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Flashcards

jan 31 friday

Shylla T English 65 cards

Cards in this deck (65)

  1. 1a-globinhas 141 amino acids
    141 codons or 423 nucleotides
  2. 2b-globinhas 146 amino acids
    146 codons or 438 nucleotides
  3. 3Adult hemoglobin is tetramera2b2
    Spontaneous assembly
  4. 4Alpha (a) and beta (b) globin are part oftwo gene clusters
  5. 5Beta (b) globin gene cluster onchromosome 11p:
    One embryonic (e)
    two fetal (Ag and Gg)
    two adult (d and b) genes
  6. 6Alpha (a) globin cluster onchromosome 16p:
    One embryonic (z)
    two adult (a) genes
  7. 7b-Globin Regulation: SwitchingInteraction between regulatory sequences in each promoter and locus control region (LCR).
    ----Mediated by lineage-specific and stage-specific regulatory proteins
    Protein-protein interactions lead to DNA looping
    ---LCR subdomains are brought closer to promoters
  8. 8b-thalassemiab chain deficiency leads to (b-thalassemia)
    Deficiency of b means: very little or no a2b2 a-globin gets degraded in the absence of b
    Splicing defects are known to be responsible for it
  9. 9b-thalassemia majorb0-Thalassemia (both alleles mutated).
  10. 10b-thalassemia minorAsymptomatic heterozygote
    b0 Heterozygote
    b+ Heterozygote
  11. 11b0 Heterozygoteone normal and one mutant allele
  12. 12b+ Heterozygoteone normal allele, and a mutant allele producing some normal globin
  13. 13Silencing of Fetal Globin by BCL11A (Repressor)Bcl11A levels are highest in adult erythroid precursor cells
    Very little g-globin (fetal globin) expression
    Bcl11A levels are lowest in fetal liver erythroid precursor cells
    Highest g-globin (fetal globin) expression
  14. 14BCL11A inactivation/deletion canenhance HbF expression
  15. 15b-thalassemia and sickle cell disease can be potentially treated byBCL11A inactivation
  16. 16Persistent expression of fetal globin genes would lead to tetramer formation betweeng- and a- globin.
    a2g2
  17. 17CRISPR/Cas9 system tocorrect the defect in sickle cell disease
  18. 18CRISPR/Cas9 system toinactivate BCR11A
  19. 19a-Globin For few weeks during embryonic development controlsz-globin is expressed.
  20. 20a-major regulatory element (MRE) controlsz- and a-globin transcription
  21. 21a MRE does whatIt is an enhancer element
    MRE activates transcription from z and a promoters
    MRE is recognized by erythroid specific factors
    MRE is genetically polymorphic
  22. 22PorphyrinsPorphyrins form cyclic structures that readily bind one metal ion (Fe2+ or Fe3+).
    Heme is the most common porphyrin (protoporphyrin IX + Fe2+ or Fe3+)
  23. 23Maturation of ProtoporphyrinFollowing cyclization of porphyrin in cytosol, iron binds to form heme inside mitochondria.
  24. 24ferrochelatase (FECH).Insertion of iron onto protoporphyrin
  25. 25Heme biosynthesis occurs inliver (15%; synthesizes cytochrome P450 proteins) and bone marrow (85%; synthesizes hemoglobin).
    Rates of heme biosynthesis in the liver is highly variable
    Heme biosynthesis in bone marrow is nearly constant, and matched by rate of globin synthesis.
  26. 26All carbons for heme biosynthesis come fromglycine (nonessential amino acid) and succinyl CoA (intermediate of TCA cycle).
  27. 27Condensation of glycine and succinyl CoA is catalyzed byδ-aminolevulinic acid synthase (ALAS1 in liver; ALAS2 in bone marrow).
  28. 28to Inhibit ALAS-1Heme Acts to Inhibit ALAS-1 in the Liver
    which is thr product of ALAS-1 when there is heme accumulation
  29. 29there are 2 isoforms of ALAS becusone is specific for liver and the other for erythorod cells or in bone marrow
    the inbition by heme happens in liver but not in bone marrow (constant)
  30. 30Transferrindelivers iron to erythroid cells.
  31. 31δ-Aminolevulinic Acid Synthase (ALAS2) is transcriptionally upregulated byiron binding to iron responsive element (IRE).
  32. 32Erythropoitin (Epo)a Cytokine (protein signaling molecule) that controls erythropoiesis (red blood cell production).
  33. 33Epo binds toReceptor (EpoR) on red blood cell progenitor to prevent apoptosis.
  34. 34Epo is regulated byHypoxia Inducing Factor (HIF).
  35. 35Hypoxic Stress Induces>1,000 fold Increase in Epo (synthesized in capillaries lining cells in renal cortex).
  36. 36low and high oxygenHigh oxygen ----HIF is inactivated
    Low oxygen (hgh altidude)---HIF is activated----upregulation of Epo---more RBC matured and less apoptosis
  37. 37P50is the oxygen partial pressure when Hb or Mb is 50% saturated with oxygen.
  38. 38Bohr EffectLoss of affinity for oxygen with decreasing pH (increased acidity)
    As oxygen is consumed and carbon dioxide (carbonic acid) is released by tissues
    Protons shift the equilibrium of hemoglobin conformation
    decreassed affinity of hem to oxygen ehances hemo ability to deliver o2 to tissue
  39. 39Cooperative O2 Bindingin hemo if there is change on 1 subunit salt bridges it changes the other salt bridges of hemo. this confirmational change wll communicate to other subunits which will lead to greater and greater bingding of ocy to hemoglobin
  40. 40Deoxy (T) statestate has a salt bridge because of protonation of His (pKa of His-146 is > 7.4 in R State)
  41. 41Oxy (R) statedisrupts salt bridge to release proton on His (pKa of His-146 is < 7.4 in T State)
  42. 42Mechanism of Cooperativity:Oxygen binding to heme pulls Asp-94 to left
    Increased separation between Asp-94 and His-146 favors deprotonation of His-146 (lowers pKa of His)
  43. 43Bohr Effect Enhances O2 Tissue Delivery[H+] ↑ Result From
    -- Increased [CO2]
    ---Anaerobic Metabolism (lactate production)
  44. 44co2, ph and o2 releationshopLow co2---low H (high pH)----increase O2 to hemoglobin
    High co2---more H (low pH)----decrease O2 to hemoglobin (more dissociation)
  45. 45bohr final summaryHigh co2---more bicarbonate which release more H----more H (low pH)- causes interference with salt bridges in hemoglobin---decrease O2 to hemoglobin (more dissociation)
  46. 46Bisphosphoglycerate (BPG)Binds Deoxy (T) Hb and stablizes the T form
    [BPG]↑ In Response to Hypoxia
    Synthesized in Shunt From Glycolytic Intermediates
    BPG is an Allosteric Effector
  47. 47stablizing the deoxy T form does whatu are allowing o2 to be dissoctaed from hb
  48. 48CO Binds Tightly to Heme IronCO Competes with O2 For Iron Binding Site.
    Loss of Oxygen Transport Capacity and Cooperativity.
    Difficult to Diagnose (Patient Remains Pink).
  49. 49CO treatmtmentTreatment Involves High [O2].
  50. 50Fetal HbHas an Decreased Affinity for BPG to Enhance Oxygen Transfer
    Adult Hb (Hb A) (α2β2)
    Fetal Hb (Hb F) (α2γ2)
  51. 51how to fetal hb and adult hb differDiffer by Mutation in BPG Binding Cleft (His143Ser in β-subunit)
  52. 52Pathways of Heme CatabolismProcessing and Excretion of Hydrophobic Products of Porphyrin Ring (Bilirubin).
    Retention and Mobilization of Iron.
  53. 53Bilirubin FormationMacrophages take up heme and break ring structure (heme oxygenase) to form biliverdin and release of ferric iron (Fe3+)
    Biliverdin is reduced to form bilirubin
    Bilirubin has limited solubility, and is transported to liver by albumin.
    Bilirubin enters hepatocyte (liver cell) and is glycated with glucuronic acid (added solubility) in the liver.
  54. 54Salicylates (aspirin) and sulfonamidescan displace bilirubin from albumin, resulting in CNS uptake (potential for neural damage in infants).
  55. 55Bilirubin diglucuronideis actively transported into bile (rate-limiting step of the degradation pathway.
  56. 56Bilirubin diglucuronide ishydrolyzed and reduced by bacteria in gut, yielding colorless urobilinogen.
    Most urobilinogen is metabolized by intestinal bacteria to stercobilin (gives feces characteristic brown color).
  57. 57Jaundice Results fromAccumulated Unconjugated Bilirubin
  58. 58Hemolytic jaundiceLiver can conjugate 3 grams of bilirubin daily, exceeding normal bilirubin production by 10-fold.
    Massive lysis of red blood cells (e.g., Sickle cell disease) may swamp system, resulting in unconjugated bilirubin release into circulation.
  59. 59Hepatocellular jaundiceDamage to liver cells (e.g., cirrhosis or hepatitis) can increase release of unconjugated bilirubin, which typically appears in urine (which darkens
  60. 60Obstructive jaundiceObstruction of bile duct (e.g., tumor or bile stones) causes liver to regurgitate conjugated bilirubin into blood, and excretion in urine
  61. 61Neonatal jaundiceNewborn infants commonly accumulate bilirubin, because the activity of glucuronyltransferase is low at birth.
    If [bilirubin] >> [albumin], bilirubin diffuses into basal ganglia and can cause toxic encephalopathy.
  62. 62Glucuronyltransferase.
  63. 63PhototherapyEnhances Solubility of Bilirubins in Newborns
    Excitation of bilirubin (B) with blue light causes photoisomerization of bilirubin (PB) to enhance water solubility.
  64. 64Photoisomerized bilirubin iswater soluble and preferentially excreted.
    Bilirubin is also oxidized by light + oxygen, enhancing solubility and allowing excretion of oxidized bilirubin (oxb).
  65. 65—

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Flashcards on jan 31 friday, created by Shylla T on 31/01/2020.
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Shylla T
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