Lecture 6: Heme Biochemistry

Question 1

Describe the structure of hemoglobin.

Answer 1

4 globular protein subunits

-each subunit is bound to iron containing heme

Question 2

What is heme?

Answer 2

Heterocyclic porphyrin ring with Fe2+ in center

-four 5-membered rings containing nitrogen

Question 3

What happens in phase 1 of the biosynthesis of heme?

Where does this happen?

Answer 3

Mitochondria of liver and erythroid cells

• Glycine + Succinyl CoA —> ALA (needs Vit B6)
• enzyme: ALA synthase

Question 4

What happens in phase 2 of the biosynthesis of heme?

Where does this happen?

Answer 4

Cytoplasm of liver and erythroid cells

1) ALA + ALA –> Porphobilinogen (PB)
- enzyme: ALA dehydratase

2) 4 PB –> Coproporphyrinogen

Question 5

What happens in phase 3 of the biosynthesis of heme?

Where does this happen?

Answer 5

Mitochondria of liver and erythroid cells

1) Coproporphyrinogen —-> Heme
- enzyme: Ferrochelatase inserts iron in heme

Question 6

A defect in any stage of heme synthesis can cause what?

Answer 6

Porphyria

Question 7

Why is lead poisoning so dangerous?

Answer 7

Inactivates ALA dehydratase and ferrochelatase

• accumulation of ALA and protoporphyrin IX, which can be toxic and anemia
• impacts ATP synthesis and energy metabolism

Question 8

What type of symptoms are seen in acute hepatic porphyrias?

Answer 8

Neurological symptoms

Question 9

What type of symptoms are seen in erythropoietic porphyrias?

Answer 9

Skin issues

Photosensitivity

Question 10

Describe acute intermittent porphyria.

Answer 10

Hepatic

• defective PBF deaminase: excess production of ALA and PBG
• autosomal dominant
• abdominal pain

Question 11

Describe congenital erythropoietic porphyria.

Answer 11

Erythropoietic

• defective uroporphyrinogen III synthase: accumulation of of uroporphyrinogen
• autosomal recessive
• photosensitivity
• red color urine and teeth

Question 12

Describe porphyria cutanea tarda.

Answer 12

Hepatoerythropoietic

• defective uroporphyrinogen decarboxylase: accumulation of uroporphyrinogen
• autosomal dominant
• most common in US
• photosensitivity
• wine red urine

Question 13

Describe variegate porphyria.

Answer 13

Hepatic

• defective enzyme: protoporphyrinogen IX oxidase
• autosomal dominant
• photosensitivity
• neurological symptoms and developmental delay in children
• celebrity porphyria

Question 14

Describe the process of heme degradation.

Answer 14

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

Question 15

What is the fate of bilirubin?

Answer 15

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

Question 16

What is the rate limiting enzyme in the conjugation of bilirubin?

Answer 16

UDP glucuronyl transferase

Question 17

What is the fate of bilirubin-diglucuronide?

Answer 17

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

Question 18

Describe pre-hepatic jaundice.

Answer 18

Increased production of unconjugated/indirect bilirubin

• excess hemolysis
• internal hemorrhage
• elevated urobilinogen levels in urine

Question 19

What can cause pre-hepatic jaundice?

Answer 19

Problems with incompatibility of maternal-fetal blood groups in neonates

Question 20

Describe intra-hepatic jaundice.

Answer 20

Impaired hepatic uptake, conjugation, or secretion of conjugated bilirubin
-normal urobilinogen levels in urine

Question 21

Where can intra-hepatic jaundice be seen?

Answer 21

Liver cirrhosis
Viral hepatitis
Criggler-Najjar syndrome
Gilbert syndrome

Question 22

Describe post-hepatic jaundice.

Answer 22

Problems with bilirubin excretion

-pale stool and dark urine

Question 23

What can cause post-hepatic jaundice?

Answer 23

Obstruction to biliary drainage
Cholangiocarcinoma
Gallstones
Infiltrative liver disease
Lesions
Drugs

Question 24

Describe neonatal jaundice.

Answer 24

Jaundice due to elevation of unconjugated bilirubin

• deficiency of UDP-GT enzyme
• breakdown of fetal hemoglobin

Question 25

How would you treat neonatal jaundice?

Answer 25

1) Exposure to blue fluorescent light, bilirubin forms more soluble isomers
2) Injection of tin-mesoporphyrin to prevent heme breakdown to form bilirubin

Question 26

Criggler-Najjar syndrome results from a deficiency of what?

Answer 26

UDP-GT enzyme

Question 27

Describe Criggler-Najjar syndrome (type I).

Answer 27

Severe hyperbilirubinemia

-bilirubin accumulates in brain of babies and can cause encephalopathy

Question 28

Describe Gilbert syndrome.

Answer 28

Reduced activity of UDP-GT

Question 29

What is hepatitis?

Answer 29

Inflammation of liver leading to liver dysfunction

• increased levels of unconjugated and conjugated bilirubin in blood
• can cause yellow discoloration and dark colored urine