Heme Synthesis, Degradation and Porphyrias - Part 1 Flashcards Preview

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Flashcards in Heme Synthesis, Degradation and Porphyrias - Part 1 Deck (32):

In which cells is heme mainly synthesized?

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.


What is the difference between heme and hemin?

-Heme contains ferrous iron and hemin contains ferric iron.

-Hemin is formed from heme when it cannot be incorporated into a protein.


What is the general concept of heme synthesis?

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.


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

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.


Give six examples of proteins or enzymes that need heme.

cytochromes P450,
cytochromes of the ETC,
nitric oxide synthase


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

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

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

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


Where in the cell is porphobilinogen formed?

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


During the formation of porphobilinogen, what is used?

two ALAs with release of water


What are two other names for ALA synthase?

-ALA dehydratase
-Porphobilinogen synthase


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

Four porphobilinogens are used for the synthesis of one hydroxymethylbilane


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

4 ammonia


What scavenges the ammonia released during the synthesis of HMB?

Glutamine Synthetase


What is another name for Porphobilinogen deaminase?

Hydromethylbilane synthase


What enzyme catalyzes the conversion of 4 porphobilinogens to HMB?

Porphobilinogen deaminase (Hydromethylbilane synthase)


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

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


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

Pyrrol ring D is asymmetric in the porphyrin ring system.


What is the first porphyrin ring leading to heme?

The first porphyrin leading to heme is uroporphyrinogen III


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



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



Hereditary deficiency of the ALAS2 gene leads to what?

X-linked sideroblastic anemia


Do both ALAS1 and 2 need PLP?

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


Which enzyme in heme synthesis is inhibited by lead?

-Cytosolic ALA dehydratase (porphobilinogen synthase)

-Mitochondrial ferrochelatase


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



Lead binds to what of ALA dehydratase?

Sulfhydryl groups


What accumulates during lead poisoning?

-Protoporphyrin IX


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

HMB synthase (porphobilinogen deaminase)


ALA has a similar structure to which neurotransmitter?



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?

Acute Intermittent Porphyria (AIP)


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

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


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

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


How would you treat a patient with AIP?

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.


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

-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