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MIRACLE Molecule(NO)
&
The SILENT killer (CO)!!!
As signalling molecules
1
Nitric oxide(NO)
Discovered in 1772 by Joseph Priestly
He referred to it “nitrous air”.
A colorless and a toxic gas
Since ...
THE NOBEL ASSEMBLY AT KAROLINSKA INSTITUTE
awarded Nobel
Prize in Physiology & Medicine in October 12,1998 jointly to
Robe...
4
What is Nitric Oxide?
 First described in 1979 as a potent relaxant of
peripheral vascular smooth muscle.
 Used by the b...
The structure and nature of
Nitric Oxide
 Nitric oxide is a diatomic free radical consisting of one atom
of nitrogen and ...
Synthesis of Nitric Oxide
Nitric oxide is synthesized from L-arginine
This reaction is catalyzed by nitric oxide
synthas...
Types of NOS
 NOS I / nNOS
 Central and peripheral neuronal cells
 Ca+2 dependent, used for neuronal communication
 NO...
Properties of NOS
 NOS l & NOS lll are called as constitutive forms of NOS
 They produce less NO in the body
 On the ot...
Properties of NOS
 All three NOS are isoenzymes and are dimers
 Similar/homologous with cytochrome P450
 Each isoform c...
Properties of NOS
 NOS enzymes are functionally BIMODAL in nature which is
associated with distinct structural domains
 ...
Regulation
 L-Arginine is usually present in excess in endothelial cell cytoplasm, so the rate of
production of NO is det...
Activation of NOS
 Glutamate neurotransmitter binds to NMDA receptors
 Ca++ channels open causing Ca influx into cell
 ...
Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.h
14
What is the role of Nitric Oxide
in the human body?
 Nitric Oxide in the human body has many uses which are
best summariz...
Nitric Oxide in the Nervous
System
 Nitric oxide as a neurotransmitter
 NO is a signaling molecule, but not necessarily ...
Is Nitric Oxide a
“neurotransmitter?”
 NO serves in the body as a neurotransmitter, but there
are definite differences be...
Nitric Oxide in the Circulatory
System
 NO serves as a vasodilator
 Released in response to high blood flow rate and sig...
Nitric Oxide in the Muscular
System
 NO was orginally called EDRF (endothelium derived
relaxation factor)
 NO signals in...
20
 Endothelium-derived NO acts locally on underlying vascular smooth
muscle or on adherent monocytes or platelets.
 The po...
• Haem has an affinity for NO > 10 000 times greater than for oxygen. In the
absence of oxygen, NO bound to haem is relati...
• Key features of the proposed mechanism include the following.
• Nitrosylation of haemoglobin is reversible.
• It depends...
Nitric Oxide in the Immune
System
 NOS II catalyzes synthesis of NO used in host defense
reactions
Activation of NOS II ...
Nitric Oxide in the Digestive
System
 NO is used in adaptive relaxation
 NO promotes the stretching of the stomach in re...
Nitric Oxide Metabolism
NO may also be involved in the regulation of protein activity
through S-nitrosylation. In the extr...
 By analogy with cytochrome P450, it is believed that the flavins accept
electrons from NADPH and transfer them to the ha...
Nitric Oxide Metabolism
SIGMA-ALDRICH
28
New research ideas involving
Nitric Oxide
The role NO might play in neuronal
development
The mechanism of NO inhibiting ...
Silent Killer !!!
30
Carbon Monoxide
 Carbon monoxide (CO) is a colorless, odorless, and tasteless gas
that is slightly less dense than air. I...
 In biology, carbon monoxide is naturally produced by the action
of heme oxygenase 1 and 2 on the heme from hemoglobin br...
Carbon monoxide is produced naturally by the human body
as a signaling molecule.
Thus, carbon monoxide have a physiologica...
The most common symptoms of carbon monoxide poisoning may
resemble other types of poisonings and infections, including
sym...
 carbon monoxide has received a great deal of clinical attention as a
biological regulator. In many tissues, all three ga...
 Endogenous:
› Normal heme
catabolism:
 Only biochemical
reaction in the body
known to produce CO.
› Levels increased in...
 Exogenous:
› House fires.
› Gas–powered electrical
generators.
› Automobile exhaust.
› Propane-powered
vehicles.
› Heate...
 Methylene chloride:
› Paint and adhesive
remover.
› Converted to CO in the
liver after inhalation.
38
 Kills 5,000 people in US each year
 Survivors of CO poisoning can suffer from
brain damage, loss of sight or hearing, o...
 Headache
 Nausea
 Vomiting
 Dizziness
 Confusion
 Tiredness
 Weakness
 Sleepiness
 Tightness in
chest
 Trouble
...
41
Mechanism of action of CO
 CO combines reversibly with the oxygen binding sites
of hemoglobin and has an affinity Hemoglo...
Oxyhemoglobin
oxygen
Thus brain and heart are most
affected
The free carboxy group present combines
with hemoglobin, thus ...
1. CO binds to platelet hemoproteins and
increases NO efflux.
2. Platelet-derived NO reacts with neutrophil-
derived super...
CO regulates blood
flow and blood fluidity
Vascular tone SMC proliferation Platelet aggregation
By inhibiting
45
Cross talk between CO AND NO
 CO AND NO are two endogenously produced gases that can act as second
messenger molecules
 ...
REFERENCES
• RANG and DALE’S Pharmacology. Sixth edition (2007). 265-
274.
• The sources on the world wide web.
47
Thank you
48
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No and co final by syed kashifpptx

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contains details about carbon monoxide & nitric oxide as a signalling molecule
Its synthesis & role in the human body

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No and co final by syed kashifpptx

  1. 1. MIRACLE Molecule(NO) & The SILENT killer (CO)!!! As signalling molecules 1
  2. 2. Nitric oxide(NO) Discovered in 1772 by Joseph Priestly He referred to it “nitrous air”. A colorless and a toxic gas Since then, it has received the label of being a toxic gas and an air pollutant until over two hundred years He had also discovered “Oxygen” 2
  3. 3. THE NOBEL ASSEMBLY AT KAROLINSKA INSTITUTE awarded Nobel Prize in Physiology & Medicine in October 12,1998 jointly to Robert F. Furchgott, Louis J. Ignarro and Ferid Murad for their discoveries concerning “nitric oxide as a signalling molecule in the cardiovascular system". J 3
  4. 4. 4
  5. 5. 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 messenger 5
  6. 6. 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 gas  The nitrogen atom in NO is derived from the terminal guanidino group of L- arginine N O 6
  7. 7. Synthesis of Nitric Oxide Nitric oxide is synthesized from L-arginine This reaction is catalyzed by nitric oxide synthase, a 1,294 aa enzyme COO- C (CH2)3 NH C H2N H NH2+ +H3 N Arginine NOS NADPH + O2 NAD+ COO- C (CH2)3 NH C H+H3 N N + H2N H OH N-w-Hydroxyarginine COO- C (CH2)3 NH H+H3 N + NO NOS C O NH2 Citrulline 7
  8. 8. Types of NOS  NOS I / nNOS  Central and peripheral neuronal cells  Ca+2 dependent, used for neuronal communication  NOS II / iNOS  Most nucleated cells, particularly macrophages  Independent of intracellular Ca+2  Inducible in presence of inflammatory cytokines  NOS III / eNOS  Vascular endothelial cells  Ca+2 dependent  Vascular regulation 8
  9. 9. Properties of NOS  NOS l & NOS lll are called as constitutive forms of NOS  They produce less NO in the body  On the other hand NOS ll / iNOS produces more NO in the body because 1. Its high concentration & Activity in the body 2. Pathological conditions are associated with the cytokines 9
  10. 10. Properties of NOS  All three NOS are isoenzymes and are dimers  Similar/homologous with cytochrome P450  Each isoform contains iron protoporphyrin ix (heam) , flavin adenin dinucleotide (FAD) , flavin mononucleotide (FMN) & thetrahydrobiopterin (H4B) as bound prosthetic group  These prosthetic group and the ligand which is going to bind to the enzyme in the presence of the reduced NADPH control the assembly of the enzyme into “The Active Dimer form” 10
  11. 11. Properties of NOS  NOS enzymes are functionally BIMODAL in nature which is associated with distinct structural domains  The oxygease domain binds to Heam while reductase bind to calcium calmodulin , FMN , FAD , NADPH  NOS enzymes are the only Flavo Heam enzymes that use H4B as a redox cofactor  The crystal nature of the NOS heam (oxygenase) domain in iNOS & eNOS has revealed how L arginine heam & H4B bind in the active site 11
  12. 12. Regulation  L-Arginine is usually present in excess in endothelial cell cytoplasm, so the rate of production of NO is determined by the activity of the enzyme rather than by substrate availability.  Nevertheless, very high doses of L-arginine can restore endothelial NO biosynthesis in some pathological states (e.g. hypercholesterolaemia) in which endothelial function is impaired. Possible explanations for this paradox include:  compartmentation: i.e. existence of a distinct pool of substrate in a cell compartment with access to the synthase enzyme, which can become depleted despite apparently plentiful total cytoplasmic arginine concentrations  competition with endogenous inhibitors of NOS such as asymmetric dimethylarginine (ADMA), which is elevated in plasma from patients with hypercholesterolaemia  reassembly/reactivation of enzyme in which transfer of electrons has become uncoupled from L-arginine  relative depletion of arginine, which can inhibit NOS activity by inhibiting translation of iNOS mRNA 12
  13. 13. 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 body system  NO synthesis takes place in endothelial cells, lung cells, and neuronal cells 13
  14. 14. Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.h 14
  15. 15. 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 15
  16. 16. 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 16
  17. 17. 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 in cytoplasm, enters the target cell, and binds with intracellular guanylyl cyclase  Similarities to normal NTs  Present in presynaptic terminal  Natural removal from synaptic junction 17
  18. 18. 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 shoots  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 18
  19. 19. Nitric Oxide in the Muscular System  NO was orginally called EDRF (endothelium derived relaxation factor)  NO signals inhibition of smooth muscle contraction  Ca2+ 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 Ca2+ concentration in the cell  This causes muscle relaxation 19
  20. 20. 20
  21. 21.  Endothelium-derived NO acts locally on underlying vascular smooth muscle or on adherent monocytes or platelets.  The potential for action at a distance is neatly demonstrated by Rhodnius prolixus, a blood-sucking insect that produces a salivary vasodilator/platelet inhibitor with the properties of a nitrovasodilator. This consists of a mixture of nitrosylated haemoproteins, which bind NO in the salivary glands of the insect but release it in the tissues of its prey.  The consequent vasodilatation and inhibition of platelet activation presumably facilitates extraction of the bug's meal in liquid form.  A strong, but still controversial, case has been made that NO can also act at a distance in the mammalian circulation via reversible interactions with haemoglobin 21
  22. 22. • Haem has an affinity for NO > 10 000 times greater than for oxygen. In the absence of oxygen, NO bound to haem is relatively stable, but in the presence of oxygen NO is converted to nitrate and the haem iron oxidised to methaemoglobin. • Distinct from this inactivation reaction, a specific cysteine residue in globin combines reversibly with NO under physiological conditions. • The resulting S-nitrosylated haemoglobin is believed to be involved in various NO-related activities, including the control of vascular resistance, blood pressure and respiration. 22
  23. 23. • Key features of the proposed mechanism include the following. • Nitrosylation of haemoglobin is reversible. • It depends on the state of oxygenation of the haemoglobin, which consequently takes up NO in the lungs and releases it in tissues, in concert with release of oxygen. • Haemoglobin acts as an O2 sensor and could regulate vascular tone (and hence tissue perfusion) in response to the local partial pressure of O2 by releasing NO in this way. This mechanism is impaired in sickle cell disease (a common inherited disorder caused by a molecular variant of haemoglobin). • NO is not released into the cytoplasm of erythrocytes (where it would promptly be inactivated by haem), but is transported out of the red cells via cysteine residues in the haemoglobin-binding cytoplasmic domain of an anion exchanger called AE1. • S-nitrosylated albumin also constitutes a source of circulating NO bioactivity. An alternative view is that nitrite anion, rather than nitrosylated protein, is the main intravascular NO storage molecule 23
  24. 24. 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 24
  25. 25. 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 25
  26. 26. Nitric Oxide Metabolism NO may also be involved in the regulation of protein activity through S-nitrosylation. In the extracellular milieu, NO reacts with oxygen and water to form nitrates and nitrites. NO toxicity is linked to its ability to combine with superoxide anions (O2–) to form peroxynitrite (ONOO–), an oxidizing free radical that can cause DNA fragmentation and lipid oxidation. In the mitochondria, ONOO– acts on the respiratory chain (I- IV) complex and manganese superoxide dismutase (MnSOD), to generate superoxide anions and hydrogen peroxide (H2O2), respectively. 26
  27. 27.  By analogy with cytochrome P450, it is believed that the flavins accept electrons from NADPH and transfer them to the haem iron, which binds oxygen and catalyses the stepwise oxidation of L-arginine, via a hydroxyl-arginine intermediate, to NO and citrulline.  In pathological states, the enzyme can undergo structural change leading to electron transfer between substrates, enzyme cofactors and products becoming 'uncoupled', so that electrons are transferred to molecular oxygen, leading to the synthesis of superoxide anion rather than NO.  This is important, as superoxide anion is a reactive oxygen species and reacts with NO to form a toxic product (peroxynitrite anion) 27
  28. 28. Nitric Oxide Metabolism SIGMA-ALDRICH 28
  29. 29. New research ideas involving Nitric 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 stroke 29
  30. 30. Silent Killer !!! 30
  31. 31. Carbon Monoxide  Carbon monoxide (CO) is a colorless, odorless, and tasteless gas that is slightly less dense than air. It is toxic to humans when encountered in concentrations above about 35 ppm  Carbon monoxide consists of one carbon atom and one oxygen atom, connected by a triple bond that consists of two covalent bonds as well as one dative covalent bond. It is the simplest oxocarbon 31
  32. 32.  In biology, carbon monoxide is naturally produced by the action of heme oxygenase 1 and 2 on the heme from hemoglobin breakdown.  This process produces a certain amount of carboxyhemoglobin in normal persons, even if they do not breathe any carbon monoxide. Following the first report that carbon monoxide is a normal neurotransmitter in 1993, as well as one of three gases that naturally modulate inflammatory responses in the body 32
  33. 33. Carbon monoxide is produced naturally by the human body as a signaling molecule. Thus, carbon monoxide have a physiological role in the body, such as a neurotransmitter or a blood vessel relaxant. Because of carbon monoxide's role in the body, abnormalities in its metabolism have been linked to a variety of diseases, including neurodegenerations, hypertension, heart failure, and inflammation. 33
  34. 34. The most common symptoms of carbon monoxide poisoning may resemble other types of poisonings and infections, including symptoms such as headache, nausea, vomiting, dizziness, fatigue, and a feeling of weakness. Affected families often believe they are victims of food poisoning. Infants may be irritable and feed poorly. Neurological signs include confusion, disorientation, visual disturbance, syncope and seizures. Some descriptions of carbon monoxide poisoning include retinal hemorrhages, and an abnormal cherry-red blood hue 34
  35. 35.  carbon monoxide has received a great deal of clinical attention as a biological regulator. In many tissues, all three gases are known to act as anti-inflammatories, vasodilators, and encouragers of neovascular growth.  However, the issues are complex, as neovascular growth is not always beneficial, since it plays a role in tumor growth, and also the damage from wet macular degeneration, a disease for which smoking (a major source of carbon monoxide in the blood, several times more than natural production) increases the risk from 4 to 6 times.  Endogenous  Exogenous  Methylene chloride 35
  36. 36.  Endogenous: › Normal heme catabolism:  Only biochemical reaction in the body known to produce CO. › Levels increased in:  Hemolytic anemia.  Sepsis 36
  37. 37.  Exogenous: › House fires. › Gas–powered electrical generators. › Automobile exhaust. › Propane-powered vehicles. › Heaters. › Camp stoves. › Boat exhaust. › Cigarette smoke. 37
  38. 38.  Methylene chloride: › Paint and adhesive remover. › Converted to CO in the liver after inhalation. 38
  39. 39.  Kills 5,000 people in US each year  Survivors of CO poisoning can suffer from brain damage, loss of sight or hearing, or heart problems 39
  40. 40.  Headache  Nausea  Vomiting  Dizziness  Confusion  Tiredness  Weakness  Sleepiness  Tightness in chest  Trouble breathing  All of these are flu- like symptoms 40
  41. 41. 41
  42. 42. Mechanism of action of CO  CO combines reversibly with the oxygen binding sites of hemoglobin and has an affinity Hemoglobin about 220times that of oxygen. The product formed carboxyhemoglobin, cannot transport oxygen. 42
  43. 43. Oxyhemoglobin oxygen Thus brain and heart are most affected The free carboxy group present combines with hemoglobin, thus forming carboxy hemoglobin. Therefore Reduces the oxygen supply to the tissues. 43
  44. 44. 1. CO binds to platelet hemoproteins and increases NO efflux. 2. Platelet-derived NO reacts with neutrophil- derived superoxide which activates platelets and causes platelet-neutrophil aggregates. 3. Reactive products and adhesion molecules promote firm aggregation and stimulate degranulation of neutrophils. 4. Endothelial cells acitaved by myeloperoxidase facilitating firm neutrophil adhesion and further degranulation. 5. Reactive oxygen species (ROS) initiate lipid peroxidation and adducts interact with brain myelin basic protein. The altered myelin basic protein triggers an adaptive immunologic response that causes neurologic dysfunction. 44
  45. 45. CO regulates blood flow and blood fluidity Vascular tone SMC proliferation Platelet aggregation By inhibiting 45
  46. 46. Cross talk between CO AND NO  CO AND NO are two endogenously produced gases that can act as second messenger molecules  Heme oxygenase and nitric oxide synthase are the enzyme systems responsible for generating CO and NO share similar properties, such as ability to activate soluble guanylate cyclase to increase cyclic GMP.  it is becoming increasingly clear that these 2 gases do not always work independently, but rather can modulate each others activity.  Although much is known about the heme oxygenase/CO and nitric oxide synthase/nitric oxide pathways, how these two imp systems interact is Less well understood.  The current known relationship between CO and NO it relates to their production and physiological function. 46
  47. 47. REFERENCES • RANG and DALE’S Pharmacology. Sixth edition (2007). 265- 274. • The sources on the world wide web. 47
  48. 48. Thank you 48

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