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UWEC CHEM 412 - Nitric Oxide

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Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Nitric OxideNitric OxideBy Steven KnappChemistry 4124-12-99What is Nitric Oxide?What is Nitric Oxide?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 messengerThe structure and nature of The structure and nature of Nitric OxideNitric 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 gasN OSynthesis of Nitric OxideNitric oxide is synthesized from L-arginine This reaction is catalyzed by nitric oxide synthase, a 1,294 aa enzymeCOO-C(CH2)3NHCH2NHNH2++H3NArginineNOSNADPH+ O2NAD+COO-C(CH2)3NHCH+H3NN+H2NHOHN-w-HydroxyarginineCOO-C(CH2)3NHH+H3N+NONOSCO NH2CitrullineActivation of NOSGlutamate neurotransmitter binds to NMDA receptorsCa++ channels open causing Ca influx into cellActivation of calmodulin, which activates NOSMechanism for start of synthesis dependent on body systemNO synthesis takes place in endothelial cells, lung cells, and neuronal cellsHttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.htmTypes of NOSNOS ICentral and peripheral neuronal cellsCa+2 dependent, used for neuronal communicationNOS IIMost nucleated cells, particularly macrophagesIndependent of intracellular Ca+2Inducible in presence of inflammatory cytokinesNOS IIIVascular endothelial cellsCa+2 dependentVascular regulationWhat is the role of Nitric What is the role of Nitric Oxide in the human body?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 systemNitric Oxide in the Nervous Nitric Oxide in the Nervous SystemSystem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 NOIs 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 junctionNitric Oxide in the Circulatory Nitric Oxide in the Circulatory SystemSystem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 skyrockets(Diagram of vasodilation mechanism after muscular system)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 CO2Nitric Oxide in the Muscular Nitric Oxide in the Muscular SystemSystem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 relaxationHttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-11.htmNitric Oxide in the Immune Nitric Oxide in the Immune SystemSystem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 bodyNitric Oxide in the Digestive Nitric Oxide in the Digestive SystemSystem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 neuronsNew research ideas involving New research ideas involving Nitric OxideNitric OxideThe role NO might play in neuronal developmentThe mechanism of NO inhibiting the different forms of NOSDiazeniumdiolates as NO releasing drugsExcessive NO release as the cause of most brain damage after strokeReferencesReferencesMarieb, Elaine N. Human Anatomy and Physiology. (1998) 4th ed. California, Benjamin/Cummings Science Publishing. 391, 826-27, 533, 859Stryer Lubert. Biochemistry. (1996) 4th ed. New York, W. H. Freeman and Company. 732Keefer, Larry K. “Nitric oxide-releasing compounds: From basic research to promising drugs.” Modern Drug Discovery. November/December 1998. 20-29.Sources on the World Wide Webhttp://www.duj.com/Article/Lue.htmlhttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-(01-20).htm (01-20) stands for 20 distinct sites.


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