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28 Cards in this Set
- Front
- Back
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Globular Proteins
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Globular Hemeproteins:
*a group of specialized proteins *heme as a tightly bound prosthetic group *of cytochrome: electron carrier *of catalase: part of active site *of Hb and Mb: reversibly bind oxygen |
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Structure and Function of Myoglobin
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*present in heart and skeletal muscle
*a reservoir for O2 and an O2 carrier *a single polypeptide chain (Mb+O2<--> MbO2 *composed of helices A-H **hemoglobin: 4 units **myoglobin: 1 unit |
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Structure and Function of Hemoglobin
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*exclusively in red blood cells
*adult hemoglobin: four polypeptide chains -2 alpha, 2 beta *each subunit has a heme-binding pocket *Hb can transport H+ and CO2 from tissues to lungs *Hb can carry 4 O2 molecules from lungs to tissues *allosteric regulation |
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Quaternary Structure of Hemoglobin
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*Hb tetramer: 2 identical dimers (alpha-beta)1 and (alpha-beta)2
T-Form: deoxy form, taut (tense) -low-oxygen-affinity R-Form: O2 bound, relaxed form -high-oxygen-affinity |
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Allosteric Effects
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*Hb reversibly bind oxygen
*allosteric "other-site" effectors *pO2; pH; pCO2 and 2,3-bisphosphoglycerate *affinity decreases as O2 is bound *lung: high O2 for loading *peripheral tissue: low O2 unloads |
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Bohr Effect
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*the release of O2 from Hb is enhanced when the pH is lowered
*or when the Hb is in the presence of an increased partial pressure of CO2 -decreases oxygen affinity of hemoglobin -stabilized T state |
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Effect of 2,3-bisphosphateglycerol on Oxygen Affinity
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*2,3-BPG: the most abundant organic phosphate in RBC
*synthesized from an intermediate of the glycolytic pathway *decreases O2 affinity of Hb by binding to deoxyHb *stabilized T form *reduces affinity, enables Hb to release O2 **lower pH (ie. lactic acid build up) causes release of O2 into tissue** |
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Binding of CO
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*binds tightly (but reversibly) to the Hb iron
*shifts to the relaxed conformation *bind oxygen with high affinity (220x) *tissue hypoxia and direct CO-mediated damage at the cellular level causes CO poisoning *CO poisoning is treated by 100% oxygen therapy *the effect of CO2 binding: stabilized T form (aka deoxy form) resulting in decrease in its affinity for oxygen |
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Sickle Cell Retinopathy Progression:
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1) peripheral arteriolar occlusions
2) peripheral arterio-venular anastomoses 3) neovascularization 4) vitreous hemorrhage 5) retinal detachment |
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Nomenclature of Enzymes
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*ends in "-ase"
-exceptions: pepsin, trypsin 1) oxidoreductases: catalyze oxidation-reduction rxns 2) transferases: catalyze transfer of C-, N- or P- containing groups 3) hydrolases: catalyze cleavage of bonds by adding water 4) lyases: catalyze cleavage of C-C, C-S and certain C-N bonds 5) isomerases: catalyze racemization of optical or geometric isomers 6) ligases: catalyze formation of bonds between caron and O, S, N coupled to hydrolysis of high energy phosphates |
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Properties of Enzymes
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*protein catalysts that increase the velocity (rate) of a chemical reaction, and are not consumed during the rxn
*ribozymes *Active Sites: -create a 3-D surface complementary to the substrate -the active site binds the substrate, from an enzyme-substrate (ES) complex -ES is converted to an enzyme-product (EP) complex -10^3-10^8 x faster |
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Holoenzymes and Regulation
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Holoenzymes:
*refers to the active enzyme with its nonprotein components *(apoenzyme is inactive) *cofactors: a small organic molecule -cosubstrate: transient association (NAD/CoA) -prothetic group: permanent association (FAD) -often from vitamins Regulation: *activated or inhibited *compartmentalized |
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How Enzymes Work:
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*enzymes provide an alternate, more energetically favorable rxn pathway vs. uncatalyzed
*active sites chemically facilitates catalysis *all chemical rxn have an energy barrier (EA- energy of activation) separating the reactants and the products *for molecules to react, they must contain sufficient energy to overcome the energy barrier of the transition state *an enzyme allows a rxn to proceed rapidly under an alternate rxn pathway with a lower free energy of activation *does not change the equilibrium of the rxn |
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Chemistry of the Active Site
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*a complex molecular machine employing a diversity of chemical mechanisms to facilitate the conversion of substrate to product
*transition-state stabilization: increases the concentration of the reactive intermediate that can be converted to product *the active site can participate in general acid-base catalysis in which amino acid residues provide or accept protons -a histidine at the active site of the enzyme gains (general base) or loses (general acid) protons, mediated by the pKa of histidine in proteins being close to physiologic pH |
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Factors Affecting Reaction Velocity
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*substrate concentration
*temperature *pH Maximal Velocity: the rate of an enzyme-catalyzed rxn increase with a substrate concentration until maximal velocity (Vmax) is reached (saturation) *Michaelis-Menten kinetics: Vo vs [S] = hyperbolic curve allosteric = sigmoid curve |
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Temperature & pH
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Temperature:
*increase of velocity with increased temp *decrease of velocity with higher temp (denaturation) *the optimum temp for most human enzymes is between 35-40 degrees C pH: *effect of pH on the ionization of the active site *effect of pH on enzyme denaturation *the pH optimum varies for different enzymes -pepsin at pH 2 |
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What happened to Topaigne's joints?
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Topaigne's gout is caused by excess depositions of monosodium urate crystals in the joint of her big toe, causing severe pain. At a blood pH of 7.4, all of the uric acid has dissociated a proton to form urate, which is not very water-soluble and forms crystals of the Na+ salt.
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Michaelis-Menten Equation
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Vo = Vmax [S]/Km+[S]
*some assumptions: ES; steady state; Vo *characteristic of Km: Km (the Michaelis constant) reflects the affinity of the enzyme for that substrate *Km = 1/2 Vmax -large Km = lower affinity of enzyme for the substrate |
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Lineweaver-Burk Plot
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*Vo vs. [S], hyperbolic, hard to find exact Vmax
*if 1/Vo vs. 1/[S], straight line is obtained *also called a double-reciprocal plot *calculate Km and Vmax *determine the mechanism of action of enzyme inhibitors **x-intercept = 1/Km **y-intercept = 1/Vmax |
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Competitive Inhibition
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*Km: a competitive inhibitor increases the apparent Km for a given substrate
*Vmax: unchanged |
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Noncompetitive Inhibition
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*Vmax: decrease the apparent Vmax of the reaction
*Km: unchanged |
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Allosteric Modulators
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Vmax and Km are both altered, but it is difficult to predict
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Regulation of Enzymes:
substrate inhibition |
Typical Effector: substrate
Results: change in velocity (Vo) Time for Change: immediate |
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Regulation of Enzymes:
product inhibition |
Typical Effector: product
Result: change in Vmax and/or Km Time for Change: immediate |
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Regulation of Enzymes:
allosteric control |
Typical Effector: end product
Result: change in Vmax and/or Km Time for Change: immediate |
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Regulation of Enzymes:
covalent modifications |
Typical Effector: another enzyme
Result: change in Vmax and/or Km Time for Change: immediate to minutes |
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Regulation of Enzymes:
synthesis or degradation of enzyme |
Typical Effector: hormone or metabolite
Results: change in the amount of enzyme Time for Change: hours to days |
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Case of Topaigne:
How to Manage Gout: |
*allopurinol therapy in an oral dose of 150mg twice per day
-allopurinol is an inhibitor of the enzyme xanthine oxidase, which is involved in the degradation of purine nucleotides AMP and GMP to uric acid *within several days of therapy, serum uric levels decrease *within several weeks, serum uric levels were normal |
