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Nitric Oxide

By Steven Knapp

Chemistry 4124-12-99

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What is Nitric Oxide?

First described in 1979 as a potent relaxant of peripheralvascular 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

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The structure and nature

of Nitric Oxide

Nitric oxide is a diatomic free radical consisting of oneatom of nitrogen and one atom of oxygen

Lipid soluble and very small for easy passage betweencell membranes

Short lived, usually degraded or reacted within a fewseconds

The natural form is a gas

N O

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Synthesis 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)3

NH

C

H2N

H

NH2+

+H3N

Arginine

NOS

NADPH

+ O2

NAD+

COO-

C

(CH2)3

NH

C

H+H3N

N+

H2NH

OH

N-w-Hydroxyarginine

COO-

C

(CH2)3

NH

H+H3N + NO

NOS

C

O NH2

Citrulline

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Activation 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 bodysystem

NO synthesis takes place in endothelial cells, lung cells,and neuronal cells

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Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.htm

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Types of NOS

NOS I

Central and peripheral neuronal cells

Ca+2 dependent, used for neuronal communication

NOS IIMost nucleated cells, particularly macrophages

Independent of intracellular Ca+2

Inducible in presence of inflammatory cytokines

NOS IIIVascular endothelial cells

Ca+2 dependent

Vascular regulation

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What is the role of Nitric

Oxide in the human body?

Nitric Oxide in the human body has manyuses which are best summarized under

five categories.NO in the nervous system

NO in the circulatory system

NO in the muscular systemNO in the immune system

NO in the digestive system

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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, adaptiverelaxation, and localized vasodilation

Nitric oxide believed to play a role in long term memory

Memory mechanism proposed is a retrograde messenger thatfacilitates long term potentiation of neurons (memory)

Synthesis mechanism involving Ca/Calmodulin activates NOS-I

NO travels from postsynaptic neuron back to presynaptic neuronwhich activates guanylyl cyclase, the enzyme that catalyzes cGMPproduction

This starts a cycle of nerve action potentials driven by NO

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Is Nitric Oxide a

neurotransmitter?

NO serves in the body as a neurotransmitter, but thereare definite differences between other neurotransmittersused commonly in the body

NO is synthesized on demand vs. constant synthesisNO 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

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Nitric Oxide in the

Circulatory System

NO serves as a vasodilator

Released in response to high blood flow rate and signalingmolecules (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 gasexchange

Excess NO is picked up by HGB with CO2

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Nitric Oxide in the

Muscular System

NO was orginally called EDRF (endothelium derivedrelaxation 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 cellThis causes muscle relaxation

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Nitric Oxide in the Immune

System

NOS II catalyzes synthesis of NO used in host defensereactions

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 nearthe gums

This kills bacteria in the mouth that may be harmful to the

body

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Nitric Oxide in the

Digestive System

NO is used in adaptive relaxationNO promotes the stretching of the stomach in

response to filling.

When the stomach gets full, stretch receptors trigger

smooth muscle relaxation through NO releasingneurons

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New research ideas

involving Nitric Oxide

The role NO might play in neuronaldevelopment

The mechanism of NO inhibiting the differentforms of NOS

Diazeniumdiolates as NO releasing drugs

Excessive NO release as the cause of most brain

damage after stroke

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References

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.

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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.

http://www.med.nyu.edu/Research/S.Abramson-res.html

http://biophysics.aecom.yu.edu/rousseau/nos/nos.htm

http://keck.ucsf.edu.neuroscience.bredt.htm

The following are all Omim sources written by McKusick, Victor A.

NOS II http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163729

NOS IIA http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163730

NOS I http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163731

NOS Chon http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163728

NOS IIC http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600719

NOS IIB http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600720

http://www.duj.com/Article/Lue.htmlhttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-(01-20).htmhttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-(01-20).htmhttp://www.med.nyu.edu/Research/S.Abramson-res.htmlhttp://biophysics.aecom.yu.edu/rousseau/nos/nos.htmhttp://keck.ucsf.edu.neuroscience.bredt.htm/http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163729http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163729http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163730http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163731http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163728http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600719http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600720http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600720http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600720http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600720http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600719http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600719http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600719http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163728http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163728http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163728http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163731http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163731http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163731http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163730http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163730http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163730http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163729http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163729http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163729http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?163729http://keck.ucsf.edu.neuroscience.bredt.htm/http://keck.ucsf.edu.neuroscience.bredt.htm/http://biophysics.aecom.yu.edu/rousseau/nos/nos.htmhttp://www.med.nyu.edu/Research/S.Abramson-res.htmlhttp://www.med.nyu.edu/Research/S.Abramson-res.htmlhttp://www.med.nyu.edu/Research/S.Abramson-res.htmlhttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-(01-20).htmhttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-(01-20).htmhttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-(01-20).htmhttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-(01-20).htmhttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-(01-20).htmhttp://www.duj.com/Article/Lue.html

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