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GER Unit 6 > MCP > Flashcards

MCP Flashcards

1
Q

pH and Bohr Effect of CO2

A
  • In active tissues where [CO2] is high, pH decreases as does affinity for O2
    • promotes efficient unloading
  • In the lungs where [CO2] is low, pH is raised which increases the affinity for O2
    • promotes efficient loading
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2
Q

carbamylation of Hb due to CO2

A

CO2 combines reversely with N-terminal amino to form carbamates; stabilizes the T state, reducing affinity of Hb for O2

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3
Q

BPG (2, 3 DPG)

A

stabilizes the T state, reducing affinity for O2 and shifting the curve right

  • increases efficiency of unloading in uscle by moving the steepest part of the curve
  • in absence of BPG, Hb would be a poor O2-delivering system
  • people in high alt. have altered BPG levels
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4
Q

sickle cell anemia (HbS)

A
  • form of hemolytic anemia due to Glu→Val mutation in ßchain
  • HbS polymerize into extended fibers that span RBC
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5
Q

a and ß thalassemia

A

insufficient a or ß chains leads to insufficient/nonfunction Hb in RBCs

  • major: complete lack of function chains vs. minor: decreased production of functional chains
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6
Q

methemoglobinemia

A
  • caused by
    • mutation in Hb that stabilizes oxidized form
    • defect in enzyme (CYB5R) that normally reduces MetHb to Hb
    • chemical agents (Na+ or K+)
  • unable to combine reversibly with O2 or CO2
  • cyanosis occurs because MetHb is greenish/black due to oxidation of heme Fe (2+ to 3+)
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7
Q

myoglobin

A
  • intracellular O2 transport and storage protein
  • predominantly a-helix with heme moiety
  • hyperbolic O2 binding curve, O2 binds under conditions in which Hb releases it
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8
Q

hemoglobin (Hb)

A
  • predominant O2 carrier in circulatory system
  • tetrameric protein (a2ß2)
    • stable, rigid aß dimers (protomers) come together to form loose tetramer
    • each a and ß chain is noncovalently found to heme
    • **cooperative allostery **results from structure of tetramer being in equilibrium between T state (low affinity for O2) and R state (high affinity for O2)
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9
Q

heme group

A
  • 3 different species, all contain a porphyrin ring structure with Fe as the chelated metal
  • Protoporphyrine: 4 pyrolle rings that create binding site for Fe; isomer in heme is protoporphyrin IX
  • Enzymes bind heme by ligating axially to Fe with amino acids
  • deoxyHb: Fe(II) is 5 coordinate
  • oxyHb: Fe(I) is 6 coordinate, O2 binds to distal histadine
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10
Q

Hb O2 binding curve

A
  • sigmoidal curve due to convolution of high affinity R state and low affinity T state
  • At high [O2]: dissociation curve is close to R curve, as [O2] decreases, it approaches T curve
  • negative effectors (pH, BPG, CO2) cause right shift of curve
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11
Q

effect of pH on Hb O2 binding curve

A
  • oxygenation of Hb makes it a stronger acid
  • high pH (low H+): Hb has higher affinity for O2, more O2 is loaded
  • low pH (high H+): Hb has lower affinity for O2, more O2 is released
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12
Q

5 steps of heme synthesis

A
  1. ∂-aminolevulinate (ALA) synthesis from glycine and succinyl CoA in mitochondria: **committing/regulating step
  2. Porphobilinogen synthesis: ALA dehydrase Zn cofactor can be inhibited by Pb
  3. Uroporphyrinogen synthesis
  4. Protoporphyrin IX synthesis: no energy input needed
  5. Protoheme IX (heme) synthesis: no energy input needed, ferrochelatase enzyme in mitochondria can be inhibited by Pb
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13
Q

porphyrias

A

diseases associated with inability to synthesize heme

  • hepatic: come as induced attacks
  • erythropoietic: chronic conditions
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14
Q

Congenital erythropoietic porphyria (CEP)

A

deficiency in uroporphyrinogen III co-synthase that flips D ring

  • build up of photoreactive heme precursors
  • origin of werewolf legend
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15
Q

Protoporphyria

A

partial deficiency in ferrochelatase (last step of biosynth), similar but milder symptoms as CEP, occurs in erythroid cells and less severely in liver

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16
Q

Acute intermittent porphyria

A

most common porphyria, caused by deficiency of porphobilinogen (PBG) deaminase in liver, attacks usually occur following use of an agent that induces heme synthesis

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17
Q

Porphyria cutanea tarda

A

deficiency in utoporphyrinogen decarboxylase, asymptomatic until liver disorder is imposed (e.g., HepC); attacks usually occur following use of an agent that induces heme synthesis

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18
Q

HbSS

A

homozygous or doubly heterzygous state of mutation in RBCs that causes polymerization of Hb upon deoxygenation→hemolytic anemia and blockage of capillaries

  • most common life-threatening genetic disorder; 1/400 African-Americans
  • most severe form of sickle cell disease
  • clinical variations in severity are poorly understood
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19
Q

Sickle Cell Trait (HbAS)

A

silent carrier state of sickle cell disease; >55%HbA, the rest is HbS

  • parents of most newly diagnosed infants with SS didn’t know they were carriers
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20
Q

HbC

A

does not sickle but increases Hbß viscosity

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21
Q

HbSC Disease

A

AS x AC; results in a milder disease

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22
Q

Sickle ß-thalassemia

A

AS x ß-thalassemia; can be as severe as HbSS if there is no HbA production

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23
Q

how does HbF affect sickle cell disease?

A

don’t develop signs and symptoms until 3-4 mo when production of HbF switches to HbA after birth

  • the higher [HbF] relative to [HbS] the milder the disease because HbF blocks polymerization of HbS
    • different ethnicities have different levels of HbF throughout life (Arab-indians and Senegalese have higher HbF, most severe disease is related to the Bantu and the Benin)
    • research aimed at changing transcriptional switch so levels of y-subunit are maintained
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24
Q

why is overwhleming infection such a risk for HbSS patients?

A

spleen clear encapsulated bacteria (e.g., pneumococcus) for which you don’t have antibody, slow circulation making it sluggish and hypoxic→sickling

  • bacterial sepsis: 30-50% mortality, 2/3 of dsease within 8 hours of 1st symptoms; most common death <5
  • prophylactic penicillin and aggressive treatment of fever
25
Q

painful vaso-occlusive episodes

A

most common complication of sickle cell disease

  • pain is excruciating and can be anywhere (hand-foot syndrome in children)
  • impairs ability to attend school regularly/be employed
  • pain management is essential, basiased and inappropriate therapy based on race and assumptions they are drug-seeking
26
Q

what are the common co-morbidities of sickle cell disease?

A
  • bacterial sepsis
  • painful vaso-occlusive episodes
  • stroke
  • acute chest syndrome
  • acute splenic sequestration crisis
27
Q

stroke in sickle cell disease patients

A
  • 10% incidence; classic hemiparesis usually from major vessel obstruction
  • prevent with transcranial Doppler
  • treat with exchange transfusion; maintain chronic transfusion program to prevent reoccurance
28
Q

acute chest syndrome

A

unique term of acute lung disease in sickle cell patients; difficult to determine cause so treat all bases

  • antibiotics, O2, incentive spirometry, transfusion
  • major cause of mortality in adult sickle cell patients
29
Q

acute splenic sequestration crisis

A

sudden enlargement of speel due to acute vaso-occlusion→hemorrhaging

  • occurs in 1st 5yrs of life and can rapidly result in shock
  • treat with fluid resuscitation and transfusion, teach parents splenic palpation
30
Q

what is the role of genetic counseling in sickle cell disease?

A

empower patients to make their own reproductive decisions; harvest cord blood from newborn if they do not have sickle cell disease because they could be a donor if next child has sickle cell disease

31
Q

hydroxyurea

A

milke chemotherapeutic agent used to treat sickle cell disease

  • results in 50% reduction in the incidence of complications
  • long-term toxicity is very rare
32
Q

what is the only cure for sickle cell disease?

A

bone marrow transplantation; candidates: have had/at risk for stroke, debilitating pain, recurrent acute chest syndrome

  • requires HLA-identical siblings (only 25% of full siblings are HLA identical, available in only 14% of families
33
Q

what is the mutation that results in sickling of RBCs?

A

single amino acid substitution (A→T) in HbB on chromosome 11 (val instead of glutamic acid)

  • causes dramatic effect in Hb; deoxyHbS forms 14 stranded polymers
34
Q

reversibly sickled cells vs. irreversibly sickled cells

A

reversibly sickled: switch back and forth based on polymerization status of HbS

irreversibly sickled: locked into sickle shape even when HbS is depolymerized and oxygenated

  • Oxidative stress changes membrane skeleton composed of spectrin and actin interactions
    • Disulfide bridge creates actin filament that cannot depolymerize; spectrin with diminished ubiquitination→association between spectrin and actin
    • Oxidative stress causes reduced flippase activity and increased scramblase activity so phosphatidyl serine appears on outside of RBC bilayer→hypercoagulation and thrombosis because it makes sickle RBC adherent to blood vessel wall and it enables recognition by macrophages→anemia
35
Q

what is the pathophysiology of sickle cell vaso-occlusion?

A
  • activation of endothelial cells associated with blood vessel; WBCs are more adhesive and adhere to vessel endothelium, RBCs also adhere; WBCs and RBCs adhere to each other→hypoxia
36
Q

ischemia-reperfusion in vaso-occlusion crises of sickle cell disease

A
  • ischemia: metabolic response to hypoxia→xanthine oxidase to covert O2 to superoxide ROS
  • **reperfusion: **burst of ROS when blood flow is restored; activated NFkB transcription factor→expression of inflammatory molecules→inflammation→new expression of adhesion proteins on cells that interact with adjacent cells
  • sickle RBCs have 3x as much oxygen radicals compared to normal RBCs and very low levels of reduced glutathione (GSH)
    • increased activity of SOD→elevated H2O2 but decreased activity of GPX and SCD so no conversion of H2O2→water and oxygen, instead H2O2→OH-
    • No antioxidant enzyme binds up OH- so oxidative damage occurs to proteins and lipids on membrane skeleton of RBCs→sickling
37
Q

molecular basis of dense ISCs

A
  • induced cation leak channel due to damage from sickle cycling, K+ and Mg2+ leave cell; Ca2+ in
    • activates other channels (including Gardos channel); more K+ leads and water follows→dense cells
  • active oxidation diminished spectrin ubiquinilation→locked sickle cells→dense ISCs
38
Q

potential therapies for sickle cell disease

A
  • Effect oxidative stress (NAC is an antioxidant that easily enters cells AND increases GSH levels)
  • Effect K+ leakage from RBCs (Gardos channel inhibitor)
  • Effect inflammation
  • Effect HbF
  • Gene therapy: viral vectors to insert normal ß-chain via benign illness without immunosuppression of transplant
39
Q

Km

A

substrate concentration that gives you half Vmax

  • catalytic rate of enzye most sensitive to substrate when [S] is < Km
  • approximately the same as the dissociation constant when K2>>K3 (substrate binds and dissociates many times before going to product)
40
Q

Vmas

A

maximal velocity achievable for specific concentration of enzyme

  • at this point, enzymes are saturated with substrate; increase Vmax by increasing [E]
41
Q

Kcat

A

intrinsic constant that shows how fast one enzyme could convert substrate (Vmax/[E]); higher Kcat implies higher efficiency of the enzyme

42
Q

lineweaver-burk plot

A

linearized michaelis-menten, use to estimate constants

  • -1/Km= x-int
  • 1/Vmax= y-int
43
Q

quantitative properties of inhibitors

A
  • Ki: strength with which an inhibitor binds to an enzyme; dissociation constrant for enzyme-inhibitor complex; higher Ki implies weaker inhibition
  • competitive: compete with substrate for binding to active site; overcome by increasing [S]
    • curves intersect at y-axis
  • noncompetitive: bind to a site other than active site
    • curves intersect at x-axis
44
Q

how do enzymes affect energetics of chemical reaction?

A

do not change ∆G, lower activation energy by direct stabilization of transition state and/or creation of new reaction pathways

45
Q

common features of enzyme active sites

A
  • small part of total enzyme volume
  • 3D structure
  • bind substrates through multiple weak, noncovalent interactions
  • water is excluded unless it is a reagent
  • highly specific binding of substrate (induced fit)
  • can include non-protein prosthetic groups/cofactors
46
Q

6 basic strategies for enzymatic catalysis

A

Direct stablization of transition state

  • preferential binding of transition state with greater affinity than substrate or products (better fit)
  • proximity and orientation effects; enzymes immobilize substrates

Chemical assistance at active site

  • acid-base: weak acid on enzyme provides partial proton transfer/weak base accepts (histidine usually involved)
  • covalent: transient formation of covalent bond
  • metal ion catalysis
  • electrostatic catalysis
47
Q

suicide inhibitors

A

bind to enzyme because of resemblance to substrate and are converted into an irreversible inhibitor

  • ex. penicillin: suicide inhibitor of glycopeptide transpeptidase, crtical for bacterial cell wall biosynthesis
  • ex. AChE (degrades ACh in synaptic cleft) is irreversibly inhibited by nerve gas, reversibly inhibited by aricept/cognex (used to improve cognitive function)
48
Q

structure-based drug design

A

best inhibitors mimic transition state conformation (enzymes show preferential binding of the transition state)

  • most drugs are reversible inhibitors: turn down function of target enzyme but don’t completely inhibit activity
49
Q

HIV-protease inhibitors

A
  • developed using knowledge of aspartyl protease mechanism and protein structure
  • resistance: high error rate by RT and large number of virus particles synthesized daily; use drug combinations
    • resistant virus is insensitive to drug (high Ki) and normal catalytic activity (wt Kcat/Km)
50
Q

allosteric regulation

A

frequently operate at control points (rate-limiting steps_ in metabolic pathways; activity of enzyme is modulated either by levels of substrate or byactivating inhibitory modulators

  • feedback inhibition: end product acts at allosteric inhibior of first enzymatic step
  • does not follow michaelis-menten
  • e.g. ATCase catalyzes first step in CTP synthesis
    • CTP is negative regulator
    • ATP is positive regulator
51
Q

reversible covalent modificaiton

A

causes conformational change that affects catalysis; alter celular location of enzyme, alter interactions with other proteins

  • ex. phosphorylation: kinase activates enzyme, phosphatase dephosphorylates to inactivate
52
Q

irreversible covalent modification

A

synthesize enzyme in inactive form and active in the time/place where they are needed

  • ex. zymogen: inactive precursor form of protease that is activated by specific proteolytic cleavage by another protease (irreversible by activated proteases can be turned off through inhibitors)
    • digestive enzymes: enteropeptidase cleaves trypsinogen to trypsin in small intestine
    • coagulation cascade
    • **protein-protein interaction: **enzyme activity can be regulated reversibly by interactions with other proteins (PKA regulated by cAMP which releases inhibition; calmodulin shows Ca2+ depedent interactions with multiple enzymes)
      *
53
Q

coagulation cascade as an example of irreversible covalent modification

A
  • rapid activation of blood coagulation: cascade of zymogen activations allow sequential activation of series of serine proteases
  • localization of clot to injury site
  • *rapid termination after clot formation to prevent thrombosis: *reverse zymogen cascae hydrolyzes close
54
Q

deficiencies to protease inhibitors

A
  • mutant pancreatic trypsin inhibitor inhibits inappropriately activated digestive proceases in pancrease by protein-protein interactions
  • antithrombin deficiency: excessive clotting
  • a1-antitrypsin deficiency: too much active elastas in lung eventually causes COPD
55
Q

Diagnostic measurement of enzyme levels

A
  • measure rate of product formation in presence of excess susbtrate because product formation with time will be linear
  • coupled enzyme system: one of the products of the first reaction is stoichiometrically converted to a detectable product by second reaction
56
Q

using enzymes clinically to measure of substrate

A

e.g., blood glucose: used coupled enzyme assay, NADPH is detected by ability to reduce colored dye to form colored product

57
Q

using enzymes to diagnose tissue damage by isozyme distribution

A
  • isozymes: different forms of enzyme that carry out same reaction; different amino acid sequences and specific expression in different tissues or a specific pattern of expression during development
  • non-plasma specific enzymes can appear in serum because of damage to tissue of origin or because “spillover” due to overproduction in tissue of origin
    • e.g., following MI: CK-2, AST, LDH-1 appear and have characteristic rise and fall (vs. DMD long term rise in CK-3)
58
Q

list of tissue-specific isozymes

A
  • **ALT: **viral hepatitis
  • amylase: acute pancreatitis
  • **lipase: **acute pancreatitis
  • lactate dehydrogenase 5: liver disease
  • alk. phos: various bone disorders, obstructive liver disease
  • **creatine kinase: **muscle disorders and MI
  • **phos, acid: **metastatic carcinoma of prostate

GER Unit 6 (5 decks)

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