Porphobilinogen synthase

Porphobilinogen synthase (PBGS), also known as aminolevulinic acid dehydratase or ALAD, is an enzyme that is crucial in the biosynthesis of heme, which is a component of hemoglobin, cytochromes, and other hemoproteins. This enzyme catalyzes the second step in the heme biosynthetic pathway, specifically the condensation of two molecules of 5-aminolevulinic acid (ALA) to form porphobilinogen (PBG). Due to its essential role in heme production, defects in PBGS activity can lead to various diseases, most notably a group of disorders known as the porphyrias.

Function

Porphobilinogen synthase is found in the mitochondria of cells and is widely distributed across all kingdoms of life, indicating its fundamental role in cellular metabolism. The enzyme's primary function is to catalyze the condensation reaction of two molecules of 5-aminolevulinic acid to produce porphobilinogen. This reaction is a critical early step in the biosynthetic pathway that leads to the production of heme. Heme is an essential component of many proteins, including oxygen-transporting hemoglobins, enzymes like cytochrome c oxidase, and various other hemoproteins involved in electron transport and drug metabolism.

Structure

Porphobilinogen synthase is a metalloenzyme, requiring zinc ions for its catalytic activity. The enzyme's structure has been elucidated through X-ray crystallography, revealing a homooctameric assembly in some species, which means it is composed of eight identical subunits. Each subunit binds to a zinc ion, which is essential for the enzyme's activity. The active site of the enzyme, where the condensation reaction takes place, is located at the interface between two subunits.

Clinical Significance

Mutations in the gene encoding porphobilinogen synthase can lead to a decrease in enzyme activity and are associated with a rare condition known as Acute Intermittent Porphyria (AIP). AIP is characterized by a deficiency in heme production, leading to an accumulation of toxic precursors such as ALA and PBG in the body. Symptoms of AIP can include abdominal pain, neuropathy, and psychological symptoms, which can be triggered by certain drugs, diet, and stress.

Diagnosis and Treatment

Diagnosis of disorders related to PBGS deficiency, such as AIP, involves measuring the levels of PBG and ALA in the urine. Treatment is focused on managing symptoms and preventing the accumulation of toxic precursors. This can include the administration of heme in the form of hemin, which suppresses the synthesis of ALA, and glucose infusions to reduce the demand for heme synthesis.

See Also

• Heme synthesis
• 5-Aminolevulinic acid
• Porphyria
• Acute Intermittent Porphyria