Heme Synthesis and Porphyria

Question 1

describe the structure of heme

Answer 1

• 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

Question 2

name the tissues where heme is needed

Answer 2

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

Question 3

describe the overview of heme synthesis

Answer 3

Question 4

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

Answer 4

• 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

Question 5

describe function of ALA synthase

Answer 5

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

Question 6

describe the regulation of ALA synthase

Answer 6

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

Question 7

describe heme synthesis in the liver

Answer 7

• 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

Question 8

describe hemoglobin synthesis in bone marrow

Answer 8

• 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

Question 9

give the overview of enzymes used in heme synthesis

Answer 9

Question 10

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

Answer 10

• 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

Question 11

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

Answer 11

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

Question 12

describe acute intermittent porphyria

Answer 12

• 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

Question 13

describe AIP onset and treatment

Answer 13

• 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)

Question 14

describe congenital erythropoietic porphyria

Answer 14

• 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

Question 15

explain why there is severe photosensitivity in CEP

Answer 15

• 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

Question 16

name the clinical features of CEP

Answer 16

• 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

Question 17

describe porphyria cutanea tarda (PCT)

Answer 17

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

Question 18

contrast the cause/onset of CEP and PCT

Answer 18

• 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