Heme Synthesis and Porphyria Flashcards Preview

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Flashcards in Heme Synthesis and Porphyria Deck (18)
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describe the structure of heme

  • ferrous protoporphyrin IX
  • 4 pyrrole rings (A-D) are linked via methenyl bridges
  • side chains:
    • A: methyl, vinyl
    • B: methyl, vinyl
    • C: methyl, propionyl
    • D: propionyl, methyl
  • Ring D is asymmetric


name the tissues where heme is needed

  • bone marrow: hemoglobin synthesis
  • hepatocytes: cytochrome P450 synthesis
    • needed as prosthetic group for enzymes


describe the overview of heme synthesis


describe the steps of heme synthesis (# of each molecule needed for each step)

  • succinyl CoA and glycine form ALA in the mitochondria
  • ALA leaves the mt and 2 ALAs form PBG in cytosol
  • 4 PBGs form HMB
  • HMB rings closed to form uroporphyrinogen III
  • coporphyrinogen III is formed in the cytosol and transported to mitochondria
  • insertion of ferrous iron into protoporphyrin IX leads to heme


describe function of ALA synthase

regulated step

  • succinyl CoA and glycine are the substrates of ALA synthase and glycine is decarboxylated to form ALA
  • PLP is needed as a coenzyme


describe the regulation of ALA synthase

  • heme inhibits ALA synthase in hepatocytes
  • low iron inhibits in erythroid cells


describe heme synthesis in the liver

  • heme synthesis stops when heme accumulates and is not incorporated into proteins since heme can damage cells
    • ALAS1 is directly controlled by intracellular heme levels
    • heme reduces ALAS1 transcription, translation and stability of mRNA and import of ALAS1 from cytosol to mt
  • low intracellular heme stimulates ALAS1
  • drugs increase ALAS1 activity when they lead to CYP 450 synthesis


describe hemoglobin synthesis in bone marrow

  • erythropoietin is released by the kidney at low O2 levels in tissues and stimulates RBC and hemoglobin synthesis
  • iron uptake is stimulated in erythroblasts and iron availability in erythroid cells controls heme synthesis 
  • ALAS2 is regulated by intracellular iron
    • the gene for ALAS2 is on the X-chromosome and deficiency leads to X-linked sideroblastic anemia


give the overview of enzymes used in heme synthesis


describe the function of ALA dehydratase (porphobilinogen synthase) and PBG deaminase (HMB synthase)

  • ALA dehydratase (PBG synthase) uses 2 ALAs to form porphobillinogen
    • zinc is needed as a cofactor
      • lead poisoning covers zinc and inhibits enzyme
  • PBG deaminase (HMB synthase) aligns and deaminates 4 porphobilinogens to form hydroxymethylbilane (HMB)
    • it is critical that the enzymatic ring closure of HMB form the porphyrin III ring system and leads to an asymmetric pyrrole ring D


what 2 factors can inhibit erythroid heme synthesis and lead to microcytic anemia?

  1. lead inhibition
    • lead interacts with the zinc cofactors for ALA dehydratase and ferrochelatase
    • mostly ALA and some protoporhyrin IX accumulate in blood and urine
  2. deficiency of vitamin B6
    • PLP is needed as a coenzyme for ALA synthase 
    • isoniazid used for TB treatment leads to PLP depletion, therefore vit B6 supplement needed 


describe acute intermittent porphyria

  • deficiency of hepatic PBG deaminase (aka HMB synthase)
  • porphobilinogen cannot be used to form HMB
  • ALA accumulates as synthesis of ALA synthase is stimulated by low hepatic heme levels
    • ALA has a similar structure to GABA and competes for binding of GABA receptors
    • patients are not photosensitive as HMB and porphyrins cannot be formed
  • porphobilinogen accumulates in blood and urine and is changed by air air and light to purple


describe AIP onset and treatment

  • severity of acute symptoms can be diminished by IV glucose and saline
    • glucose reduces ALAS1 gene expression
  • IV hemin may be needed in order to directly inhibit ALAS1 gene expression
  • BARBITUATES SHOULD NOT BE USED since it stimulates cytochrome P450 synthesis (which needs heme)


describe congenital erythropoietic porphyria

  • defect only in bone marrow
  • deficiency of erythroid uroporphyrinogen III synthase leads to abnormal porphyrins and severe photosensitivity 
    • photosensitivity caused by accumulation of HMB turning into uroporphyrin I and coproporphyrin  I 


explain why there is severe photosensitivity in CEP

  • erythroid uroporphyrinogen III synthase is deficient and HMB spontaneously forms the abnormal porphyrin I ring
  • both abnormal porphyrinogens type I lead to red colored uroporphyrin I and coproporphyrin I which accumulate in skin and tissue which leads to extremely severe and painful photosensitivity caused by ROS formation
  • urine is red


name the clinical features of CEP

  • ROS damage leads to poor wound healing, severe blisters and ulcers
  • teeth are reddish-brown
  • hypertrichosis is severe in CEP with werewolf features, hairy face and arms


describe porphyria cutanea tarda (PCT)

  • caused by deficiency in uroporphyrinogen decarboxylase
  • common photosensitivity with cutaneous lesions caused by uroporphyrin III accumulation in liver, blood and skin


contrast the cause/onset of CEP and PCT

  • CEP = caused by deficiency of uroporphyrinogen III synthase
    • childhood onset
  • PCT = uroporphyrinogen III decarboxylase
    • adult onset
    • Type I = chronic disease of the liver (hepatitis, ethanol abuse)
    • Type II = familial