Lecture 6: Heme Biochemistry Flashcards
Describe the structure of hemoglobin.
4 globular protein subunits
-each subunit is bound to iron containing heme
What is heme?
Heterocyclic porphyrin ring with Fe2+ in center
-four 5-membered rings containing nitrogen
What happens in phase 1 of the biosynthesis of heme?
Where does this happen?
Mitochondria of liver and erythroid cells
- Glycine + Succinyl CoA —> ALA (needs Vit B6)
- enzyme: ALA synthase
What happens in phase 2 of the biosynthesis of heme?
Where does this happen?
Cytoplasm of liver and erythroid cells
1) ALA + ALA –> Porphobilinogen (PB)
- enzyme: ALA dehydratase
2) 4 PB –> Coproporphyrinogen
What happens in phase 3 of the biosynthesis of heme?
Where does this happen?
Mitochondria of liver and erythroid cells
1) Coproporphyrinogen —-> Heme
- enzyme: Ferrochelatase inserts iron in heme
A defect in any stage of heme synthesis can cause what?
Porphyria
Why is lead poisoning so dangerous?
Inactivates ALA dehydratase and ferrochelatase
- accumulation of ALA and protoporphyrin IX, which can be toxic and anemia
- impacts ATP synthesis and energy metabolism
What type of symptoms are seen in acute hepatic porphyrias?
Neurological symptoms
What type of symptoms are seen in erythropoietic porphyrias?
Skin issues
Photosensitivity
Describe acute intermittent porphyria.
Hepatic
- defective PBF deaminase: excess production of ALA and PBG
- autosomal dominant
- abdominal pain
Describe congenital erythropoietic porphyria.
Erythropoietic
- defective uroporphyrinogen III synthase: accumulation of of uroporphyrinogen
- autosomal recessive
- photosensitivity
- red color urine and teeth
Describe porphyria cutanea tarda.
Hepatoerythropoietic
- defective uroporphyrinogen decarboxylase: accumulation of uroporphyrinogen
- autosomal dominant
- most common in US
- photosensitivity
- wine red urine
Describe variegate porphyria.
Hepatic
- defective enzyme: protoporphyrinogen IX oxidase
- autosomal dominant
- photosensitivity
- neurological symptoms and developmental delay in children
- celebrity porphyria
Describe the process of heme degradation.
1) Heme oxygenase removes bridge between pyrrole rings of heme (needs oxygen)
2) Iron converted from Fe 2+ to Fe 3+
3) Biliverdin synthesized
4) Biliverdin –> Bilirubin via biliverdin reductase and NADPH
What is the fate of bilirubin?
1) Free/unconjugated bilirubin released into blood stream and is bound to albumin.
2) Free/unconjugated bilirubin transported to liver
3) In liver, bilirubin is conjugated with glucuronic acid (now soluble)
4) Known as bilirubin-diglucuronide
What is the rate limiting enzyme in the conjugation of bilirubin?
UDP glucuronyl transferase
What is the fate of bilirubin-diglucuronide?
1) Can enter gallbladder as part of bile
2) Becomes urobilinogen in small intestine and colon
Option 1: Converts to urobilin in kidney and excreted as urine
Option 2: Converts to stercobilin and excreted as feces
Describe pre-hepatic jaundice.
Increased production of unconjugated/indirect bilirubin
- excess hemolysis
- internal hemorrhage
- elevated urobilinogen levels in urine
What can cause pre-hepatic jaundice?
Problems with incompatibility of maternal-fetal blood groups in neonates
Describe intra-hepatic jaundice.
Impaired hepatic uptake, conjugation, or secretion of conjugated bilirubin
-normal urobilinogen levels in urine
Where can intra-hepatic jaundice be seen?
Liver cirrhosis
Viral hepatitis
Criggler-Najjar syndrome
Gilbert syndrome
Describe post-hepatic jaundice.
Problems with bilirubin excretion
-pale stool and dark urine
What can cause post-hepatic jaundice?
Obstruction to biliary drainage Cholangiocarcinoma Gallstones Infiltrative liver disease Lesions Drugs
Describe neonatal jaundice.
Jaundice due to elevation of unconjugated bilirubin
- deficiency of UDP-GT enzyme
- breakdown of fetal hemoglobin
How would you treat neonatal jaundice?
1) Exposure to blue fluorescent light, bilirubin forms more soluble isomers
2) Injection of tin-mesoporphyrin to prevent heme breakdown to form bilirubin
Criggler-Najjar syndrome results from a deficiency of what?
UDP-GT enzyme
Describe Criggler-Najjar syndrome (type I).
Severe hyperbilirubinemia
-bilirubin accumulates in brain of babies and can cause encephalopathy
Describe Gilbert syndrome.
Reduced activity of UDP-GT
What is hepatitis?
Inflammation of liver leading to liver dysfunction
- increased levels of unconjugated and conjugated bilirubin in blood
- can cause yellow discoloration and dark colored urine
