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Name the catecholamines:

  • Dopamine

  • Norepinephrine

  • Epinephrine

Where are catecholamines made?

  • Neurons

  • Adrenal medulla cells (epinephrine only produced in adrenal medulla cells)

Draw the chemical structure of Tyrosine.
Describe the sequence of reactions that converts tyrosine into catecholamines.
 
Tyrosine ==> dopa ==> Dopamine ==> Norepinephrine ==> Epinephrine
 
what does "dopa" stand for?
dihydroxiphenylalanine
 
Draw out the reaction, the enzyme and the cofactors required to convert Tyrosine ==> dopa:
Tyrosine + BH4 + O2 (tyrosine hydroxylase) ==> dopa + BH2 + H2O
 
Draw out the reaction, the enzyme and the cofactors required to convert dopa ==> dopamine:
dopa (dopa decarboxylase: PLP) ==> dopamine + CO2
 
Draw out the reaction, the enzyme and the cofactors required to convert dopamine ==> norepinephrine:
dopamine + O2 (dopamine ß-hydroxylase: Cu2+, Vitamin C [ascorvic acid] => the oxidized form of Vitamin C [dehydro ascorvic acid]) ==> norepinephrine + H2O
 
Draw out the reaction, the enzyme and the cofactors required to convert norepinephrine ==> epinephrine:
norepinephrine + S-adenosyl methionine (phenylethanolamine N-methyltransferase) ==> epinephrine + S-adenosyl homocysteine
 
Distinguish between the chemical structures of tyrosine, (L-)dopa, dopamine, norepinephrine, and epinephrine.
 

  • tyrosine: amino acid -CH2-phenol ring-OH

  • dopa: tyrosine with an extra -OH on the phenol ring

  • dopamine: dopa loses its COO-

  • norepinephrine: gets another -OH on the ß carbon

  • epinephrine: gets a methyl group on the Nitrogen atom.



Describe the inactivation and catabolism of catecholamines involving the enzymes monoamine oxidase (MAO) and catechol O-methyltransferase (COMT)
This has two components to the pathway that can be done in either order:
Norepinephrine

  1. (MAO) ==> XXX + NH4+ (oxidation) ==> XXX + SAM (COMT) ==> SAH +

  2. + SAM (COMT) ==> XXX + SAH (MAO) ==> XXX + NH4+ (oxidation) ==>


3-Methoxy-4-hydroxymandelic acid [vanillylmandelic acid, VMA]


  • The inactivation and breakdown of catecholamine can be done in two different orders.  One order removes the    hydroxyl group of the phenyl part and replaces it with an CH3O, the other path removes the amine group then oxidizes the aldehyde that is left behind to make it into a carboxyl group.

  • monoamine oxidase (MAO)



  • catechol O-methyltransferase (COMT).



  • The MAO step comes before the oxidation step.


 
What does MAO stand for?
monoamine oxidase
What does COMT stand for?
catechol O-methyltransferase
name the urinary product that indicates the amount of catecholamine degradation:
3-Methoxy-4-hydroxymandelic acid [vanillylmandelic acid, VMA]
What is the reducing agent needed in the hydroxylation of aromatic amino acids?
 
the extra reducing agent needed is not NADPH but BH4(tetrahydrobiopterin).
 
What does catechol mean?
 
a phenyl ring with two hydroxyl groups on adjacent carbons.
 
What is the cofactor required for any reaction  catalyzed by a decarboxylase?
 
PLP (pyridoxal-phosphate, vitamin B6)
 
If a patient is overproducing catecholamines, what type of tumor might he/she have and where is likely location of this tumor?

  • The name of this type of tumor is Theochromocytoma.

  • The most likely location of this type of tumor would be in the adrenal medulla.


 

  • The inactivation and breakdown of catecholamine can be done in two different orders.  One order removes the    hydroxyl group of the phenyl part and replaces it with an CH3O, the other path removes the amine group then oxidizes the aldehyde that is left behind to make it into a carboxyl group.


    • monoamine oxidase (MAO)



    • catechol O-methyltransferase (COMT).



    • The MAO step comes before the oxidation step.


Draw out the catecholamine synthesis pathway
Draw out the catecholamine degragation pathway
Describe the sequence of reactions that converts Tryptophan into Seratonin and Melatonin.
 
Tryptophan ==> 5-Hydroxytryptophan ==> Seratonin ==> N-acetyl Serotonin ==> Melatonin
 
Draw out the reaction, the enzyme and the cofactors required to convert Tryptophan ==> 5-Hydroxytryptophan:
Tryptophan + O2 + BH4 (Tryptophan hydroxylase) ==> 5-Hydroxytryptophan + H2O + BH2
 
Draw out the reaction, the enzyme and the cofactors required to convert 5-Hydroxytryptophan ==> Serotonin:
5-Hydroxytryptophan (dopa decarboxylase: PLP) ==> Serotonin + CO2
 
Draw out the reaction, the enzyme and the cofactors required to convert Serotonin ==> N-acetyl Serotonin:
Serotonin + Acetyl CoA (Serotonin N-acetyl transferase) ==> N-acetyl Serotonin + CoASH
 
"the transfer of an acetyl group to a nitrogen (N-acetylation)"
 
Draw out the reaction, the enzyme and the cofactors required to convert N-acetyl Serotonin ==> Melatonin:
N-acetyl Serotonin + SAM (methyl transferase) ==> Melatonin + SAH
 
"Methyl Transferase is used to methylate the OH group on the indole ring (O methylation)"
 
Describe the inactivation and catabolism of serotonin involving monoamine oxidase (MAO)

  • Serotonin (MAO-A) ==> 5-Hydroxyindoleacetaldehyde + NH3

  • 5-Hydroxyindoleacetaldehyde + NAD+ (oxidation) ==> 5-Hydroxyindoleacetic acid + NADH


 

  • name the urinary product that indicates the amount of serotonin degradation:

  • What type of tumor are you looking for when you are checking these levels?


 

  • The urinary product is 5-Hydroxyindole acetic acid.



  • When you check for 5-Hydroxyindole acetic acid you're checking for carcinoid tumor.



  • The urinary product is 5-Hydroxyindole acetic acid.



  • When you check for 5-Hydroxyindole acetic acid you're checking for carcinoid tumor.

Draw out the Serotonin / Melatonin syntheses and degragation pathway.
Describe the reactions that convert histidine into histamine
 
Histidine is converted to Histamine by Histidine decarboxylase which has a PLP in its active site.  The alpha CO2 is given off.
 
Things to know about Histamine
 

  • Histimine is important in the secretion of stomach acid.  It tells prietal cells to produce more acid. Near them there are cells that make and secrete histamine (ECL - enterochromaffin-like cells)

  • Chromaffin cells are the cells in the adrenal medulla that make epinephrine. Its usually chromaffin cells that become tumorous in pH.

  • ECL makes histamine

  • Histamine goes to the H2 receptors on the parietal cells.  The parietal cells make stomach acid.

  • If there is a blocker of stomach acid, it is blocking the H2 receptor.

  • The reaction that makes stomach acid is the carbonic anhydrase reaction.
    H2O + CO2 ==> H2CO3 ==> H1+ + HCO31- (Stomach acid)

  • At the same time that the prietal cells produce the stomach acid, they secrete HCL at the same time. (Listen to audio to verify this)


 
Things to know about GABA
 

  • Know how to draw γ-Aminobutyric acid (GABA)

  • GABA is an inhibitory transmitter.

  • Neurons that produce and secrete GABA are called GABAergic

  • GABA receptors


    • Allows potassium ions to come out of the neuron. (causes the membrane to hyper polarize)

    • Allows fluoride ions to enter the neuron (causes the membrane to hyper polarize)


  • When you hyper polarize a neurons membrane you make it much less  (LESS OR MORE?) likely that another depolarization will occur to create an action potential.  Hence GABA is an inhibitory neurotransmitter.


 
Tell me about acetylcholine.
 
Describe the synthesis and inactivation of acetylcholine.

  • Acetylcholine works at the neural muscular junction which tells the muscle cell to contract.
    These acetylcholine receptors allow sodium ions to flow in.

  • Your bodies ability to make choline.

    • phosphatidyl serine ==> CO2 + phosphatidyl ethanolamine

    • phosphatidyl ethanolamine + 3SAM ==> phosphatidyl choline +3SAH

    • phosphatidyl choline + acetyl CoA (choline acetyltransferase)==> acetylcholine + CoA

    • acetylcholine (Acetylcholinesterase) ==> choline + acetic acid



  • Phosphatidyl choline is lecithin

  • Choline acetyltransferase catalyzes the ester bond between acetyl CoA and Choline

  • Acetylcholinesterase catalyzes the hydrolyses reaction in acetylcholine.


 
Draw out the synthesis and degragation pathway of acetyl choline along with the chemical structures of all the components.
 
Draw the synthesis of nitric oxide (NO).
What are the three type of enzymes that produce NO synthase and which cells make them?

  • Endothelial cells: Endothelial NO synthase (activated by Ca2+)

  • Neurons: Neuronal NO synthase (activated by Ca2+)

  • Immune cells such as neutrophils: Inducible NO synthase


  • Describe the importance of NO in the respiratory burst of a phagocytic cell

  • Mention the role of NO as a neurotransmitter

  • Describe the mechanism of nitric oxide’s action in vasodilation.


 

  • NO synthase is a flavo protein

  • BH4 is required for the hydroxylation of aeromatic amino acids and NO synthase

  • Endothelial cells have an enzyme to produce NO. Some neurons and many cells of the immune system such as neutrophils.  Cells involved in inflammation.

  • They don't use exactly the same enzyme.  They all have their own version of nitric oxide synthase.

  • Endothelial cells - Endothelial NO synthase (activated by Ca2+)

  • Stimulator molecule might raise the level of Calcium ion inside the endothelial cell.  Calcium stimulate endothelium and neuronal NO synthase.

  • The stimulator molecule can be acetyl choline from a parasympathetic nervous system. (post ganglionic)

  • Some acetyl receptor are coupled to a G protein that will activate phospho lipase C. Phospho lipase C breaks some membrane some membrane phospholipid molecules into a couple of secondary messengers.  One is IP3, IP3 opens up doorways for Calcium ions, letting calcium ion concentrate increase.  This will lead to a rise in calcium ion which will activate endothelial NO synthase.

  • The NO stimulates the Guanylate cyclase which catalyzes a reaction which makes cGMP.  cGMP activates a protein kinase called protein kinase G. Protein kinase G phosphoralates some proteins that lead to a level of calcium ions in that smooth muscle cell decreasing and causing relaxation.

  • Acetyl choline is the most common neurotransmitter from post ganglionic neurons of the parasympathetic nervous system.

  • Neurons - Neuronal NO synthase (activated by Ca2+). NO is a retrograde neurotransmitter (NT).  It is the post synaptic neuron that has the Neuronal NO synthase.

  • The NO is associated with long term memory

  • The cells of the immune system such as the neutrophils have an inducible version of NO synthase - Inducible NO synthase.

  • The control of this is by induction.  The cells that has been stimulated to participate in inflammation produces more NO synthase enzyme.

  • Inside the neutrophil there is an inducible NO synthase.  Because of the bacterial infection the neutrophil is stimulated to increase its production of NO synthase.  The NO is able to kill the bacteria. The neutrophil will wrap its membrane around the bacteria and begin the phagocytosis process.


 

Describe / Draw amino acid metabolism in the liver

  • Describe the fates of the carbon skeletons of amino acids in the liver.

  • Describe the fate of amino acid nitrogen in the liver.


 
The carbons of the amino acids are used for 3 things


  • To make fat

  • To make ketone bodies

  • Used for gluconeogenesis to make glucose


The nitrogens of the amino acids end up in the urea cycle




  • Describe how amino acid metabolism in the liver after a high protein meal resembles amino acid metabolism in the liver in the fasting state.

  • Describe the effects of a high protein meal on the levels of glucagon and insulin.

  • Describe how an increase in the carbohydrate content of the meal would change this.


 

  • When fasting gluconeogenesis is feeding everyone.

  • When you eat a protein meal insulin signals increase but not enough that glycolysis is going to happen because there isn't enough carbohydrates to make that happen.

  • Protein synthesis keeps happening because amino acids are coming in but the insulin signals are not going up enough to make it so that gluconeogenesis stops.

  • A high protein meal does not effect glucagon or insulin much.

  • If you have carbohydrates the insulin levels would go up enough to trigger glucagon to go down.  This would switch the action of the liver from gluconeogenesis to glycolysis.


 
Name the branched chain amino acids
 

  • Valine

  • Leucine

  • Isoleucine


 
Describe the oxidation of branched chain amino acids (BCAA) in skeletal muscle

  • Transamination reaction => α-keto acid

  • Then using oxidative carboxylation, you are going to get NADH and CO2

  • Eventually valine is going to propionyl CoA which goes to succinyl CoA which makes it glucogenic.

  • Isoleucine can go either way to Acetyl CoA or propionyl CoA.

  • Leucine goes to Acetyl CoA or acetyl acetoacetate (they are both keto genic)


 
Explain why the liver cannot catabolize BCAA significantly.
 
The liver doesn't have branched chained amino acid transaminase therefore it can't oxidize BCAA fully.
 

  • Draw the chemical structure of glutamine.

  • Describe the conversion of branched chain amino acids (BCAA) into glutamine.

  • Describe the route by which the carbons from valine or isoleucine can become the carbons of glutamine.

  • Explain how (describe the route by which) the nitrogens from BCAA can become nitrogens of glutamine.


 

 

  • The conversion of BCAA into glutamine involves the α-KG (left side of figure 42.10)

  • The carbons from valine or isoleucine can become carbons of glutamate by going through the TCA cycle. (bottom entrance in figure 42.9)

  • Nitrogens from BCAA become nitrogens of Glutamine (right side of figure 42.10)


 

  • Describe the turnover of cellular proteins. 

  • Include descriptions of both lysosomal protein turnover and the ubiquitin-proteasome pathway.


 
There are two ways to do this:

  • Lysosome pathway - Used hydrolysis to degrade the protein chain. The enzymes in the lysosome pathway are either proteases or peptidases. An example of a protease is Cathepsins.

  • Ubiquitin-proteasome pathway - You have a 20S proteasome. For this to work you need a PA700 Cap protein and a PA28 protein.
    You start with your 20S proteasome, you need ATP to put a PA70 cap protein on it.  Then you need a PA28 on the bottom. To tag a protein that we want to break down you have to put a tail of ubiquitin on it. Once you have that tail of ubiquitin, it can start being degraded.  Once the protein has been degraded to be small enough you don't need the cap protein anymore.  That phase does not require ATP.  As long as you are using the PA700, you need to use ATP.


 
The sedimentation coefficient is how quickly something sediments (how quickly the protein goes through). That is measured in the number of Svedbergs. Ubiquitin is not destroyed in this reaction, it is recycled.
Describe the changes in hormonal signals that lead to a net degradation of skeletal muscle protein (degradation greater than synthesis) during the fasting state.
 

  • This is facilitated by the ubiquitin pathway.  An increase of cortisol is going to happen and cortisol is going to go to a glucocorticoid receptor. This is going to make a transcription factor by the nucleus that is going to tell the pathway to increase the breakdown of skeletal muscle.  The hormone that does this IS NOT glucagon.  There are no receptors for glucagon in the muscle cells.

  • As you raise your level of cortisol you decrease your level of insulin.  An increase amount of cortisol means you will get an increase protein degradation and decreased protein synthesis.


 
Describe how infection of cells of the uterine cervix with certain types of human papilloma virus (HPV) increases the risk of cervical cancer.

  1. Describe how infection of cells of the uterine cervix with certain types of human papilloma virus (HPV) increases the risk of cervical cancer.

The virus is going to insert its genome into a cell on the cervix.  This will produce a protein that increases the attachment of ubiquitin to a tumor suppressor (P53).  This means that you will have decreased tumor suppression because its ubiquitinated.  With lowered tumor suppression you have an increase risk of cancer.
 
Describe how your kidneys can use the nitrogens from glutamine to excrete acid and help maintain acid-base balance in your body.  Also describe how your kidney cells can use the carbons from glutamine as fuel or for gluconeogenesis.
 

  • Ammonium that you get off the glutamine that would be excreted by the urea cycle can bind to extra protons and be excreted thereby increasing pH.

  • Once you get glutamine using glutaminase going to glutamate, which can also using glutamine dehydrogenase goes to alpha-ketoglutarate.  The α-ketoglutarate can eventually go to glucose in gluconeogenesis, this is all happening in the renal cortex. Glucose can go to CO2 in the renal medulla, that’s using it as fuel.

  • Using the carbons as fuel, glutamine is going to feed into the TCA cycle via α-ketoglutarate.  That’s going to go to OAA which is then using PEPCK is going to get your carbons all oxidized into PEP, which will either go down to pyruvate (to acetyl CoA) or it can go up to gluconeogenesis. 


  • Describe the use of glutamine by your enterocytes.

  • Explain the use of glutamine to support cell division in your intestinal mucosa. 

  • Describe how your enterocytes can use glutamine as a fuel.


 

  • The Glutamine can be used as fuel.  The enterocyte has Malic enzyme which will oxidize your carbons completely to Pyruvate.  Pyruvate can then be converted to Acetyl CoA.

  • Glutamine is the preferred fuel of the cell. Nitrogens are important for the nucleoside synthesis of purines.

  • The nitrogens are used to make purines and pyrimidine which will facilitate the DNA creation needed for cell division.


 

  • Describe the mechanism and benefits of increased protein catabolism in skeletal muscle (usually resulting in a negative nitrogen balance) during a hypercatabolic state such as sepsis.

  • Describe the sources and roles of corticotrop(h)in releasing hormone (CRH), adrenocorticotrop(h)ic hormone (ACTH), and cortisol in this process. 

  • Describe the functions served by the glutamine released from skeletal muscle during sepsis.


 

  • In sepsis your hypothalamis will release CRH (corticotrophin releasing hormone) which will cause the anterior petuitary to release ACTH (adrenocorticotrophic hormone) which causes the adrenal cortex to release cortesol which will cause the ubiquitin protesome process to be induced.

  • Once you get the glutamine, it helps the kidney release ammonia, the nitrogen helps white blood cells.  It is used in macrophages, lymphocytes and fibroblasts.  Glutamine also helps the liver release urea and it has acute phase proteins.  These are proteins which have plasma concentrations that can increase and decrease in response to inflammation.


 

  • Summarize regarding the importance of glutamine to cells of the kidneys, the gut, and cells of the immune system.


 

  • Glutamine for marathon runners to cut down on URI after a marathon.

  • During fasting, glutamine is one of the main sources of fuel for the gut.


 
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