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153 Cards in this Set
- Front
- Back
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Thrombus
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Medical term for clot
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Thrombin (factor IIa)
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enzyme that converts fibrinogen to fibrin
-activated via factor Xa and cofactor Va (from prothrombin) |
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Factor VII
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integral membrane protein that is a member of immunoglobin super family called tissue factor
-Begins extrinsic pathway |
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Factor XII (Hageman factor)
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starts intrinsic pathway
binds to negative surface activated form XIIa |
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Serine Proteases in hibited by AT-III heparin complex
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IXa,Xa,XIa,XIIa, VIIa, IIa (thrombin)
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Warfarin
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blocks gamma carboxylation (vit k dependent) of prothrombin II, VII, IX, X
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prothrombin time
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measures extrinisic pathway, inhibited by warfarin
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activated thromboplastin time-
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measured intrinsic pathways, inhibited by heparin
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Platelets
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measured by platelet function
should be 50,000 per mm^3 binding to COX 1 prevents platelet activation half life is 10 days |
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vitamin k
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post translational mod
adds an additional carboxyl to glutamic side chains forming gamma-carboxyglutamic acids (Gla) |
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Gla
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gamma-carboxyglutamix acids
binds to Ca2+ (which anchors proteins to phospholipid membranes of platelets at site of injury) |
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Warfarin
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coumadin
prevents post trans resulting in Gla inihibits enzyme responsible for reduction of Vit K inhibits the extrinsic pathway the most |
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phospatidyserine
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usually on cytoplasmic side, but on outer surface of activated platelet
sticks to Ca+2 on Gla domains |
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heparin
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activates anti thrombin II (ATIII)
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ATIII
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Serine protease inhibitor (Serpin)
Arg at its inhibitor site |
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Alpha I At Pittsburgh
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results in hemophilia
Met to Arg thrombin inhibiting without heparin activation |
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Plasmin
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degrades fibrin, activated by tissue plasminogen activator(actually binds to fibrin)
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Henderson Hasselback
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ph = pka + log (base/acid)
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Isoelectric point
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pI = pka1 + pka2 /2
net charge is zero |
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Ionization of AA
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Carboxyl is ionized first
Amine group next side chain dependent on pka |
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pka
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1/2 of protons have been removed from that group
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cysteine to cystine
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via oxidation forming disulfide bonds
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AA light absorption
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trp>tyr>phe
(phe is greater than tyr @ 200) |
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Kinases
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phosphorylate proteins
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Orthinine
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not coded for my dna and not used to make protein
(hydrolysis of arginine -->orthinine and urea |
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Sickle cell AA mutation
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glu to val
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Hydrophobicity of AA
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large aromatics are most hydrophobic, most acidic are least hydrophobic
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Proteome
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complement of proteins expressed by a genome
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peptide bond
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amide linkage, 50% double bond character(cant rotate)
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Trysin
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clease Arg and Lys groups
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Non redundant AA
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Met (start codon-ATG)
Trp |
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Secondary protein structure stabilized by
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hydrogen bonds (h on Alpha amino and o on carboxyl)
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Alpha helix characteristics
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3.6 residues/turn
R groups point outward prolines disrupt helix ex. wool majority of hemaglobin |
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Beta sheet
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R groups are above an below
small R groups ex. silk majority of trypsin |
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Tertiary structure stabilized by
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h bonds, salt bridges,hydrophobic interactions,disulfide bonds,van der waals
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4 protein structure
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2 or more polypeptide chains
h bonds,salt bridges,hydrophobic,van der waals |
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Proteins with Ig domains
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MHC, CD4, Titin
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Physical denaturation
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loss of 2,3,4 structure
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chaperonins
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heat shock proteins
protect newly formed proteins from proteolysis and facilitate correct folding |
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Disulfide isomerases
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enzymes that break and form disulfide bonds to ensure correct s-s links needed for stability
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Kcat
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Turnover number
number of substrate transformed per unit of enzyme when the enzyme is fully saturated with the enzyme |
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Trypsin cleaves...
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carboxyl side of Lys or Arg
(negative arg at binding site forms salt bridges with these two) |
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Chymotrypsin cleaves...
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carboxyl side of aromatic AA
(the more hydrophobic and longer...the better substrate it is) |
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Thrombin cleaves...
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between Arg and Gly
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Elastase cleaves...
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after Gly or Ala
(narrowed binding pocket due to Vals) |
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Enzyme characteristics
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Stereospecific
compartmentalized |
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Enzymes Thermodynamically
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Lowers free energy of activation(lower the energy of the transition state)
Free energy of overall rxn stays the same They increase the rate at which eq. is attained |
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Enzymes Chemically
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stablize transition states of substrates
Active sites provide groups that aid in the formation of the transition state |
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Vmax
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enzyme is in ES form
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Effects on rate
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Increasing temp, increases rate
PH dependent |
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Michaelis Menten Equation
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V0=(vmax [s])/Km + [S]
Vo: initial rxn velocity Vmax: maximal velocity |
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Km
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Michealis constant
substrate concentration @ 1/2 Vmax Measure of enzymes affinity to substrate Best sustrate have low Km |
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Kcat/Km
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gives catalytic efficiency
How fast a substrate is processed and how well it binds to an enzyme |
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Lineweaver Buerke plot
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1/Vo by 1/[S]
X axis: -1/Km Y axis: 1/Vmax slope: Km/Vmax best to analyze inhibitors on enzymes |
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Competitive inhibitor effect on kinetics
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Km changed
Vmax unchanged |
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Non competitive inhibitor effect on kinetics
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Vmax decreased (increasing S cannot overcome inhibition)
Km unchanged binds to the E or the ES |
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Non competitive inhibitor
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Bind to both free enzyme and ES complex
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COX1
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Need for blood platelets to make thromboxanes
Irreversibly inhibited by aspirin |
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Phospotases
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dephoosphorylate
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Keratins
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2 alpha helix colied to make a protofibril which twist to make microfibril
in skin, nails and hair alpha keratin (hair) is rich in S-S bonds |
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Collagen type I
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found in skin, tendon and bone
2 alpha 1, 1 alpha 2 subunits fibril structure |
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Location of Collagen type II
type III, IV |
found in cartilage
cardiovascular system basement membrane (mesh like) |
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Structure of collagen
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Triple helical
1/3 glycine (on inside, allows close packing) 1/4 proline (stabalizes collagen) contain HyP (hydroxyproline) and HyK(hydroxylysine) |
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Biosynthesis of collagen
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1.synthesis of pro alpha chain
2. hydroxylation of pro and lys 3. glycosolation of HyLys 4.Procollagen triple helix formation (from C terminal) 5. Secretion out of er/golgi 6. cleavage of propeptides (end) via procollagen propeptidases 7. tropocollagen self assembly into fibril 8. aggregation to form fiber |
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collagen fibril assembly
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quarter staggered array (tensile strength)
covalent cross link |
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Ehlers Dahlos VII
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hyperextensible joints and stretchy skin
abnormal N terminal procollagen peptidase (deletion) long tropocollagen prevents tight stacking and crosslink |
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Ehlers Dahlos IV
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type 3 collagen
ruptured arteries and bowel |
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Ehlers Dahlos VI
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deficiency in lysylohydroxylase (reduction in HyLys)
joint hypermobility and ocular rupture |
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Scurvy
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oxygen and Vit C are required for correct formation fo prolxl hydoxylase and lysyl hydroxylase (hydroxylate Pro and Lys)
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Carb chains on collagen
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attach to HyLys on OH groups
makes collagen more hydrophilic (only collagen contains HyLys) diff types of collagen have diff numbers of CHO chains |
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HyPro
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Stabilizes triple helix of collagen
increase Tm |
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Menkes Disease
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failure to properly transport Cu 2+ (needed for lysyl oxidase rxn), not able to crosslink, weak collagen and fragile bones
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HyLys
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improves crosslinking
reduced in ED type VI |
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Osteogenesis Imperfecta
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mutations resulting in replacement of gly with bulky groups (helix cant wind as tight)
Mutations at C terminal more severe (where winding begins) |
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Elastin
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minor amt of HyPro (No HyLys)
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desmosine
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in elastin
crosslinks formed from 4 lysine residues btwn two peptide chains |
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Fibrillin
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in elastic tissue
defect causes Marfans Syndrome |
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proteoglycans
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convalently linked glusoaminglycans
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Glycosaminglycan carb chains
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very hydrophilic (carboxyl and sulfate groups)
added sulfates make these more hydrophilic |
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ECM protein binding
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Collagen binds to fibronection and laminin --> attach to cell membrane via Integrins -->bind to RGD motif
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Heme/Hemin effect on porphyrin synthesis
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negative feedback inhibition
stops synthesis of glycine a succinyl COA to ALA (not directly, actually decrease g-ALA synthesase mRNA stability/synthesis) |
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Lead effect on pophyrin synthesis
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1. non competitive inhibitor that prevents dehydration of ALA to porphobilinogen (inhibits g-ALA dehydrogenase)
(leads to increased levels of ALA and anemia) 2. non competitive inhibitor of ferrochelatase |
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ferrochelatase
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influences rate of Fe+2 incorporation into protoporphyrin X
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Porphyrias
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autosomal dominant and heterogeneous
increased excretion of porphyrins and precusors (purple urine) erythropoetic or hepatic |
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Porphyria cutanea tarda
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most common
bone marrow and liver pts are PHOTOSENSITIVE build up of uroporphyrinogen III deficiency of uroporphyrinogen decarboxylase results from iron overload, hepatitis, HIV |
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Acute intermittent Porphyria
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deficiency in hydroxymethybilane synthesase
dark urine (porphobilinogen) caused by use of barbituates and ethanol (increase cp450) pts ar not photsensitive |
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Yellow color of urine
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urobilin
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Brown color of feces
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bacteria metabolism converts bilirubin-diglucoronide to stercobilin
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Lead poisoning
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effects 2nd step and last step
Ferrochelatase (protophyrin accumulates) and ALA dehydratase (ALA accumulates) non competitive inhibitor |
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breakdown of bilirubin
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In kupffer cells:
Heme to biliverdin (green)(release of CO) -->reduced to bilirubin (red-orange) Bilirubin-albumin complex is transferred to the blood Liver attaches carbohydrate to form diglucuronide (increases solubility) Bilirubin diglucuronide is secreted in the bile |
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hemolytic jaundice
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massive lysis of RBCs can lead to increased levels of unconjugated bilirubin in tissue because liver cant handle all of it
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hepatocelluar jaundice
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liver damage
bilirubin leaking from liver Urine is dark and feces are pale |
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obstructive jaundice
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blocked bile duct
pale feces and dark urine |
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Jaundice in newborns
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common with premature babies
serum levels of bilirubin may rise to toxic levels low levels of bilirubin glucuronyltransferase (liver enzyme) TRT: exposure to UV light (bilirubin doesnt have to be conjugated to be secreted) |
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Bilirubin testing
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"direct reacting"- conjugated bilirubin
"indirect reacting"- unconjugated -->jaundice |
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Urobilinogen
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forms in intestine
glucuronic acid is removed by bacteria from conjugated bilirubin |
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Heptaglobin
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carries Hb
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hemopexin
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carries heme
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transferrin
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carries 2 Fe 3+
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Oxidoreductase
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Catalyse oxidation-reduction reactions
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Transferases
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Catalyze C-, N-, or P-group transfer reactions
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Hydrolases
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Catalyze cleavage of bonds by water
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Lyases
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Catalyze addition groups to double bonds. Cleave of C-C, C-S, C-N
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Isomerases
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Catalyze racimization/isomeration reactions
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Ligases
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Catalyze condensation of 2 molecules wtih bonds between C,O,S,N (and cleavage of ATP and GTP)
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Irreversible inhibition
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covalently bonds
kinetics like non competitive inhibitors |
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Marker for MI
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Creatine kinase MB
(found in heart muscle) start to raise within a few hours of an MI and stay elevated for days |
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Heme is present in...
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Hemoglobin
myoglobin cytochromes |
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enterpeptidase
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activates trypsionogen by limited proteolysis; cleaves at lysine preceded by 4 aspartic acids
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Trypsin activates
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chymotrypsinogen-chymotrysin
proelastase-elastase procarboxtpeptidase-carboxypeptidase prolipase-lipase |
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albumin
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prealbumin peak
makes up 50% of blood volume maintains osmotic pressure carries bilirubin to liver binds metal ions used to treat shock from blood loss |
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alpha 1 region
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include alpha1-antitrypsin (inhibits nuetrophil elastase)
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alpha 2 region
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ceruloplasmin,GC globin,alpha 2 lipoprotein (HDL),haptoglobin,prothrombin,antithrombin II
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ceruloplasmin
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carries copper
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GC-globulin
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carries Vit D
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beta region
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transferrin and hemopexin
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gamma region
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contains Immunogloblins
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Deficiency in alpha1 antitrypsin
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Glu to Lys mutation
leads to pulmonary emphysema smoking makes it worse-->oxidizes inhibitory site (met) and it can no longer inactivate elastase because it cant fit in the active site |
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alpha 2 lipoprotein
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carries HDL
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Immune response
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IgM and then IgG
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hypervariable region
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at amino terminal of Ig
light and heavy variable region antigen binding site |
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light chains
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kappa or lambda
a lymphocyte produces one or the other,not both linked by disulfide bonds |
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heavy chains
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linked to each other by S-S bonds
have Asn carbohydrate chains constant region give integrity and binding sites for cell surface receptors |
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Papain
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cleaves IgG into 2 Fab fragments and one Fc fragment
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Fab fragment
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binds (noncovalent) one antigenic epitope can be used for immunological test
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IgG
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most prevalent in blood
crossed placenta gamma heavy chains |
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IgA
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in respiratory and intestinal mucus and colostrum
dimer, alpha heavy chains, J chain, secretory component |
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IgM
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largest
pentamer, mu heavy chains, j chains can bind 10 antigens |
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IgE
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monomeric, found on surface of mast cell
epsilon heavy chains |
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IgD
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delta heavy chains
exists on surface of B cells, acts as antigen receptor to signal proliferation |
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Monoclonal antibodies
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single epitope
very specific large scale production tight or loose binding |
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Major Histocompability complex (MHC)
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important for immune system to recognize own proteins and to present peptide fragments of non host proteins
hypervariable binding domains anchored by membrane spanning regions important to match with organ transplant |
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Alpha hemoglobin
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2 alpha subunits
2 beta subunits |
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Fetal Hemoglobin
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two alpha subunits
two gamma subunits (Ser (neu) instead of His (+) higher affinity for O2 binds BPG less tightly present until about 6 mo curve shift to left with HbF |
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Hb A2
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2 alpha chains
2 delta chains |
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Embryonic Hb
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2 zeta chains
2 epsilon chains first 3 months in womb |
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Distal His
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on side of O2 binding
protects from CO poisioning because it makes the CO bind less tightly |
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Methemoglobinemia (HbM)
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oxidation of Fe2+ (ferrous) to Fe3+
beta chains do not bind O2 proximal His is replace by Tyr blue fingers and blue toes |
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HbS
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Glu --> Val (6 position Beta chain)
DeoxyS is less soluble than HbA |
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Carbonic anhydrase buffer
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CO2 + H20 <-->H2CO3<-->HCO-3 + (H+)
pka is 6.1 |
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Basic Amino Acids
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positively charges
His Arg Lys |
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Acidic Amino Acids
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negative charge
Asp Glu no charge Gln Asn |
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Hydrophic side chains
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Val
Ala Leu Ile Met Phe Tyr Trp |
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Ionizable side chains
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Asp
Glu His Lys Arg Cys |
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Hydrogen bonding side chains
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thr
ser Asn Gln |
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Isozymes
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catalyze the same reaction
genetically, physically and kinetically different |
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DNA helicase
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unwinds DNA helix
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Single stranded DNA binding proteins (ssb)
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stabilize single stranded regions
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Primase
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RNA polymerase,synthesizes short RNA stretches
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DNA polymerase III
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makes leading strand and lagging strand
3-5 exonuclease activity |
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DNA polymerase I
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3-5 exonuclease activity
5-3 exonuclease (removes RNA primer) fills in gaps in Ozaki frags |
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clotimazole
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inhibition of Gardos Channel (KCL cotransport)
prevents water loss from cell |
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Hydroxyurea
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increase HbF
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