Heme Metabolism and Porphyria

Question 1

Give another name for heme.

Answer 1

Fe protoporphyrin IX

Question 2

What is the word that means “heme-containing protein”?

Answer 2

Porphyrin is a heme-containing protein

Question 3

Name at least 3 proteins that contain heme.

Answer 3

Hemoglobin, myoglobin and cytochromes.

Question 4

What 2 molecules provide all of the atoms for heme synthesis?

Answer 4

Glycine + succinyl CoA –> 5-aminolevulinate (ALA) via the ALA synthase

Question 5

Where does heme synthesis take place (tissue)?

Answer 5

1. Bone Marrow (hemoglobin)

2. Liver (cytochromes)

Question 6

Where does heme synthesis take place (subcellular compartment)?

Answer 6

1. Mitochondria (first step and last three steps)

2. Cytoplasm (middle four steps)

Question 7

How is heme synthesis controlled in the liver and hematopoietic tissue?

Answer 7

Heme inhibits the activity of and transport of ALA synthase in the liver as does glucose inhibit the synthesis of ALA synthase. Steroids induce the synthesis of heme in the liver. In bone marrow, heme inhibits Fe uptake (but not enzyme activity) and erythropoietin induces all enzymes of the pathway.

Question 8

What is Porphyria?

Answer 8

Porphyria is the lack of heme due to a decrease in the work of enzymes needed for its synthesis by 50%.

Question 9

How many porphyrias are there? What are the 2 most common ones?

Answer 9

There are many types of porphyrias. Dr. Groseclose lists 6 in her notes. The two most common are acute intermittent porphyria and porphyria cutanea tarda.

Question 10

What is are the effects of acute intermittent porphyria?

Answer 10

It is a problem with porphyrinogen deaminase causeing excretion of ALA an porphyrinogen. The symptoms include mainly abdominal pain and constipation.

Question 11

What are the effects of porphyria cutanea tarda?

Answer 11

There is a mutation or problem with uro’gen decarboxylase, which causes a build-up or uro’gen III and symptoms of hepatic dysfunction and photosensitivity.

Question 12

What is the enzyme that opens the porphyrin ring of heme and what are its products? Discuss the importance of CO in tissue.

Answer 12

Heme oxygenase opens the porphyrin ring of heme and produces biliverdin, CO and Fe. CO is only released when heme oxygenase breaks down heme. It can be fatal if too much is created.

Question 13

Discuss the breakdown of heme, from ring-opening to excretion. Name the hepatic enzyme that catalyzes the attachment of sugar-acids to bilirubin.

Answer 13

1. ) Heme + 2 02 + NADPH + H –> Biliverdin + CO + Fe + NADP+ (enzyme = heme oxygenase)
2. ) Biliverdin + NADPH + H –> Bilirubin (enzyme = biliverdin reductase)
3. ) Bilirubin + 2 UDP-glucuronate –> bilirubin diglucuronide (enzyme = UDP-glucuronyl transferase)
4. ) Bilirubin diglucuronide –> Urobilinogen
5. ) Urobilinogen –> Stercobilin

Question 14

The changing color of a bruise is mostly attributable to the release and breakdown of heme at the site of trauma. Discuss this phenomenon, based on your knowledge of heme metabolism, including the colors of the intermediates.

Answer 14

During the breakdown of heme (which is blue/black) it is first converted to biliverdin (green), then bilirubin (yellowish/brown) and finally bilirubin diglucuronide which is excreted in the urine. This is why bruises change from blue/black to green to a yellowish/brown and then finally fade away.

Question 15

What is jaundice?

Answer 15

Jaundice is the yellowing of skin/eyes form and increase in the amount of bilirubin.

Question 16

What are 3 common causes of jaundice in adults?

Answer 16

1. Excess bilirubin production
2. Inability of UDP-glucuronyl transferase to do its job
3. Obstruction of bile duct

Question 17

What are the reasons for neonatal jaundice?

Answer 17

1. Immature liver

2. Decrease in UDP-glucuronyl transferase