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32 Cards in this Set
- Front
- Back
Regulatory Strategies for Enzymes
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A. Allosteric: distinct regulatory sites
B. Multiple forms of an enzyme C. Reversible covalent modification D. Proteolytic cleavage E. Controlling the amount of enzyme present |
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How much more energy can our cells extract from glucose with oxygen compared to without oxygen?
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In the presence of O2, cells can extract 15X more energy from glucose than when oxygen is absent
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How do cells get adequate oxygen?
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1. Circulatory System
2. Oxygen binding proteins -Myoglobin: oxygen storage (MUSCLE) -Hemoglobin: oxygen transport |
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Myoglobin - what is it? what is its function?
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-a protein expressed in muscle cells
-SINGLE polypeptide chain = MONOMER -reservoir supply of oxygen when needed |
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Hemoglobin: what is it? function?
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-protein in RBCs
-Tetramer: 2alpha, 2beta chains -carries oxygen from lungs to tissues -transports CO2 and H+ from tissues to lungs -chains bind O2 COOPERATIVELY |
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Heme
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-gives red color of blood and muscle
-allows O2 to bind |
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What state is iron in myoglobin/hemoglobin?
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-Ferrous: Fe2+
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Structural changes at iron sites in myoglobin and hemoglobin
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1) Fe2+ binds to 4 pyrrole nitrogen atoms at Heme center
2) 5th coordination site: Fe2+ binds to the imidazole ring of proximal His 3) 6th coordination site: Fe2+ binds O2, changes electronic structure, allows Fe2+ to sit within the plane of the porphyrin in heme -changes magnetic properties, can take advantage of the magnetic properties of the brain and use fMRI! study brain function |
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Reactive Oxygen Species
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-myoglobin's structure inhibits their release
-resonance structures distribute electrons between oxygen and iron -2nd His in O2 binding pocket, donates H bond to O2 --> O2's superoxide ion hcaracter strengthens the bond |
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Myoglobin O2 binding
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-non-cooperative (simple chemical equilibrium)
-P50 = 2 torr |
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Hemoglobin O2 binding
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-COOPERATIVE, sigmoid binding, S shaped, lag before binding occurs
-P50 = 26 torr |
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Allosteric enzymes
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-ADJUST TO MEET THE IMMEDIATE NEEDS OF THE CELL, KEY REGULATOR OF METABOLIC PATHWAYS
-multiple active sites -sigmoid kinetics -can have cooperative binding -regulatory molecules bind to sites other than the active site |
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PO2 tissues
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20 torr
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PO2 lungs
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100 torr
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hemoglobin cooperativity
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-allows delivery of 1.7X more O2 than it would if the sites were independent
-66% drop in saturation (38% if independent, 7% for myoglobin) |
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deoxyhemoglobin
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-T state
-heme groups are well separated -favors non-binding of the substrate |
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oxyhemoglobin
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-R State
-1 pair of alpha/beta subunits rotates 15 degrees with respect to the other upon O2 binding -favors binding of substrate |
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O2 binding: changes hemoglobin structure
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-dimer rearrangement at interface
-communication between subunits enables cooperativity -beta chain movement! -T->R shift allows the binding of O2 to increase the binding affinity at the other sites! |
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Sequential Model
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-As you bind O2 at one site, you increase the binding affinity of neighboring sites
-One site changes from T to R at a time -NOT a full conversion from T to R from one binding |
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Concerted model
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-the overall moecule can only exist in two forms: T and R
-binding O2 shifts the equilibrium between the two states -when 2/4 are bound, equal likelihood of R and T |
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Actual cooperative binding of O2 to hemoglobin
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-Sequential when 1/4 occupied
-remains in T state -binds O2 3X stronger than when fully de-O2 -Concerted when 3/4 occupied -exists in R state -binding of 4th O2 --> 20X more affinity than when fully de-O2 |
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2,3-BPG
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-DECREASES O2 AFFINITY FOR HEMOGLOBIN
-2,3-bisphosphoglycerate -works at the interface between B1 and B2 chains -same concentration in RBCs as hemoglobin (~2mM) -binds preferentially to adult deoxyhemoglobin, stabilizes T form |
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Fetal hemoglobin
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-2alpha, 2 gamma (gene duplication of the beta chain)
-gamma has 2 fewer positive charges in 2,3-BPG binding site b/c: Ser substitution at His 143 --> reduced affinity for 2,3-BPG, therefore increased affinity for O2 *efficient transfer of O2 from maternal to fetal RBCs* |
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Bohr Effect
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-hydrogen ions and CO2 increase O2 transporting efficiency
-Proton Effect: favors O2 release -CO2 effect: favors O2 release |
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Bohr Effect: Proton
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-acidic pH: amino termini and His side chains are protonated, which locks His beta 146 in a salt bridge with Asp 94
-basic pH: His beta 146 is deprotonated and will not form a salt bridge with Asp 94 |
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Bohr Effect: CO2
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-CO2 reacts with primary amines to form carbamate groups
--> salt bridges within hemoglobin! -stabilize the T state -carbamate groups are at the interface of alpha/beta dimers |
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How is CO2 transported in the blood?
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86% as bicarbonate
14% as carbamate |
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Sickle Cell Anemia
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-HbS: Val6 instead of glutamate on beta chain
-fibrous aggregates spanning RBC -clog small capillaries and impair blood flower -reduced life span --> anemia -DeoxyHbS has low solubility |
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Sickle cell trait
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-one copy of HbB, one copy HbS
-resistant to malaria -malaria caused by plasmodium falciparum |
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alpha-thalassemia
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-HbH: alpha chain not produced at sufficient quantities
-binds O2 with high affinity and no cooperativity |
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beta-thalassemia
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-thalassemia major or Cooley anemia
-beta chain is not produced at sufficient quantities -alpha chains form insoluble aggregates, precipitate inside immature RBC |
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AHSP
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-alpha-hemoglobin stabilizing protein
-binds to deoxy and oxy alpha-hemoglobin on the same face at beta-hemoglobin -beta hemoglobin displaces AHSP when it is present |