Heme Metabolism

Question 1

What are the main features of heme?

Answer 1

Cyclic compound - Porphyrin IX

Ring coordinated by central reduced iron ion (Fe 2+)

Question 2

What are proteins that contain heme?

Answer 2

Hemoglobin

Myoglobin

Cytochromes

Enzymes (catalase, peroxidase)

Question 3

Where does heme synthesis most commonly happen?

Answer 3

Bone marrow

Liver

Question 4

What are the features of 5-aminolevulinate (5-ALA) synthase? What does it form?

Answer 4

Uses vitamin B6 (PLP)
Rate limiting step
Inhibited by heme

Converts glycine and succinyl-CoA to form 5-aminolevulinate (5-ALA)

Question 5

What does ALA dehydratase or PB synthase do? What inhibits it?

Answer 5

2 5-ALA molecules form porphobilinogen

Inhibited by lead (Pb)

Question 6

What do the enzymes PB Deaminase and Uroporphyrinogen III synthase do?

Answer 6

PB deaminase takes 4 porphobilinogens to form hydroxymethylbilane

Uroporphyrinogen III synthase converts hydroxymethylbilane to uroporphyrinogen III

Question 7

What does UP III decarboxylase do?

Answer 7

Converts UP III to Coproporphyringogen III

Question 8

What is coproporphyrinogen III oxidized to when making heme?

Answer 8

Protoporphyringogen IX

Question 9

What enzyme forms heme? What inhibits that enzyme?

Answer 9

Ferrochelatase forms heme from protoporphyrin IX through incorpartion of Fe2+

Inhibited by lead

Question 10

What does high heme concentrations cause in heme synthesis?

Answer 10

Inhibits ALA synthase (step1)

Question 11

How does alcohol consumption regulate heme synthesis?

Answer 11

Alcohol stimulates hepatic heme synthesis by inducing MEOS (microsomal ethanol oxidizing system)

MEOS is a heme containing cytochrome P450 enzyme acting in the liver

Alcohol consumption can worsen heme synthesis disorders

Question 12

What happens to heme synthesis with vitamin B6 deficiency?

Answer 12

Vitamin B6 needed for ALA synthase (step 1)

ALA lowered and low protoporphyrin IX levels

Can lead to sideroblastic anemia and iron accumulates

Question 13

What occurs with lead poisoning in heme synthesis?

Answer 13

Lead inhibits PB synthase (ALA dehydratase, step 2) and ferrochelatase (step 6)

ALA and protoporphyrin IX accumulates in urine

Serum iron and ferritin accumulate

Poisoning leads to anemia, nausea, and neuropathy

Question 14

What occurs with iron deficiency in heme synthesis?

Answer 14

Ferrochelatase incorporate Fe2+ into heme ring

Deficiency leads to increased Protoporphyrin IX but normal ALA

Can cause microcytic hypochromic anemia and low serum iron and low ferritin

Question 15

What is indirect bilirubin?

Answer 15

Unconjugated bilirubin

Formed from destruction of aged red blood cells (heme degradation)

Question 16

What are the steps to form indirect bilirubin?

Answer 16

Heme oxygenase cleaves heme ring producing biliverdin

Biliberdin reductase converts biliverdin into bilirubin in a NAPDH dependent rxn

Water insoluble

Question 17

How is Direct (Conjugated) Bilirubin formed?

Answer 17

Bilirubin is made hydrophilic by UDP glucuronyl transferase (UGT) when UGT adds 1 or 2 glucuronic acids

Water soluble

Question 18

How is bilirubin excreted?

Answer 18

Heme in the spleen from old red blood cells is converted into unconjugated bilirubin, which enters the blood. Albumin binds unconjugated bilirubin to transport to the liver.

Conjugated bilirubin is made in the liver and secreted into the bile duct and then the gut.

Gut bacteria convert conjugated bilirubin into urobilinogen which is spontaneously oxidized to stercobilin (brown color of feces)

Some urobilinogen is reabsorbed and oxidized to urobilin, which is excreted with the urine (yellow color)