Heme Synthesis, Degradation and Porphyrias - Part 1

Question 1

In which cells is heme mainly synthesized?

Answer 1

Heme synthesis takes place in all cells but in larger scale mainly (85 %) in bone marrow (in erythroid cells, not mature RBC) and the rest mainly in the liver.

Question 2

What is the difference between heme and hemin?

Answer 2

• Heme contains ferrous iron and hemin contains ferric iron.
• Hemin is formed from heme when it cannot be incorporated into a protein.

Question 3

What is the general concept of heme synthesis?

Answer 3

The general concept of heme synthesis is to use succinyl CoA and glycine, form ALA, and porphobilinogen as building blocks and then hyddroxymethylbilane.

• Ring closure needs the switch to asymmetric pyrrol ring D.
• Finally the side chains are modified and the correct double bonds arranged.

Question 4

Where does Heme synthesis take place in the cells? Are the reactions reversible? What is special about the intermediates?

Answer 4

The synthesis starts and ends in mitochondria, other steps take place in cytosol. All reactions are irreversible. The enzymes have to act fast in order to prevent the spontaneous formation of abnormal porphyrins from intermediates.

Question 5

Give six examples of proteins or enzymes that need heme.

Answer 5

Hemoglobin, 
myoglobin, 
cytochromes P450, 
cytochromes of the ETC, 
catalase,         
nitric oxide synthase

Question 6

Describe the reaction catalyzed by ALA synthase: cellular location, substrates, coenzyme.

Answer 6

ALA synthase is a mitochondrial enzyme that uses succinyl CoA and glycine.

-The formation of gamma-aminolevulinic acid (ALA) includes the decarboxylation of
glycine

-ALA synthase needs PLP (vitamin B6) as coenzyme.

Question 7

Where in the cell is porphobilinogen formed?

Answer 7

ALA leaves from mitochondria into the cytosol and porphobilinogen is formed in cytosol

Question 8

During the formation of porphobilinogen, what is used?

Answer 8

two ALAs with release of water

Question 9

What are two other names for ALA synthase?

Answer 9

• ALA dehydratase

- Porphobilinogen synthase

Question 10

How many porphobilinogens are needed for synthesis of hydroxymethylbilane (HMB)?

Answer 10

Four porphobilinogens are used for the synthesis of one hydroxymethylbilane

Question 11

During the synthesis of hydroxymethylbilane (HMB), what is released in this reaction?

Answer 11

4 ammonia

Question 12

What scavenges the ammonia released during the synthesis of HMB?

Answer 12

Glutamine Synthetase

Question 13

What is another name for Porphobilinogen deaminase?

Answer 13

Hydromethylbilane synthase

Question 14

What enzyme catalyzes the conversion of 4 porphobilinogens to HMB?

Answer 14

Porphobilinogen deaminase (Hydromethylbilane synthase)

Question 15

How many succinyl CoAs and glycines are needed for the synthesis of one heme?

Answer 15

Succinyl CoA and glycine are needed to form ALA.

Two ALAs are needed to form porphobilinogen.

Four porphobilinogens are needed to form hydroxymethylbilane.

Totally 8 succinyl CoAs and 8 glycines are needed for the synthesis of one heme

Question 16

What is special about pyrrol ring D in the heme porphyrin ring system?

Answer 16

Pyrrol ring D is asymmetric in the porphyrin ring system.

Question 17

What is the first porphyrin ring leading to heme?

Answer 17

The first porphyrin leading to heme is uroporphyrinogen III

Question 18

The liver isoform for ALA synthase, which is down-regulated by heme/hemin accumulation, is known as what?

Answer 18

ALAS1

Question 19

The erythroid cell isoform for ALA synthase, which is down-regulated at low amounts of intracellular iron, is known as what?

Answer 19

ALAS2

Question 20

Hereditary deficiency of the ALAS2 gene leads to what?

Answer 20

X-linked sideroblastic anemia

Question 21

Do both ALAS1 and 2 need PLP?

Answer 21

• Yes

- Both ALAS1 and ALAS2 decarboxylate glycine and need PLP as coenzyme

Question 22

Which enzyme in heme synthesis is inhibited by lead?

Answer 22

• Cytosolic ALA dehydratase (porphobilinogen synthase)

- Mitochondrial ferrochelatase

Question 23

Which cofactors do Cytosolic ALA dehydratase (porphobilinogen synthase) and Mitochondrial ferrochelatase need?

Answer 23

Zinc

Question 24

Lead binds to what of ALA dehydratase?

Answer 24

Sulfhydryl groups

Question 25

What accumulates during lead poisoning?

Answer 25

• ALA

- Protoporphyrin IX

Question 26

Acute Intermittent Porphyria (AIP) results from deficiency of which enzyme?

Answer 26

HMB synthase (porphobilinogen deaminase)

Question 27

ALA has a similar structure to which neurotransmitter?

Answer 27

GABA

Question 28

A patient comes to you with severe abdominal pain, respiratory problems, and is high agitated. Blood and urine analysis shows accumulation of both ALA and porphobilinogen. The color of the urine sample was noticed to have changed from yellow to dark red/purple. This patient most probably has?

Answer 28

Acute Intermittent Porphyria (AIP)

Question 29

The urine color in a patient with AIP changes how? Why?

Answer 29

The urine color changes from yellow to dark red, purple, as porphobilinogen is changed to the colored porphobilin by air contact.

Question 30

Why can treatment with Phenobarbital be fatal in patients with AIP?

Answer 30

Phenobarbitol (barbituate) stimulates cytochrome P450 synthesis system in liver, thus worsening condition.

Question 31

How would you treat a patient with AIP?

Answer 31

Treatment can include i.v. injection of hemin in order to inhibit the synthesis of ALA synthase. This treatment can also be used in other severe cases of hepatic porphyrias but not for treatment of erythropoietic porphyrias, as ALAS2 is not down-regulated by hemin.

Question 32

What is the name of the porphyrin ring system that leads to heme after incorporation of ferrous iron?

Answer 32

• It is protoporphyrin IX (red color) that leads to heme after incorporation of ferrous iron.
• This process can happen spontaneously but is mainly catalyzed by ferrochelatase