Case study- Porphyria


Heme metabolism 

Heme synthesis

Heme biosynthesis involves eight enzymatic steps in the conversion of glycine and succinyl-CoA to heme (figure). The first and last three enzymes in the pathway are located in the mitochondrion, whereas the other four are in the cytosol.

Heme is required for a variety of hemoproteins such as hemoglobin, myoglobin, respiratory cytochromes, and the cytochrome P450 enzymes (CYPs). Hemoglobin synthesis in erythroid precursor cells accounts for approximately 85% of daily heme synthesis in humans. Hepatocytes account for most of the rest, primarily for synthesis of CYPs, which are especially abundant in the liver endoplasmic reticulum, and turn over more rapidly than many other hemoproteins, such as the mitochondrial respiratory cytochromes.

As shown in figure- pathway intermediates are the porphyrin precursors, ALA and PBG, and porphyrins (mostly in their reduced forms, known as porphyrinogens). At least in humans, these intermediates do not accumulate in significant amounts under normal conditions or have important physiologic functions.

Summary of steps

  • The first and rate-controlling step is the condensation of glycine and succinyl–coenzyme A (CoA) to form δ-aminolevulinic acid (ALA).
  • The enzyme, ALA-synthase  catalyzing this step is activated by Pyridoxal phosphate.
  •  In the liver, this rate-limiting enzyme can be induced by a variety of drugs, steroids, and other chemicals.
  • The ALA formed is transported into the cytoplasm, where the second enzyme, ALA dehydratase (also known as Porphobilinogen synthase), condenses two molecules of ALA to form the monopyrrole Porphobilinogen.
  • The third enzyme, Porphobilinogen deaminase (also known as hydroxymethylbilane synthase), forms a linear tetrapyrrole, hydroxymethylbilane, which is normally rapidly converted, mainly to the cyclic intermediate uroporphyrinogen III, by the enzyme uroporphyrinogen III synthase (also known as uroporphyrinogen cosynthase).
  • The enzyme uroporphyrinogen decarboxylase carries out the stepwise decarboxylation of uroporphyrinogen I or III to form intermediates with 7-, 6-, 5-, and 4-carboxyl groups.
  • Coproporphyrinogen is the common name for the 4-carboxyl–containing intermediate.
  • Coproporphyrinogen III is transported back into mitochondria, where the enzyme Coproporphyrinogen III oxidase carries out the stepwise oxidative decarboxylation forming Protoporphyrinogen IX.
  • Next, the enzyme Protoporphyrinogen oxidase carries out the oxidation of Protoporphyrinogen IX to form protoporphyrin IX, after which the enzyme Ferrochelatase (also called heme synthase) inserts ferrous iron into the protoporphyrin IX to form the end product heme (figure).
  • Heme biosynthesis occurs in most mammalian cells with the exception of mature erythrocytes, which do not contain mitochondria.

Steps of heme synthesis

 Figure-1- steps of Heme synthesis


A  21-year-old young woman, who recently began taking birth control pills, presents to the emergency room with cramping abdominal pain, anxiety, paranoia, and hallucinations. A surgical evaluation, including ultrasound and computed tomography (CT) scan, fails to demonstrate an acute abdominal process. A urine analysis reveals an increase in urine porphyrins. Which of the following is the most likely defect?

A. Congenital erythropoietic porphyria

B. Variegate porphyria

C. Porphyria cutanea tarda

D. Acute intermittent porphyria

E. Erythropoietic porphyria

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