Seminar III: Biological Molecules Sue Werness, PhD.
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Transcript of Seminar III: Biological Molecules Sue Werness, PhD.
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Seminar III: Biological MoleculesSue Werness, PhD
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•Proteins•Sickle Cell Anemia
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What Do You Know About Hemoglobin?
What kind of biomolecule is it? Carbohydrate? Nucleic Acid? Protein? Lipid?
What does it do?What kind of cells have hemoglobin molecules?
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Manufacturing a Protein?
How do you manufacture a protein?
Step 0: Where does the blueprint for a protein come from?
Step 1: How are the basic components of proteins put together? The components of proteins are synthesized into long chains (polypeptides) with the help of an enzyme (helper, catalyst).What are these basic components of proteins?
Step 2: How does a fully functional protein get made from simple chains of these components?
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Manufacturing a Protein?
How do you manufacture a protein?
Step 0: Where does the blueprint for a protein come from? Central Dogma: DNA -> RNA -> Protein
Step 1: How are the basic components of proteins put together? The components of proteins are synthesized into long chains (polypeptides) with the help of an enzyme (helper, catalyst).What are these basic components of proteins?
Step 2: How does a fully functional protein get made from simple chains of these components?
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Manufacturing a Protein?
How do you manufacture a protein?
Step 0: Where does the blueprint for a protein come from? Central Dogma: DNA -> RNA -> Protein
Step 1: How are the basic components of proteins put together? The components of proteins are synthesized into long chains (polypeptides) with the help of an enzyme (helper, catalyst). What are these basic components of proteins? Amino acids
Step 2: How does a fully functional protein get made from simple chains of these components?
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Manufacturing a Protein?
How do you manufacture a protein?
Step 0: Where does the blueprint for a protein come from? Central Dogma: DNA -> RNA -> Protein
Step 1: How are the basic components of proteins put together? The components of proteins are synthesized into long chains (polypeptides) with the help of an enzyme (helper, catalyst).What are these basic components of proteins? Amino acids
Step 2: How does a fully functional protein get made from simple chains of these components? Assemble the pieces (polypeptides) togetherAdd finishing touches such as sugars or phosphatesFold into the correct shape
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What Is an Amino Acid?The carboxyl (COOH) and amino (NH2) groups are
components of every amino acid. Wolfe described an amino acid as consisting of a central C (carbon) with 4 components attached.
What are the other 2 components attached to the central carbon?
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What Is an Amino Acid?The carboxyl (COOH) and amino (NH2) groups are also
components of every amino acid. Wolfe described an amino acid as consisting of a central C (carbon) with 4 components attached.
What are the other 2 components attached to the central carbon?H atomR group that depends on the specific amino acid20 different amino acids
R|
NH2 - C – COOH
|H
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Functions of ProteinsList several functions or roles of proteins in cells.
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Protein FunctionsList several functions or roles of proteins in cells. Enzymes – to catalyze reactions Support – collagen, keratin Contraction - muscle Hormones - insulin Receptors – recognizes signals Storage – milk, egg white Defense - antibodiesTransport - hemoglobin
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Protein StructureFor proteins, shape is key to their proper functioning.
Explain the 4 levels of protein structure (shape):Primary?
Secondary?
Tertiary?
Quaternary?
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Protein StructureFor proteins, shape is key to their proper functioning.
Explain the 4 levels of protein structure (shape):Primary? Unique sequence of amino acids in the polypeptide,
determined by DNA
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Protein StructureFor proteins, shape is key to their proper functioning.
Explain the 4 levels of protein structure (shape):Secondary? results from hydrogen bonding between amino
acids within the polypeptide chain and leads to regular patterns such as alpha-helixes and beta-pleated sheets
HN
NH
HN
O
O
O
NH
HN
HNHN
O
O
O
NH
HN
HO
O
O
O
H2N
O
Beta Pleated Sheet
Alpha Helix
Hydrogen Bonds
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What is Hydrogen Bonding?YOU are experts in hydrogen bonding!
Have you ever seen a drop of water?Have you ever seen ice?
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Protein Structure, Polar Molecules and Hydrogen Bonding
Polar molecules are formed when atom of high electronegativity bonds with atoms of smaller electronegativity
Molecule forms locally charged areas
Oxygen
HydrogenHydrogen
Oxygen
Negative Pole
Positive Pole
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Hydrogen bond
Opposite charges attract!
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Protein StructureFor proteins, shape is key to their proper functioning.
Explain the 4 levels of protein structure (shape):Tertiary? 3-D shape of a protein caused by interactions
between R groups3-D Shape achieved by folding via proteins called Chaperonins
Polypeptide enters
Chaperonin
Protein exits Chaperonin
1 2 3
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Protein StructureFor proteins, shape is key to their proper functioning.
Explain the 4 levels of protein structure (shape):Quaternary? three-dimensional shape of a protein caused by
linking together of multiple polypeptides
http://commons.wikimedia.org/wiki/File:Hemoglobin_structure.JPG
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What Happens if the Protein Has a Single Amino Acid in Error?
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What Happens if the Protein Has a Single Amino Acid in Error?
DNA point mutation causes 1 error in primary structureIn general, primary structure errors can devastate
secondary, tertiary, and quaternary structureProteins are like tools; they have to be the correct shape
for the job or they don’t work at all!
Using the right tool Using the wrong tool
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Any Questions So Far?
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How Does Sickle Cell Disease Occur?How do you “catch” the disease?What is the difference between sickle cell disease (SCD or
SCA) and sickle cell trait (SCT)?
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NormalSC Trait SC DiseaseSC TraitNormalCarrier Carrier
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What happens to the protein hemoglobin in SCD?
What does it have to do with protein structure?Just 1 amino acid substitution
What amino acid is replaced with what amino acid on -hemoglobin? Normal :
Sickled:
Impact on secondary, tertiary, quaternary structure?Impact on overall properties of hemoglobin?
Val HisLeu
Thr Pro Glu Glu……
Val HisLeu
Thr Pro Val Glu……
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Hemoglobin in Sickle Cell DiseaseHemoglobin consists of 4 polypeptides, 2 -hemoglobins and 2 -
hemoglobins interlocked together in quaternary protein structureThe 4 polypeptides stick to each other in hemoglobin complex and do not
NORMALLY interact with one another In SCD, -hemoglobin has 1 wrong amino acid and this affects primary,
secondary and tertiary structure
Normal hemoglobin does not interact with
each other
Abnormal hemoglobin sticks together and
forms crystals when in low oxygen
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It Gets Even Worse!Hemoglobin polymerizes into sticky strings and
distorts red blood cell shape into a sickled shapeSickling causes potassium and water to flow out of cell
Causes cell dehydrationCell sickles even more
Sticky stringy hemoglobin does not carry nitric oxide readilyNitric oxide has recently been discovered to be important
blood gas that RELAXES the capillaries and lets the RBCs though*
Normal hemoglobin carries nitric oxide as well as oxygenOxygen doesn’t get to tissues -> causes MORE polymerization
of Hemoglobin (happens in low O2 environment) *John R. Pawloski, Douglas T. Hess, and Jonathan S. Stamler, Impaired vasodilation by red blood cells in sickle cell disease.
PNAS 2005 102:2531-2536; published online before print February 7, 2005, doi:10.1073/pnas.0409876102
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RBC(with HbS)
GardosPotassium Ion Channel
↑ Dense / sickled cells↑ Hemolysis
↓ Hemoglobin (Anemia)
Clogging of arteriesand capillaries in tissues= PAIN and ORGAN Damage
H2OK+
Dense/Sickled RBC
K+
H2O
Dehydrated, hypersicklable RBC
Deoxygenation
↑Ca++
Stiff Capillaries
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History of Sickle Cell Trait/DiseaseAny questions so far?Get ready for a 5 minute “field trip”http://www.pbs.org/wgbh/evolution/library/01/2/l_012_02.html
1.Click on Information2.Open new browser window
1. When http address is pasted into chat, select it, and then control-C to copy
2. Control - v (paste) into address bar of new browser windowWhen you get to the Evolution page, click on QuickTime OR
Real Player -> video in upper right corner
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USA - 2,000,000 African Americans have SCT (8%)Africa – 20% have SCT
http://en.wikipedia.org/wiki/File:Malaria_distribution.jpg
Historical distribution of malaria (no longer endemic in Europe) shown in green
http://en.wikipedia.org/wiki/File:Sickle_cell_distribution.jpg
Distribution of the sickle-cell trait shown in pink and purple
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http://en.wikipedia.org/wiki/File:Paludisme_-_Frequence_statistique.png
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Consequences to Body of Hemoglobin Mis-folding?
Two kinds of things happen to red blood cells (RBCs) as a result of the “bad” hemoglobinSickled cells lyse (break apart) and die after only 10 – 20 days –
consequences?Sickled shape cells clog and stick to stiffened blood vessels –
consequences?What organs are affected by these maladies and how are
they affected?What symptoms occur?
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Consequences of Early RBC Lysis and Death
Anemia – Low Red Blood Cell (RBC) countsNot enough RBCs to carry oxygen to tissuesSymptoms: fatigue, dizziness, weakness, fast pulseConsequences: Slow growth (children), risk of pulmonary hypertension
Bone marrow tries to keep making more red blood cellsBone marrow can sometimes quit (aplastic anemia) after viral infection
Several organs are overwhelmed by job of cleaning up after destroyed red blood cellsSpleen can become clogged with debris and eventually destroyed
RBCs blocked from getting to organs, extreme weakness, can result in death Consequence: Spleen is part of immune system; ability to fight infections
compromised -> Leads to Acute Chest Syndrome (infections) Most common cause of death is infection
Liver can become jaundiced and blocked with RBC debrisKidneys can become overloadedGall bladder can form gallstones, can become inflamed
From Mayo clinic web site: Sickle Cell Anemia (2009). Retrieved September 4, 2009 from http://www.mayoclinic.com/health/sickle-cell-anemia/DS00324From Harvard web site: Sickle Cell Disease(2007). Retrieved August 24, 2009 from http://sickle.bwh.harvard.edu/menu_sickle.htmlFrom WebMD web site: Sickle Cell Disease (2008). Retrieved September 4, 2009 from http://www.webmd.com/a-to-z-guides/sickle-cell-disease-topic-overview
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Consequences to Body of Hemoglobin Mis-folding?
Two kinds of things happen to red blood cells (RBCs) as a result of the “bad” hemoglobinSickled cells lyse (break apart) and die after only 10 – 20 days –
consequences?Sickled shape cells clog and stick to stiffened blood vessels –
consequences?What organs are affected by these maladies and how are
they affected?What symptoms occur?
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Consequences of Clogged Stiff Capillaries and Arteries
Brain - strokes (kill children), aneurysmsEye retinas - retinal bleeding, blindnessJoints – frequent sites of PainBones – death of bone tissue, deformity, pain, osteoporosisHeart – damage to heart tissueLungs
Acute chest syndromePulmonary hypertension
Genitals – priapism (long lasting erection)Hand-foot syndrome – swelling, pain in hands, feet from
joint damageLegs – skin ulcers
From Mayo clinic web site: Sickle Cell Anemia (2009). Retrieved September 4, 2009 from http://www.mayoclinic.com/health/sickle-cell-anemia/DS00324From Harvard web site: Sickle Cell Disease(2007). Retrieved August 24, 2009 from http://sickle.bwh.harvard.edu/menu_sickle.htmlFrom WebMD web site: Sickle Cell Disease (2008). Retrieved September 4, 2009 from http://www.webmd.com/a-to-z-guides/sickle-cell-disease-topic-overview
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Can You Be Sick and Die With Sickle Cell Trait?
People with sickle cell trait usually have no symptomsBut - Athletes have died because of intense exercise
inducing sickle cell crises (low oxygen -> death of spleen tissue, rapid breakdown of muscle tissue and renal failure)Risk of sudden death during exercise is ~15% higher with SCTSome not aware they have sickle cell trait2010 Fall – All Division I athletes will undergo screening for
sickle cell trait Worry that false positives won’t be followed up Worry that athletes won’t receive genetic counseling Will they get discrimination because of positive results?
Should there be such a screening program?Johns Hopkins Medical Institutions (2010, September 21). New sickle cell screening program for college athletes comes with serious
pitfalls, experts say. ScienceDaily. Retrieved September 22, 2010, from http://www.sciencedaily.com/releases/2010/09/100908171120.htm
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Any Questions So Far?
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Risk/Benefit Analysis of Established Treatments
Symptom ManagementPain medication for painful crisesAntibiotics for infectionVaccines to prevent infectionsTransfusions for short term “correction”Oxygen for breathing difficulties
Disease Modifying DrugsHydroxyurea
CuresBone marrow transplant
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Risk/Benefit Analysis of Established Treatments
Symptom ManagementPain medication for painful crises; possible addiction, possible
under-medication?Antibiotics for infection; possible antibiotic resistance?Vaccines to prevent infections; possible reactions to vaccines?Transfusions for short term “correction” and prevention; possible
iron overload, risk of hepatitis?Oxygen for breathing difficulties
Disease Modifying DrugsHydroxyurea
CuresBone marrow transplant; risk, lack of siblings with matching
tissue, cost
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Hydroxyurea TreatmentTreatment Effects
Boosts production of fetal hemoglobin from bone marrowIncreases destruction of sickled cells
Side EffectsLow white blood count, damage to bone marrowPossible leukemiaVomitingBreaks chromosomes
from Hydroxyurea for Sickle Cell Patients (2008). Retrieved from Web site of News-Medical.Net - Latest Medical News and Research from Around the World. http://www.news-medical.net/news/2008/02/28/35770.aspx http://www.rxlist.com/droxia-drug.htm
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Hydroxyurea TreatmentTreatment Effects and Benefits
Boosts production of fetal hemoglobin from bone marrowIncreases destruction of sickled cells
Side Effects/RisksLow white blood count, damage to bone marrowPossible leukemiaVomiting and other digestive disordersRashesChromosome damage
from Hydroxyurea for Sickle Cell Patients (2008). Retrieved from Web site of News-Medical.Net - Latest Medical News and Research from Around the World. http://www.news-medical.net/news/2008/02/28/35770.aspx http://www.rxlist.com/droxia-drug.htm
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Experimental TreatmentsGene therapy
Putting correct gene in bone marrow Turning off “bad” gene and activating gene to generate only fetal hemoglobin
Butyric Acid – food additive that may boost fetal hemoglobinL-Glutamine – amino acid keeps sickled cells from sticking to veinsClotrimazole – anti-fungal medicine that may prevent dehydration
and sickling of red blood cellsNitric Oxide – may reduce sickle cell clumping, may help Hb bind
oxygen Medical College of Georgia (2010, October 19). Inhaling nitric oxide eases pain crises in sickle cell patients, researchers find. ScienceDaily. Retrieved October 20, 2010, from http://www.sciencedaily.com/releases/2010/10/101019121758.htm
Nicosan – herbal treatment from Nigeria, mixture of 4 Nigerian plants, nontoxic, company in bankruptcy, not approved in the US
From Mayo clinic web site: Sickle Cell Anemia (2009). Retrieved September 4, 2009 from http://www.mayoclinic.com/health/sickle-cell-anemia/DS00324
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A Phase III, 52-Week, Randomized, Double-Blind,
Placebo-Controlled Study of the Clinical Efficacy and Safety
of ICA-17043 with or without Hydroxyurea Therapy in
Patients with Sickle Cell Disease
Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia, Ataga, Kenneth, et. al. BLOOD, Volume 111( 8): 3391-3397, 2008.
SURPRISING RESULT
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Potential of Ion Channel Blocking Drug• Hypothesis: Blocking of Gardos potassium ion
channel with a novel ion channel blocker drug can reduce dehydration, hemolysis, and sickling of RBCs in sickle cell disease (SCD) and lead to clinical improvement.
New drug should reduce anemia, reduce clogging
Fewer painful crises
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RBC(with HbS)
GardosPotassium Ion Channel
↑ Dense / sickled cells↑ Hemolysis
↓ Hemoglobin (Anemia)
Clogging of arteriesand capillaries in tissues= PAIN and ORGAN Damage
H2OK+
Dense/Sickled RBC
K+
H2O
Dehydrated, hypersicklable RBC
Deoxygenation
↑Ca++
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↑ Hemoglobin (Improvement in anemia)
↓ Dense / sickled cells
↓ Hemolysis
RBC(with HbS)
KK++
Normal Density RBC
Blocks Gardos potassium channel
Prevents dehydration and formation of dense / sickled cells
Hopefully less SCD PainIt works
It works
It didn’t work!!
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Conclusions Concerning Novel Ion Channel Blocker Drug
Ion Channel Blocking Drug Caused a reduction in indicators of hemolysis (cells breaking down)Caused the red blood cells to have a normal round shapeCELLS WEREN’T SICKLED; DIDN’T BREAK DOWNArteries and capillaries shouldn’t have clogged!
Ion Channel Blocking Drug failed to reduce crisis rates in patients with SCDPATIENTS STILL IN PAIN
CLINCAL TRIAL WAS STOPPED
Why didn’t it work?
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Why Ion Channel Blocker May Have FailedIon channel blocker LOWERS nitric oxideSo, even though Ion channel blocker un-sickles the red
blood cells, they may NOT be able to “smooth” their way through the small arteries ---- Clogging still occurs
Painful crises still occurIf the ion channel blocker INCREASED nitric oxide, would
it have worked?Books describing sickle cell anemia do not
portray entire picture
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Alternative Treatment of Sickle Cell Disease
Arginine (amino acid) used by the body to make nitric oxidePossible diet treatment for sickle cycle disease
Arginine found in peanuts, cashews, walnuts, brazil nuts, coconut, seafood, chocolate, soybeans, chickpeas
Arginine found to be helpful for some cardiovascular conditions such as angina
Ongoing clinical trial testing arginine in acute chest syndrome Arginine Treatment of Acute Chest Syndrome (Pneumonia) in Sickle Cell
Disease Patients Clinical Trial NCT00029731 Retrieved September 6, 2009 from NIH Clinical Trials Web site at
http://clinicaltrials.gov/ct2/show/NCT00029731
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Lifestyle Management of SCD?
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Lifestyle Management of SCD?Take folic acid (bone marrow needs folic acid to keep
manufacturing red blood cells)Drink lots of water – keeps blood dilute and reduces chance of
sicklingAvoid stressModerate exercise but NOT heavy exercise!Avoid low oxygen environments such as high altitudes and
non-pressurized airplanes, cigarette smokeAvoid OTC medicine – especially pseudoephedrine or anything
that constricts blood vesselsPrevent infections with vaccines, hand washing, careful food
preparation, chronic use of antibiotics in children
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Prevention of SCD?
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Prevention of SCD?Genetic diseaseGenetic counselingPreimplantation genetic diagnosis.
Eggs from the mother fertilized with sperm from father.Fertilized eggs are tested for sickle cell gene and those free
of the sickle cell gene are implanted into the mother’s womb
Expensive , always successful.
From Mayo clinic web site: Sickle Cell Anemia (2009). Retrieved September 4, 2009 from http://www.mayoclinic.com/health/sickle-cell-anemia/DS00324