41-HEME (PORPHYRIN) SYNTHESIS & PORPHYRIAS – Dr. Groseclose

Question 1

Give another name for heme. What is the word that means “heme-containing” protein?

Answer 1

Fe protoporphyrin IX is another name for heme. Cytochrome is a heme-containing protein.

Question 2

Name at least 3 proteins that contain heme.

Answer 2

Hemoglobin, myoglobin. and CYTOCHROMES

Question 3

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

Answer 3

Glycine + succinyl CoA  5-aminolevulinate (ALA) via ALA synthase

Question 4

Where does heme synthesis take place: in which tissues and which subcellular compartment?

Answer 4

In the liver and the bone marrow:

First step and last 3 steps take place in mitochondria and the middle 4 steps in the cytoplasm.

Question 5

How is heme synthesis controlled in liver and hematopoietic tissue?

Answer 5

1) Heme inhibits: ALA synthase activity, synthesis of ALA synthase, and transportation of ALA synthase into the mitochondria. In bone marrow specifically, Heme also inhibits iron uptake.
2) Steroids INDUCE synthesis of heme
3) Glucose inhibits ALA synthase synthesis.
4) Erythropoetin INDUCES all enzymes of pathway

Question 6

What is porphyria? How many porphyrias are there? What are the 2 most common ones? What happens in each.

Answer 6

Porphyria is a hereditary disorder leading to the lack of heme due to a decrease in the work of the enzymes needed for its synthesis by 50%. So many porphyrias!

Two most common are :
1) acute intermittent porphyria (AIP): A problem with porphyrinogen deaminase causing excretion of ALA and porphyrinogen. [ABDOMINAL pain and constipation No photosensitivity]

2) porphyria cutanea tarda: problem with urobilinogen decarboxylase causing build-up of urobilinogen III and symptoms of hepatic dysfunction and photophobia. [Photosensitivity, hirsutism, imparied liver function and hepatic iron excess]

Question 7

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

Answer 7

Heme oxygenase opens the porphyrin ring of heme and produces Biliverdin, CO and Fe.

CO is important as a cell signal. The breakdown of the porphryin using heme oxygenate is the only rxn in the body that makes CO.

Question 8

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

Answer 8

1) Heme + O2 + NADPH + H+ – > biliverdin + CO + NADP+ (via heme oxygenase)
2) Biliverdin + NADPH + H+ –> bilirubin (via biliverdin reductase)
3) Bilirubin + 2-UDP glucuronate –> bilirubin diglucuronide (via UDP-glucuronyl transferase)
4) Bilirubin diglucuronide is converted back to bilirubin in the ileum, which is converted to urobilinogen.
5) Any urobilinogen that remains in the colon is converted to stercobilin, which is the brown color in fecal matter.

Question 9

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

Answer 9

During 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.

Question 10

What is jaundice? Name 3 common causes of jaundice in adults. What are the reasons for neonatal jaundice?

Answer 10

Jaundice is the yellowing of skin/eyes from increased levels of bilirubin. (> 2.0 - 2.5 mg/dl)

In adults caused by

1. hemolysis
2. liver disease
3. bile duct obstruction

In neonates

1. immature liver
2. decrease UDP-glucuronyl transferase

Question 11

What is the rate limiting step of heme synthesis?

Answer 11

glycine + Succinyl coA –> aminolevulinate

Question 12

What disease mimics porphyria? How?

Answer 12

Lead poisioning. via inhibition of ALA dehydratase and ferrochelatase