgott Louis J. Ignarro

    Ferid Murad
    The structure and nature of
    Nitric Oxide

    • Nitric oxide is a diatomic free radical consisting of one atom of


    nitrogen and one atom of oxygen

    • Lipid soluble and very small for easy passage between cell membranes

    • Short lived, usually degraded or reacted within a few seconds

    • The natural form is a gas


    NITRIC OXIDE IN OUR
    SYSTEM
    TOXIC WITHOUT THIS,
    STAY YOU
    AWAY WILL DIE!

    •First described in 1979 as a potent relaxant of peripheral


    vascular smooth muscle.
    •Used by the body as a signaling molecule.
    •Serves different functions depending on body system. i.e.
    neurotransmitter, vasodilator, bactericide.
    •Environmental Pollutant
    •First gas known to act as a biological messenger
    STRUCTURE OF NITRIC
    OXIDE SYNTHASE
    Functional NOS is a dimer formed of 2 identical subunits. Each subunit consists of 3 distinct
    Domains.

    1. The Reductase Domain: C-terminal, 600-


    residue that supplies the electrons to
    oxygenase domain for the NOS reaction.

    2. Calmodulin Binding Domain: Calmodulin


    binding is required for the activity of all the
    NOS isoforms.
    3. The Oxygenase Domain: N-terminal, 500
    residue, heme domain that catalyzes 2 steps
    for conversion of arginine into citrulline and
    nitric oxide.
    SYNTHESIS OF NITRIC
    OXIDE
    NOS-catalyzed two-stage oxidation of L-arginine (Arg) to L-citrulline (Cit) and NO via
    the stable intermediate Nω-hydroxy-L-arginine (NOHA).
    ISOFORMS OF NITRIC
    OXIDE
    Types of NOS Isoforms

    1. nNOS- (Neuronal NOS / Type I / NOS-1) isoform first found in neuronal tissue.

    2. iNOS- (Inducible NOS / Type II / NOS-2) isoform which is inducible in a wide range
    of cells and tissues.

    3. eNOS- (Endothelial NOS / Type III / NOS-3) isoform first found in vascular
    endothelial cells.

    4.Encoded by different genes with different localization, , catalytic properties and


    inhibitor sensitivity.

    5.They exhibit 51-57% homology.


    CONT….
    Human NOS Isoform
    nNOS iNOS eNOS

    Expression Constitutive Inducible Constitutive

    Protein size 1434 aa 1153 aa 1203 aa

    Protein weight 161kDa 131kDa 133kDa

    Enzyme activity Ca2+ dependent Ca2+ independent Ca2+ dependent

    Chromosomal location 12 17 7
    What is the role of Nitric
    Oxide in the human body?
    • Nitric Oxide in the human body has many uses which are best
    summarized under five categories.
    • NO in the nervous system
    • NO in the circulatory system
    • NO in the muscular system
    • NO in the immune system
    • NO in the digestive system
    Nitric Oxide in the Nervous
    System
    Nitric oxide as a neurotransmitter
    NO is a signaling molecule, but not necessarily a neurotransmitter
    NO signals inhibition of smooth muscle contraction, adaptive relaxation, and
    localized vasodilation
    Nitric oxide believed to play a role in long term memory
    Memory mechanism proposed is a retrograde messenger that facilitates long
    term potentiation of neurons (memory)
    Synthesis mechanism involving Ca/Calmodulin activates NOS-I
    NO travels from postsynaptic neuron back to presynaptic neuron which
    activates guanylyl cyclase, the enzyme that catalyzes cGMP production
    This starts a cycle of nerve action potentials driven by NO
    Is Nitric Oxide a
    “neurotransmitter?”
    • NO serves in the body as a neurotransmitter, but there are
    definite differences between other neurotransmitters used
    commonly in the body
    • NO is synthesized on demand vs. constant synthesis
    • NO diffuses out of the cells making it vs. storage in vesicles and release by
    exocytosis
    • NO does not bind to surface receptors, but instead exits cytoplasm, enters the
    target cell, and binds with intracellular guanylyl cyclase
    • Similarities to normal NTs
    • Present in presynaptic terminal
    • Natural removal from synaptic junction
    Nitric Oxide in the Circulatory
    System
    • NO serves as a vasodilator
    • Released in response to high blood flow rate and signaling molecules (Ach
    and bradykinin)
    • Highly localized and effects are brief
    • If NO synthesis is inhibited, blood pressure
    • NO aids in gas exchange between hemoglobin and cells
    • Hemoglobin is a vasoconstrictor, Fe scavenges NO
    • NO is protected by cysteine group when O2 binds to hemoglobin
    • During O2 delivery, NO locally dilates blood vessels to aid in gas exchange
    • Excess NO is picked up by HGB with CO2
    Nitric Oxide in the Muscular
    System
    NO was orginally called EDRF (endothelium derived relaxation factor)
    NO signals inhibition of smooth muscle contraction
    Ca+2 is released from the vascular lumen activating NOS
    NO is synthesized from NOS III in vascular endothelial cells
    This causes guanylyl cyclase to produce cGMP
    A rise in cGMP causes Ca+2 pumps to be activated, thus reducing Ca+2
    concentration in the cell
    This causes muscle relaxation
    Mechanism of activation of
    eNOS
    Nitric Oxide in the Immune
    System
    • NOS II catalyzes synthesis of NO used in host defense reactions
    • Activation of NOS II is independent of Ca+2 in the cell
    • Synthesis of NO happens in most nucleated cells, particularly
    macrophages
    • NO is a potent inhibitor of viral replication
    • NO is a bactericidal agent
    • NO is created from the nitrates extracted from food near the gums
    • This kills bacteria in the mouth that may be harmful to the body
    Nitric Oxide in the Digestive
    System

    • NO is used in adaptive relaxation


    • NO promotes the stretching of the stomach in response to
    filling.
    • When the stomach gets full, stretch receptors trigger
    smooth muscle relaxation through NO releasing neurons
    Prospectives for the future
    • Which post-translational modifications are significant in
    the regulation of the three isoforms ?
    • What is the significance and basis of the sub-cellular
    localization of the NOSs ?
    • Will selective iNOS, nNOS or dual iNOS-­nNOS
    inhibitors prove to be of value in the treatment of human
    diseases, and if so, which diseases, and what side-effects
    might result ?
    Summary
    1st enzyme to synthesize a gas Nitric Oxide, a signalling molecule.

    A very complex enzyme with six co-factors and three distinct


    isoforms.

    It has bidomain structure and formation of a dimer is essential for its
    activation.

    There are a number of NOS signalled pathways associated with many


    biochemical and physiological processes
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