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Starry Starry Night - Vincent


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Starry Starry Night - Vincent 2012 - 2013

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Starry Starry Night - Vincent

  1. 1. Prayer for New Beginnings God of new beginnings, we are walking into mystery. We face the future, not knowing what the days and months will bring us or how we will respond. Be love in us as we journey. May we welcome all who come our way. Deepen our faith to see all life through your eyes. Fill us with hope and an abiding trust that You dwell in us amidst all our joys and sorrows. Thank You for the treasure of our faith life. Thank You for the gift of being able to rise each day with the assurance of Your walking through the day with us. God of our past and future, we praise you. AMEN
  2. 2. NOEL MARTIN S. BAUTISTA, MD, DPPS, MBAH Department of Biochemistry, Molecular Biology and Nutritionfb
  3. 3. 3 Road Map  Understand the metabolism of Iron in the body  Distribution of iron  Sources of iron  Absorption of iron  Metabolism of iron  Disorders of iron metabolism  Understand the chemistry of Porphyrins  Understand the metabolism of Heme in the body  Biosynthesis of heme  Regulation of the synthesis of heme  Disorders of heme synthesis  Degradation of heme  Disorders of heme degradationshare IRON AND HEME METABOLISM
  5. 5. 5Iron  important trace mineral; essential for function of numerous proteins in cells  oxygen transport, electron transfer, xenobiotic metabolism  expression of proteins involved in iron uptake and sequestration carefully regulated to ensure that iron supplies are adequate  meet metabolic needs but not in excess to cause toxic damage IRON AND HEME METABOLISM
  6. 6. 6Iron  exists in two ionic states  ferrous: reduced form (Fe+2)  ferric: oxidized form (Fe+3)  different forms important in oxidation-reduction reactions  ETC, oxygen-binding molecules  excess – damage to cells and tissues by formation of free radicals (ROS) IRON AND HEME METABOLISM
  8. 8. 8Iron: Forms  iron exists in a wide range of oxidation states, −2 to + 6,  +2 and +3 are the most common and biologically important IRON AND HEME METABOLISM
  9. 9. 9Iron: Functions  oxidation-reduction reactions of energy metabolism  component of many enzyme system that create ATP and energy  structural/functional component of hemoglobin (blood) and myoglobin muscle  carries oxygen IRON AND HEME METABOLISM
  10. 10. 10Iron: Distribution  human body: 4–5 g iron (protein-bound)  heme proteins (~72%)  hemoglobin (2.5 g)  myoglobin (0.15 g)  transport and storage proteins (~26%)  transferrin (1.0 g)  serum ferritin (0.0001 g)  iron–sulfur clusters (<1%)  cofactors in the respiratory chain, other redox chains IRON AND HEME METABOLISM
  11. 11. 11Iron: Dietary Sources  average American diet: 10-50 mg iron  heme iron – readily absorbed  animal source: meat, fish and poultry  not found in milk or dairy products  non-heme iron – not readily absorbed  source: mostly plant products which contains phytates, tannins, oxalates that chelates / precipitates iron  iron supplements IRON AND HEME METABOLISM
  12. 12. Iron: Dietary Sources IRON AND HEME METABOLISM
  13. 13. 13 Iron: Sources of Heme Ironspinach IRON AND HEME METABOLISM
  15. 15. 15Iron: Absorption  occurs predominantly in the duodenum and upper jejunum  tightly regulated since there is no physiologic pathway for its excretion  feedback mechanism (“iron guarding”)  enhances iron absorption in individuals who are iron deficient  dampens iron absorption people with iron overload IRON AND HEME METABOLISM
  16. 16. 16 Iron: Absorption  physical state of iron (duodenum) greatly influences its absorption  ferrous iron (Fe2+) is better absorbed  ferric (Fe3+) iron forms large complexes (with anions, water and peroxides) which have poor solubility  at physiological pH, ferrous iron (Fe2+) is rapidly oxidized to the insoluble ferric (Fe3+) form  gastric acid lowers the pH in the proximal duodenum, enhancing the solubility and uptake of ferric iron  when gastric acid production is impaired (acid pump inhibitors, e.g., prilosec), iron absorption is reduced substantiallyfactors IRON AND HEME METABOLISM
  17. 17. Iron: Factors Affecting Absorption Physical State (bioavailability) heme > Fe2+ > Fe3+ phytates, tannins, soil/clay (pica), laundry Inhibitors starch, iron overload, antacids Competitors lead, cobalt, strontium, manganese, zinc ascorbate, citrate, amino acids, iron Facilitators deficiency, stomach acid, high altitude, exercise, pregnancyoverview IRON AND HEME METABOLISM
  18. 18. Iron: AbsorptionHT, Heme Transporter; HO, Heme Oxidase; FP, Fe2+ Transporter; HP, Hephaestin; TF,transferrin; DMT1, Divalent Metal Transporter 1
  19. 19. 19Iron: Absorption  proximal duodenum  Incoming Fe3+ is reduced to Fe2+ by a ferrireductase  vitamin C in food  reduction of Fe3+ to Fe2+  transfer of iron from the apical surfaces into inside of enterocytes by a proton- coupled Divalent Metal Transporter (DMT1) IRON AND HEME METABOLISM
  20. 20. 20Iron: Absorption inside the enterocyte, iron can either be stored as ferritin or transferred across the basolateral membrane into the plasma, where it is carried by transferrin IRON AND HEME METABOLISM
  21. 21. 21 Iron: Absorption  passage across the basolateral membrane: possibly iron regulatory protein 1 (IREG1) or Fe2+ Transporter (FP).  IREG1 (FP) protein may interact with the copper-containing protein hephaestin  hephaestin: ferroxidase activity  release of iron from cells  Fe2+ is converted back to Fe3+, the form in which it is transported in the plasma by transferrinregulation IRON AND HEME METABOLISM
  22. 22. 22 Iron Absorption: Regulation  complex and not well understood  occurs at the level of the enterocyte  “mucosal block” - further absorption of iron is blocked if a sufficient amount has been taken up  “erythropoietic regulation” – iron absorption appears to be responsive to the overall requirement of erythropoiesismetabolism IRON AND HEME METABOLISM
  23. 23. 23Iron Metabolism: Overview  iron is absorbed from the diet  transported in the blood in transferrin  stored in ferritin  used for the synthesis of cytochromes, iron-containing enzymes, hemoglobin, and myoglobin  lost from the body with bleeding and sloughed-off cells, sweat, urine, and feces IRON AND HEME METABOLISM
  24. 24. Iron: Metabolism
  25. 25. 25Iron Metabolism: Overview  Key proteins  Transferrin (Tf) - serum Fe+3 transport protein  Transferrin Receptor (TfR) - cellular uptake  Ferritin - cellular Fe+3 storage protein  Hemosiderin - denaturated, insoluble ferritin IRON AND HEME METABOLISM
  26. 26. 26Iron: Transport Transferrin (Tf)  -globulin with a mass of 80 kDa  plays a central role: transports iron  monomeric protein with two similar domains, each of which binds an Fe3+ ion  glycoprotein and is synthesized in the liver  if not bound to iron, it is known as apo- transferrin, a single chain glycoprotein composed of 2 homologous lobes which can independently bind a single Fe3+ IRON AND HEME METABOLISM
  27. 27. 27Iron: Transport Lactoferrin (Lf)  Lactotransferrin  transfer iron and control the level of free iron in the blood  multifunctional protein of the transferrin family  globular glycoprotein with 80 kDa MW  widely represented in various secretory fluids, such as milk, saliva, tears other secretions  better iron retention at low pH IRON AND HEME METABOLISM
  28. 28. 28Iron: Transport  Transferrin and Lactoferrin  maintain the concentration of free iron in body fluids at values below 10–10 mol L–1  low level prevents bacteria that require free iron as an essential growth factor from proliferating in the body IRON AND HEME METABOLISM
  29. 29. 29Cellular Iron Uptake  transferrin (Tf) binds to transferrin receptors (TfRs) on the external surface of the cell  complex is internalized into an endosome, where the pH ~ 5.5  iron separates from the transferrin molecule, moving into the cell cytoplasm  iron transport molecule shuttles the iron to various points in the cell, including mitochondria and ferritin  ferritin molecules accumulate excess iron IRON AND HEME METABOLISM
  30. 30. 30Cellular Iron Uptake  acid pH inside the lysosome causes the iron to dissociate from the protein  unlike the protein component of LDL, apoTf is not degraded within the lysosome but remains associated with its receptor, returns to the plasma membrane, dissociates from its receptor, re-enters the plasma, picks up more iron, and again delivers the iron to needy cells IRON AND HEME METABOLISM
  31. 31. 31 Iron: Storage  Ferritin  where excess iron is stored (liver, spleen, bone marrow)  normally, little ferritin in human serum, but level correlates with total body stores  450 kDa protein consisting of 24 subunits (hollow sphere)  binds Fe2+ ions, which are oxidized to Fe3+ and deposited in the interior of the sphere as ferrihydrate  can contain 3000-4500 ferric atomsbalance IRON AND HEME METABOLISM
  32. 32. 32Iron: Homeostasis synthesis of the transferrin receptor (TfR) and that of ferritin are reciprocally linked to cellular iron content specific untranslated sequences (iron response elements, IREs) of the mRNAs for both proteins interact with a cytosolic protein (iron-responsive element-binding protein or IRPs) sensitive to variations in levels of cellular iron IRON AND HEME METABOLISM
  33. 33. 33Iron: Homeostasis  when iron levels are low  IRE-binding protein (IRP) binds to IRE of ferritin mRNA, so translation of ferritin mRNA is inhibited  IRE-binding protein (IRP) binds to IRE of TfR mRNA  synthesis of TfR proceeds IRON AND HEME METABOLISM
  34. 34. 34Iron: Homeostasis  when iron levels are high  IRE-binding protein cannot bind to IRE of ferritin  translation of ferritin mRNA proceeds  IRE-binding protein cannot bind to IRE of TfR  degradation of TfR mRNA (no translation of TfR) IRON AND HEME METABOLISM
  35. 35. 35Iron: Homeostasis IRON AND HEME METABOLISM
  36. 36. 36Iron: Storage  Hemosiderin  a somewhat ill-defined molecule  appears to be a partly degraded/denatured form of ferritin but still containing iron  iron within deposits of hemosiderin is very poor source of iron when needed  detected by histologic stains (eg, Prussian blue) for iron; presence is determined histologically when excessive storage of iron occursDO IRON AND HEME METABOLISM
  37. 37. 37Iron Metabolism: Disorders  reduced iron level: negatively affects the function of oxygen transport in red blood cells  consequences of reduced iron intake or absorption  increased iron level: bind to and form complexes with numerous macromolecules  disruption in normal activities of the affected complexes  consequences of excess iron intake and storage IRON AND HEME METABOLISM
  38. 38. 38Iron Deficiency Anemia (IDA)  sideropenic anemia  ↓iron intake and/or ↑iron excretion (loss)  ↓ globin protein content in red blood cells as a consequence of the heme control of globin synthesis  microcytic (small) and hypochromic (low pigment) red blood cells IRON AND HEME METABOLISM
  39. 39. 39IDA: Causes  decreased iron intake/absorption  inadequate diet, impaired absorption, gastric surgery, celiac disease  increased iron loss  gastrointestinal bleeding (hemorrhoids, peptic ulcer, neoplasm, ulcerative colitis, hiatal hernia or the gastritis associated with chronic alcohol consumption)  excessive menstrual flow, blood donation, disorders of hemostasis  increased physiologic requirements for iron  infancy, pregnancy, lactation  idiopathic hypochromic anemia IRON AND HEME METABOLISM
  40. 40. 40IDA: Symptoms  attributable to anemia  fatigue, dizziness, headache, palpitation, dyspnea, lethargy, disturbances in menstruation and impaired growth in infancy IRON AND HEME METABOLISM
  41. 41. 41IDA: Symptoms  deficiency of iron  irritability, poor attention span, lack interest in surroundings, poor academic/work performance, behavioral disturbances  pica is the habitual ingestion of unusual substances like earth, clay, laundry starch or ice  usually a manifestation of iron deficiency and is relieved when the deficiency is treated IRON AND HEME METABOLISM
  42. 42. 42IDA: Treatment  diagnosis: determine the cause and source of the excess bleeding  supplementation: oral ferrous sulfate to replace iron loss; IV iron therapy may be necessary  severe cases: packed red blood cells transfusion IRON AND HEME METABOLISM
  43. 43. 43Hereditary Hemochromatosis  primary or type 1  siderosis  excessive iron absorption, saturation of iron-binding proteins and deposition of hemosiderin in the tissues  primary affected tissues are the liver pancreas and skin IRON AND HEME METABOLISM
  44. 44. 44Hereditary Hemochromatosis  iron deposition in the liver, pancreas and heart leads to cirrhosis/liver tumors, diabetes mellitus and cardiac failure  excess iron deposition leads to bronze pigmentation of the organs and skin  bronze skin pigmentation seen in hemochromatosis + resultant diabetes: bronze diabetes IRON AND HEME METABOLISM
  45. 45. 45Hereditary Hemochromatosis  normal HFE: forms a complex with the transferrin receptor (TfR)  regulate the rate of iron transfer into cells  mutation in HFE  increased iron uptake and substitution of Cys 282 by a Tyr storage IRON AND HEME METABOLISM
  46. 46. 46Secondary Hemochromatosis  severe chronic hemolysis of any cause, including intravascular hemolysis and ineffective erythropoiesis (hemolysis within the bone marrow)  multiple frequent blood transfusions for hereditary anemias  excess dietary iron / iron supplementation  other disorders  cirrhosis (alcohol abuse)  steatohepatitis of any cause  porphyria cutanea tarda  prolonged hemodialysis IRON AND HEME METABOLISM
  47. 47. 47Hemochromatosis: Treatment  routine phlebotomy (bloodletting)  may be fairly frequent, perhaps as often as once a week, until iron levels can be brought to normal range  iron chelators  deferoxamine - binds with iron in the bloodstream and enhances its elimination via urine and feces  deferasirox, deferiprone IRON AND HEME METABOLISM
  48. 48. 48porphyrins IRON AND HEME METABOLISM
  49. 49. 50Porphyrins cyclic compounds formed by the linkage of four pyrrole rings through (=HC-) methenyl bridges characteristic property: formation of complexes with metal ions bound to the nitrogen atom of the pyrrole rings  iron porphyrin such as heme of hemoglobin  magnesium-containing porphyrin chlorophyll  cobalt in cobalamine IRON AND HEME METABOLISM
  50. 50. 51Porphyrins  compounds in which various side chains are substituted for the eight hydrogen atoms numbered in the porphin  rings are labeled I, II, III, and IV  substituent positions on the rings are labeled 1, 2, 3, 4, 5, 6, 7, and 8  methenyl bridges (=HC-) are labeled α, β, γ, and δ IRON AND HEME METABOLISM
  51. 51. 52Porphyrins  Fischer proposed a shorthand formula:  rings are labeled I, II, III, and IV  methenyl bridges are omitted  each pyrrole ring is shown as indicated with the eight substituent positions numbered IRON AND HEME METABOLISM
  52. 52. 53Porphyrins:Substituents M : methyl : -CH3 A : acetyl : -CH2COOH P : propionyl : -CH2CH2COOH V : vinyl : -CH=CH2 IRON AND HEME METABOLISM
  53. 53. 54Porphyrins: Type I  APAPAPAP  completely symmetric arrangement of the acetyl (A) and propionyl (P) substituents  uroporphyrins were first found in the urine, but they are not restricted to urine IRON AND HEME METABOLISM
  54. 54. 55Porphyrins: Type III  APAPAPPA  arrangement of the acetyl (A) and propionyl (P) substituents in the uroporphyrin is asymmetric  in ring IV, the expected order of the A and P substituents is reversed  type III series is far more abundant  it includes heme IRON AND HEME METABOLISM
  55. 55. 56Coproporphyrin I and III  substituents are methyl (M) and propionyl (P)  first isolated in feces but are also found in urine IRON AND HEME METABOLISM
  56. 56. 57 Protoporhyphyrin III  precursor of heme  substituents are methyl (M) and vinyl (V)  MVMVMPPM  position of the methyl group is reversed on the fourth ring,  sometimes considered as type IX; designated ninth in a series of isomers by Fischername IRON AND HEME METABOLISM
  57. 57. 58Name That Porphyrin! Coproporphyrin III Uroporphyrin I IRON AND HEME METABOLISM
  58. 58. 59Name That Porphyrin! Uroporphyrin III Coproporphyrin I IRON AND HEME METABOLISM
  59. 59. 60Name That Porphyrin! Protoporphyrin III (IX) IRON AND HEME METABOLISM
  60. 60. 61Name That Porphyrin!!!Protoporphyrin III (IX)HM IRON AND HEME METABOLISM
  61. 61. Biosynthesis of Heme
  62. 62. 64Heme: Biosynthesis  bone marrow – incorporation into Hgb  liver – requirement for cytochromes  eight enzymatic steps, first and last three steps: mitchondrial  organic portions of heme derived from 8 residues of glycine and succinyl CoA  porphyrinogens – intermediates involved in reactions involving the side groups IRON AND HEME METABOLISM
  63. 63. 65STEP 1: Biosynthesis of -AminolevulinicAcid (ALA) Succinyl CoA (TCA) condenses with glycine, subsequent decarboxylation to yield -aminolevulinate (ALA) catalyzed by ALA synthase synthesis of ALA occurs in mitochondria pyridoxal phosphate activates glycine IRON AND HEME METABOLISM
  64. 64. 66STEP 2: Biosynthesis of Phorphobilinogen  2 molecules of ALA are condensed by the enzyme ALA dehydratase  porphobilinogen (PBG) and 2 molecules H2O  catalyzed by ALA dehydratase – very sensitive to inhibition by heavy metals, e.g., lead poisoning  occurs in the cytosol  first pathway intermediate that includes a pyrrole ring IRON AND HEME METABOLISM
  65. 65. 67 STEP 3: Synthesis of Hydroxymethylbilane  formation of a cyclic tetrapyrrole (porphyrin)  condensation of four molecules of PBG in a head-to-tail manner to form a linear tetrapyrrole, hydroxymethylbilane (HMB)  catalyzed by uroporphyrinogen I synthase (PBG deaminase or HMB synthase), no ring-closing function  occurs in the cytosolstructure of HMB IRON AND HEME METABOLISM
  66. 66. 68STEP 3: Synthesis of Hydroxymethylbilane IRON AND HEME METABOLISM
  67. 67. STEP 4. Synthesis of Uroporphyrinogen 69from Hydroxymethylbilane  HMB cyclizes spontaneously to form uroporphyrinogen I  HMB converted to uroporphyrinogen III by the action of uroporphyrinogen III synthase  under normal conditions, the uroporphyrinogen formed is almost exclusively the III isomer IRON AND HEME METABOLISM
  68. 68. 70STEP 5: Decarboxylation ofUroporphyrinogens to Coproporphyrinogens  decarboxylation of all acetate (A)  methyl (M) groups  catalyzed by uroporphyrinogen decarboxylase, also converts uroporphyrinogen I to coproporphyrino- gen I  porphyria cutanea tarda IRON AND HEME METABOLISM
  69. 69. STEP 6. Conversion of Coproporphyrinogen IIIto Protoporphyrinogen III  coproporphyrinogen III then enters the mitochondria  coproporphyrinogen oxidase catalyzes the decarboxylation and 6 oxidation of two propionic side chains (from P to V) to form protoporphyrinogen III  enzyme acts only on coproporphyrinogen III; why type I protoporphyrins do not generally occur in nature COO- CH2 CH2 + CO2 CH2 CH propionate vinyl
  70. 70. 72STEP 7. Conversion ofProtoporphyrinogen III to Protophyrin III  oxidation of protoporphyrinogen III (IX) to protoporphyrin III (IX) is catalyzed by protoporphyrinogen oxidase  porphyrinogen converted to porphyrin;  methylene (-CH2-) bridges oxidized to methenyl/methyne (–CH=) bridges 7  occurs in the mitochondria PP IRON AND HEME METABOLISM
  71. 71. Porphyrinogen  Porphyrin H2C N CH 2 HC CH N H H NH HN N N H -6H H H2C N CH 2 N HC CH Porphyrinogen porphyrinogen Porphyrin porphyrin  no resonance between  methylene bridges oxidized to pyrrole groups methenyl bridges  colorless (continuous resonance =  mostly non-enzymatic, stability) presence of light  colored  characteristic absorption spectrum (visible and UV) IRON AND HEME METABOLISM
  72. 72. 74Porphyrin: Absorption Spectrum  sharp absorption near 400 NM  distinguishing feature of the porphyrin ring  characteristic of all porphyrins regardless of the side chains  Soret band  fluoresce (red) when illuminated by UV IRON AND HEME METABOLISM
  73. 73. 75STEP 8. Addition of iron to ProtoporphyrinIII to form Heme  final step in heme synthesis  incorporation of ferrous iron into protoporphyrin  catalyzed by ferrochelatase (heme synthase)  occurs in the mitochondria IRON AND HEME METABOLISM
  74. 74. 76Compartmentation  ALA synthase (Step 1) and last 3 (steps 6, 7 and 8) enzymes in the pathway are located in the mitochondrion  whereas the other enzymes are cytosolic  all cells except RBC  bone marrow: ~ 85% of heme synthesis; the rest in liver IRON AND HEME METABOLISM
  75. 75. 77 Heme Biosynthesis: Regulation ALA synthase is the key and rate-regulating enzyme  induced by drugs and other substances  drug-induced porphyrias glucose (unknown mechanism): inhibits heme biosynthesis IRON AND HEME METABOLISM
  76. 76. 78 Heme Biosynthesis: Regulation ALA synthase is the key and rate-regulating enzyme  synthesis of ALA synthase is repressed by heme, the end product of the pathway (feedback inhibition)  heme also affects translation of the enzyme and its transfer from the cytosol to the mitochondrion IRON AND HEME METABOLISM
  77. 77. 79Heme Biosynthesis: Regulation  heme regulates the synthesis of hemoglobin by stimulating synthesis of the protein globin  heme maintains the ribosomal initiation complex for globin synthesis in an active state  usage of heme by other processes  cytochrome P450 in xenobiotic metabolismDO IRON AND HEME METABOLISM
  78. 78. 80Heme Biosynthesis: Disorders  Porphyrias  inherited or acquired diseases that result from an abnormal metabolism in heme biosynthesis  main causes are partial or complete enzyme deficiencies  compensatory mechanisms: attempt to make more heme  most common  Acute Intermittent Porphyria (AIP)  Porphyria Cutanea Tarda (PCT)  Protoporphyria (PP) IRON AND HEME METABOLISM
  79. 79. 81  if the enzyme lesionPorphyrias occurs before formation of porphyrinogens, ALA and PBG accumulate  clinically, patients complain of neuropsychiatric symptoms  abdominal pain  peripheral neuropathy  mental disturbance IRON AND HEME METABOLISM
  80. 80. 82  if enzyme blocksPorphyrias later  accumulation of the porphyrinogens  highly unsaturated porphyrin rings can absorb UV/visible light and become photoreactive  porphyrin derivatives cause photosensitivity IRON AND HEME METABOLISM
  81. 81. 83Photosensitivity  photosensitivity - a reaction to visible light of about 400 nm  porphyrins, when exposed to light of this wavelength  “excited” and then react with molecular oxygen to form oxygen radicals (reactive oxygen species, ROS)  species injure lysosomes and other organelles  damaged lysosomes release their degradative enzymes, causing variable degrees of skin damage, including scarring IRON AND HEME METABOLISM
  82. 82. 84Porphyria Photosensitivity IRON AND HEME METABOLISM
  83. 83. 85Porphyrias  two major groups of porphyrias according to the site of dysfunction:  Erythropoietic  Congenital Erythropoietic Porphyria  Protoporphyria  Hepatic  ALA dehydratase deficiency  Acute Intermittent Porphyria  Hereditary Coproporphyria  Variegate Porphyria  Porphyria Cutanea Tarda IRON AND HEME METABOLISM
  84. 84. 86 Porphyria Cutanea Tarda (PCT)  most common form of porphyria  hepatic; uroporphyrinogen decarboxylase deficiency  acquired disorder, associated with estrogen, drugs and alcohol use  photosensitivity is the only major manifestation  other cutaneous manifestations: dermal abrasions, superficial erosions and blister formation after trivial mechanical trauma  lesions leave depigmented and pigmented scars  hypertricosis  diagnosis: increased urinary uroporphyrin Isymptoms IRON AND HEME METABOLISM
  85. 85. 87 Porphyria Cutanea Tarda (PCT)myths IRON AND HEME METABOLISM
  86. 86. 88Porphyria Cutanea Tarda (PCT)  PCT is implicated in the origin of vampire and werewolf myths (hypertricosis)  people with the disease tend to avoid the sun due to blistering and desire iron rich foods (blood and meat) due to their enzymatic deficiency  description of the title character of Bram Stokers Dracula: "His eyebrows were very massive, almost meeting over the nose, and with bushy hair that seemed to curl in its own profusion. The mouth ... was fixed and rather cruel-looking, with peculiarly sharp white teeth; these protruded over the lips, whose remarkable ruddiness showed astonishing vitality in a man of his years ... The general effect was one of extraordinary pallor." IRON AND HEME METABOLISM
  87. 87. 89 Acute Intermittent Porphyria (AIP)  hepatic; uroporphyrinogen I synthase (PBG deaminase, hydroxymethylbilane synthase) deficiency  majority of patients are asymptomatic  abdominal pain: initial and commonest manifestation  clinical picture may mimic an acute inflammatory abdominal disease  neuropsychiatric symptoms: peripheral neuropathy, nerve atrophy, CNS abnormalities (confusion, hallucinations, delirium and seizures)  precipitating factors are drugs as barbiturates, sulfonamides, estrogens and dietary restriction of carbohydrates  diagnosis: increased erythrocytic and urinary porphobilinogen (PBG) and aminolevolinic acid (ALA) levelsvincent IRON AND HEME METABOLISM
  88. 88. 90Acute Intermittent Porphyria (AIP) VINCENT (Don Mclean) Starry, starry night. Flaming flowers that brightly blaze, Swirling clouds in violet haze, Reflect in Vincents eyes of china blue. Colors changing hue, morning field of amber grain, Weathered faces lined in pain, Are soothed beneath the artists loving hand. …For they could not love you, But still your love was true. And when no hope was left in sight On that starry, starry night, You took your life, as lovers often do. But I could have told you, Vincent, This world was never meant for one As beautiful as you. …Now I think I know what you tried to say to me, How you suffered for your sanity, How you tried to set them free. They would not listen, theyre not listening still. Perhaps they never will... IRON AND HEME METABOLISM
  89. 89. 91Protoporphyria (PP or EPP)  erythropoietic protoporphyria (EPP); ferrochelatase deficiency  mild photosensitivity occurs after sunlight exposition, characterized by painful burning or stinging sensations, pruritus, erythema, and occasional edema  mild abnormalities in liver, biliary tract (protoporphyrin gallstones) and blood may be present  diagnosis: increased fecal and red cell protoporphyrin III (IX) IRON AND HEME METABOLISM
  90. 90. 92Drug-Induced Porphyria  some drugs can induce attacks, e.g.:  barbiturates, griseofulvin, chlor oquine, dapsone, etc.  highly lipid-soluble drugs  induce cytochrome P450 which uses up here  de- represses (up-regulate) ALA synthase  ↑ levels of heme precursors IRON AND HEME METABOLISM
  91. 91. 93Lead Intoxication  can mimic symptoms of porphyrias  combines with ALA dehydratase  activity  ALA accumulates  lead inhibits ferrochelatase, accumulate protoporphyrin III (IX) IRON AND HEME METABOLISM
  92. 92. 94 Porphyrias: Treatment  symptomatic  avoid drugs that cause induction of cytochrome P450  glucose loading - ingestion of large amounts of carbohydrates  administration of hematin (a hydroxide of heme) to repress ALAS1, resulting in diminished production of harmful heme precursors  β-carotene: decrease production of free radicals, thus diminishing photosensitivity and tissue damage  sunscreens that filter out visible lightheme degradation IRON AND HEME METABOLISM
  93. 93. 95Overviewof HemeDegradation IRON AND HEME METABOLISM
  94. 94. 96Degradation of Hemoglobin  ~ 100–200 million aged RBCs/hr are broken down in a person  a 70-kg human turns over approximately 6 g/day of hemoglobin hemoglobin is destroyed:  globin  amino acids (reused)  iron enters the iron pool  iron-free porphyrin degraded, mainly in the reticuloendothelial (RES) cells of the liver, spleen, and bone marrow IRON AND HEME METABOLISM
  95. 95. 97Heme Degradation  the tetrapyrrole ring of heme is oxidatively cleaved between rings I and II by heme oxygenase NADPH + requiring O2 and + NADP+ NADPH + H+  produces green biliverdin, CO and Fe 2+ (recycled) IRON AND HEME METABOLISM
  96. 96. 98Heme Degradation  biliverdin is reduced by biliverdin reductase to the orange colored bilirubin  reduction breaks the system down into two smaller separate systems IRON AND HEME METABOLISM
  97. 97. 99Bilirubin Transport  bilirubin is transported to the liver bound to albumin  antibiotics / other drugs compete with bilirubin for the high-affinity binding site on albumin  displace bilirubin  jaundice  a transporter moves dissociated bilirubin into the liver cells  inside the cell, cytosolic proteins (ligandin , protein Y) binds bilirubin IRON AND HEME METABOLISM
  98. 98. 100Bilirubin Conjugation  bilirubin is conjugated with UDP-glucuronic acid into the water- soluble bilirubin monoglucuronides and diglucuronides  occurs in the endoplasmic reticulum  excreted into the bile IRON AND HEME METABOLISM
  99. 99. 101Bilirubin Conjugation  UDP-glucuronosyltransferase (bilirubin-UGT) forms ester type bonds between the OH group at C-1 of glucuronic acid and the carboxyl groups in bilirubin IRON AND HEME METABOLISM
  100. 100. 102 Bilirubin Conjugation  rate-determining step in hepatic bilirubin metabolism  drugs (phenobarbital, etc) induce both conjugate formation and the transport process of bilirubinB1 vs B2 IRON AND HEME METABOLISM
  101. 101. 103 Unconjugated Vs Conjugated Bilirubin B1 vs B2 Type Solubility Van den Berg Reaction Reacts more slowly; Unconjugated Still produces Indirect bilirubin Lipid/ Fat Soluble azobilirubin. Alcohol B1 makes all bilirubin react promptly Water Soluble Reacts quickly when Conjugated dyes (diazo reagent) (bound to Direct Bilirubin are added to the blood glucuronic acid) specimen to produce B2 azobilirubinexcretion IRON AND HEME METABOLISM
  102. 102. 104 Bilirubin Excretion glucuronides are then excreted by active transport (MRP-2) into the bile as bile pigments bacterial glucuronidases convert bilirubin in the intestine to urobilinogen and further reduced to stercobilinogen, which are oxidized into orange to yellow- colored stercobilin (feces) IRON AND HEME METABOLISM
  103. 103. 105Bilirubin Excretion  end products of bile pigment metabolism in the intestine are mostly excreted in feces, 10% resorbed (enterohepatic circulation)  with excessive heme degradation, urobilinogen spills out into the circulation and excreted in the urine, where oxidative processes darken it to form urobilin (urochrome)DO IRON AND HEME METABOLISM
  104. 104. 106Heme Metabolism: Disorders  Hyperbilirubinemia  when bilirubin in the blood increases beyond normal and exceeds 1 mg/dL (17.1 μmol/L)  when it reaches a certain concentration (approximately 2–2.5 mg/dL), it diffuses into the tissues, which then become yellow (jaundice or icterus) IRON AND HEME METABOLISM
  105. 105. 107Hyperbilirubinemia: Causes  Pre-Hepatic  ↑ bilirubin production  Hepatic  ↓ bilirubin conjugation  micro-obstruction  Post-Hepatic  ↓ bilirubin excretion IRON AND HEME METABOLISM
  106. 106. 108Hyperbilirubinemia: Pre-Hepatic  Hemolytic Anemia  important cause of unconjugated hyperbilirubinemia  results from excessive RBC destruction  hereditary – sickle cell, thalassemia, G6PD deficiency  acquired – hypersplenism, drugs, poisons  ↑ indirect bilirubin, urine and fecal urobilinogen  absent urine bilirubin (acholuric jaundice)  retention hyperbilirubinemia IRON AND HEME METABOLISM
  107. 107. 109 Hyperbilirubinemia: Intra-Hepatic  Neonatal “Physiologic” Jaundice  transient condition, most common cause of unconjugated hyperbilirubinemia  accelerated hemolysis  immature hepatic system for the uptake, conjugation, and secretion of bilirubin  reduced synthesis of the substrate for that enzyme, bilirubin-UGT  ↑ indirect bilirubin  ↓ urine and fecal urobilinogenphotoTx IRON AND HEME METABOLISM
  108. 108. 110Hyperbilirubinemia: Intra-Hepatic  Pathologic Jaundice  excessive unconjugated bilirubin (> (20–25 mg/dL)  penetrates the blood-brain barrier  hyperbilirubinemic toxic encephalopathy, or kernicterus, which can cause neurological deficits, mental retardation or death IRON AND HEME METABOLISM
  109. 109. 111Hyperbilirubinemia: Intra-Hepatic  Criggler-Najar Syndrome  rare autosomal recessive disorder, severe congenital jaundice; Type I and II  mutations in the gene encoding for Bilirubin-UGT  no bilirubin conjugation  often fatal (before 15 mos)  ↑ indirect bilirubin  absent urine bilirubin  ↓ urine, fecal urobilinogen IRON AND HEME METABOLISM
  110. 110. 112Hyperbilirubinemia: Intra-Hepatic  Gilbert Syndrome  caused by mutations in the gene encoding Bilirubin-UGT (~ 30% enzyme activity)  harmless jaundice seen during times of stress, fasting, drug intake  most common disorder affecting bilirubin metabolism (3-7% of population)  no treatment needed IRON AND HEME METABOLISM
  111. 111. 113Hyperbilirubinemia: Intra-Hepatic  Toxic Hyperbilirubinema  acquired disorders from hepatic parenchymal cell damage; impairs conjugation  infection or toxin- induced liver damage: hepatitis, chemicals, toxins IRON AND HEME METABOLISM
  112. 112. 114Hepatic Jaundice  Liver damage (cirrhosis, hepatitis) :  less efficient uptake and conjugation of bilirubin  leakage of unconjugated (and conjugated) bilirubin into blood IRON AND HEME METABOLISM
  113. 113. 115Hyperbilirubinemia: Post-Hepatic  Biliary Tree Obstruction  conjugated hyperbilirubinemia  blockage of biliary ducts (gallstone, cancer of the head of the pancreas, etc)  B2 cannot be excreted; regurgitated into the hepatic veins and lymphatics  regurgitation hyperbilirubinemia  B2 appears in the urine (choluric jaundice)  cholestatic jaundice IRON AND HEME METABOLISM
  114. 114. 116Hyperbilirubinemia: Post-Hepatic  Dubin-Johnson Syndrome  autosomal recessive disorder  conjugated hyperbilirubinemia  mutations in the gene encoding MRP-2, the protein involved in the secretion of conjugated bilirubin into bile  centrilobular hepatocytes contain an abnormal black pigment (derived from epinephrine)  black liver IRON AND HEME METABOLISM
  115. 115. 117 Hyperbilirubinemia: Post-Hepatic  Rotor Syndrome –  rare benign condition  chronic conjugated hyperbilirubinemia  similar to DJS except that the liver cells are not pigmented (normal liver)  cause unknown; impaired biliary excretion of conjugated BR  maybe due to an abnormality in hepatic storage named after the Filipino internist, Arturo Belleza Rotor (1907–1988)??? Dx IRON AND HEME METABOLISM
  116. 116. 119Hyperbilirubinemia: Diagnosis  pre-hepatic  ↑ unconjugated bilirubin  ↑ urine urobilinogen  ↑ fecal urobilinogen  unconjugated bilirubin does not pass into urine  no bilirubin in urine (acholuric jaundice) IRON AND HEME METABOLISM
  117. 117. 120Hyperbilirubinemia: Diagnosis ( )  intra-hepatic  ↑ unconjugated (and conjugated bilirubin)  ↓ fecal urobilinogen  ↓ urine, fecal urobilinogen  + urine bilirubin IRON AND HEME METABOLISM
  118. 118. 121 Hyperbilirubinemia: Diagnosis  post-hepatic  ↑ conjugated bilirubin  bilirubin in the urine (choluric jaundice)  absent urine, stool urobilinogenTY IRON AND HEME METABOLISM