Effect of Lead poisoning on heme biosynthetic pathway

A 3-year- old boy is brought to the emergency room with abdominal pain, mental status changes and fatigue. On taking history the physician finds the child belongs to a very poor family and lives in an old house and has the habit of licking the paint chips that have crumbled in the window sills. The physician suspects lead poisoning. Lead typically interferes with which of the following enzymes?

A) Porphobilinogen deaminase

B) Protoporphyrinogen oxidase

C) ALA synthase

D) Coproporphyrinogen oxidase

E) ALAdehydratase

The correct option is- ALA dehydratase.

All the enzymes mentioned above are related with the pathway of heme biosynthesis.

Heme is required for a variety of hemoproteins such as hemoglobin, myoglobin, respiratory cytochromes, and the cytochrome P450 enzymes (CYPs).

Hemoglobin synthesis takes place in erythroid precursor cells and liver. The heme 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.

Heme biosynthesis involves eight enzymatic steps in the conversion of glycine and succinyl-CoA to heme (Figure-1).The first and last three enzymes in the pathway are located in the mitochondrion, whereas the other four are in the cytosol.

Steps of Haem synthesis (Figure-1)

1) The first and rate-controlling step is the condensation of glycine and succinyl–coenzyme A (CoA) to form δ-aminolevulinic acid (ALA). The reaction is catalyzed by ALA synthase.

2) 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 mono pyrrole Porphobilinogen. It is this enzyme which is inhibited by Lead.

3) 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). When Uroporphyrinogen III synthase is deficient, as in congenital erythropoietic Porphyria (Gunther’s disease), hydroxymethylbilane rapidly undergoes nonenzymatic ring closure to form Uroporphyrinogen I.

Steps of heme biosynthesis

Figure-1- Steps of heme biosynthesis

4) 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.

5) Coproporphyrinogen III is transported back into mitochondria, where the enzyme Coproporphyrinogen III oxidase carries out the stepwise oxidative decarboxylation forming Protoporphyrinogen IX.

6) 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-1). The enzyme Ferrochelatase is also inhibited by Lead.

Lead thus inhibits the pathway of heme biosynthesis at two steps (figure-2). One of the first manifestations of lead toxicity is anemia. Lead-induced anemia manifests as a microcytic, hypochromic anemia.

Lead toxicity

Figure-2- Effect of lead on heme biosynthetic pathway

As regards other options

A) Porphobilinogen deaminase catalyzes the condensation and deamination of four Porphobilinogen molecules to form hydroxymethylbilane (see details above), which is converted to a cyclic structure, Uroporphyrinogen III by Uroporphyrinogen cosynthase. The deficiency of Porphobilinogen deaminase results in Acute intermittent porphyria (Figure-3)

B) Protoporphyrinogen oxidase- carries out the oxidation of Protoporphyrinogen IX to form protoporphyrin IX. The deficiency of this enzyme causes Variegate Porphyria (Figure-3).

C) ALA synthase– catalyzes the first and the regulatory step of heme biosynthesis. The enzyme, ALA-synthase is activated by Pyridoxal phosphate. In the liver, this rate-limiting enzyme can be induced by a variety of drugs, steroids, and other chemicals. Defects in the erythroid gene cause X-linked Sideroblastic anemia (XLS A). Heme represses the synthesis of the ALA-synthase mRNA. Glucose also represses the ALA synthase gene. I/V glucose and Hematin infusion are used to treat acute episodes of porphyria.

D) Coproporphyrinogen oxidase catalyzes the conversion of Coproporphyrinogen to Protoporphyrinogen. The deficiency of this enzyme causes Coproporphyria.

The Porphyrias are a group of rare metabolic disorders arising from reduced activity of any of the enzymes in the heme biosynthetic pathway. The disorders may be either acquired or inherited through a genetic defect in a gene encoding these enzymes. These deficiencies disrupt normal heme production, and produce symptoms when increased heme is required. Porphyrin precursors, overproduced in response to synthetic pathway blockages, accumulate in the body and cause diverse pathologic changes thereby becoming the basis for diagnostic tests.

Porphyria

Figure-3- Steps of heme synthesis and the enzyme defects causing different types of Porphyria

 

 

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1 Response

  1. You are best…Just amazing..everything is so clearly explained..thanks a lot.

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