Aminolevulinic acid synthase

Aminolevulinic Acid Synthase

Aminolevulinic acid synthase (ALAS) is a crucial enzyme in the biosynthesis of heme, the iron-containing prosthetic group that forms an essential component of various hemoproteins, including hemoglobin, myoglobin, and cytochromes. ALAS catalyzes the first step in the heme biosynthetic pathway, which is the condensation of glycine and succinyl-CoA to form aminolevulinic acid (ALA).

Structure and Function

ALAS is a mitochondrial enzyme that exists in two isoforms in humans: ALAS1 and ALAS2. ALAS1 is ubiquitously expressed in all tissues, while ALAS2 is erythroid-specific, being expressed primarily in the bone marrow where it plays a critical role in erythropoiesis.

The enzyme is a pyridoxal phosphate (PLP)-dependent enzyme, which means it requires the cofactor pyridoxal phosphate, a form of vitamin B6, to function. The reaction catalyzed by ALAS is as follows:

Glycine + Succinyl-CoA → Aminolevulinic acid + CoA + CO₂

This reaction is the rate-limiting step in the heme biosynthetic pathway, making ALAS a key regulatory point in heme production.

Regulation

The activity of ALAS is tightly regulated at multiple levels, including transcriptional, translational, and post-translational mechanisms. ALAS1 is regulated by feedback inhibition from heme, which decreases its transcription and activity. ALAS2, on the other hand, is regulated by iron availability, as it contains an iron-responsive element (IRE) in its mRNA that modulates its translation in response to iron levels.

Clinical Significance

Mutations in the ALAS2 gene can lead to X-linked sideroblastic anemia, a condition characterized by the presence of ringed sideroblasts in the bone marrow and impaired heme synthesis. This results in microcytic, hypochromic anemia.

In addition, ALAS is a target for certain drugs and therapies. For example, 5-aminolevulinic acid (5-ALA) is used in photodynamic therapy for cancer treatment, as it accumulates preferentially in cancer cells and can be activated by light to produce cytotoxic reactive oxygen species.

Also see

• Heme biosynthesis
• Hemoglobin
• Cytochrome
• Erythropoiesis
• X-linked sideroblastic anemia

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Aminolevulinic acid synthase gallery

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  ALAS Reaction Mechanism Image

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  Heme synthesis