7. Heme Biochemistry

Question 1

What is the name of the ring structure of heme?

Answer 1

Porphyrin ring

Question 2

Describe the biosynthesis of heme.

Answer 2

Phase I (in mitochondria): glycine and succinyl CoA is converted to ALA.

Phase II (in cytosol): two ALA combine to form PB. Four PB combine to form coproporphyrinogen III.

Phase III (in mitochondria): Coproporphyrinogen III leads to production of protoporphyrin IX. Fe2+ then inserted by ferrochelatase to make heme.

Question 3

What is the rate limiting reaction in heme synthesis? What vitamin does it need to function?

Answer 3

ALA synthase

Needs vitamin B6 to function

Question 4

How does lead poisoning cause anemia and neurological symptoms?

Answer 4

It inactives the enzymes ALA dehydratase and ferrochelatase, leading to ALA and protoporphyrin accumulation. ALA is neurotoxic, and heme production is lowered.

Question 5

What are the symptoms of acute hepatic porphyrias and eythropoietic porphyrias?

Answer 5

Acute hepatic: neurological symptoms

Erythropoietic: affect skin, photosensitivity

Question 6

What causes acute intermittent porphyria? What kind of porphyria is it?

Answer 6

PBG deaminase deficiency

Hepatic porphyria

Question 7

What causes congenital erythropoietic porphyria? What kind of porphyria is it?

Answer 7

Uroporphyrinogen III synthase deficiency

Erythropoietic porphyria

Question 8

What causes porphyria cutanea tarda (PCT)? What kind of porphyria is it?

Answer 8

Uroporphyrinogen decarboxylase deficiency

Hepatoerythropoietic porhyria

Question 9

What causes congenital variegate porphyria? What kind of porphyria is it?

Answer 9

Protoporphyrinogen IX oxidase deficiency

Hepatic porphyria

Question 10

What porphyria is the most common in the US?

Answer 10

Porphyria cutanea tarda (PCT)

Question 11

What are the symptoms of congenital erythropoietic porphyria?

Answer 11

Red color in urine, red fluorescence in teeth, destruction of RBCs, skin photosensitivity.

Question 12

Describe the process of heme degradation.

Answer 12

Heme oxygenase breaks heme ring. CO is released and taken up by Hb. Iron is oxidized from ferrous to ferric. Biliverdin is then synthesized and reduced to bilirubin via biliverdin reductase (NADPH needed)

Question 13

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

Answer 13

UDP glucuronyl transferase

Question 14

What causes pre-hepatic jaundice?

Answer 14

Increased production of unconjugated BR. Can be caused by excessive hemolysis.

Question 15

What causes intra-hepatic jaundice? What are some named examples?

Answer 15

Impaired hepatic uptake, conjugation, or secretion of conjugated BR.

Criggler-Najjar syndrome and Gilbert syndrome.

Question 16

What causes post-hepatic jaundice?

Answer 16

Problems with BR excretion. Leads to dark urine.

Question 17

What causes neonatal jaundice?

Answer 17

Deficiency in UDP-GT enzyme (immature hepatic metabolic pathways)

Question 18

What are the treatments for neonatal jaundice?

Answer 18

Phototherapy: blue fluorescent light photo-converts BR to more soluble isomers.

IM injection of tin-mesoporphyrin: strong inhibitor of heme oxygenase to prevent heme breakdown to form BR.

Question 19

What is the difference between Criggler-Najjar syndrome Type I and II?

Answer 19

Type I: complete absence of UDP-GT gene

Type II: single mutation in UDP-GT gene

Question 20

What causes Gilbert syndrome?

Answer 20

Reduced activity of UDP-GT (not from a mutation). Exact cause is unknown.