ALAS -5-aminolevulinate synthase erythroid (specific) mitochondrial (erythroid) | Elisa - Clia - Antibody - Protein

Background:

ALAS (5-aminolevulinate synthase) is an enzyme responsible for catalyzing the first step in the biosynthesis of heme, a crucial component of hemoglobin, cytochromes, and other hemoproteins. There are two main isoforms of ALAS: ALAS1 is the ubiquitous isoform found in non-erythroid tissues, such as the liver.ALAS2 is the erythroid-specific isoform found in erythroid cells, particularly in developing red blood cells in the bone marrow. ALAS2 is localized to the mitochondria of erythroid cells. Its function is vital for the production of heme, which is essential for hemoglobin synthesis and oxygen transport in red blood cells. Mutations in the ALAS2 gene can lead to a group of disorders known as erythropoietic porphyrias, which are characterized by deficiencies in heme production and can manifest as various symptoms including anemia and skin photosensitivity.).

Protein Structure:

• Mitochondrial Localization: ALAS2 is localized in the mitochondria, where it catalyzes the condensation of glycine and succinyl-CoA to form 5-aminolevulinate (ALA).
• Subunit Composition: ALAS2 functions as a homodimer, with each subunit containing a pyridoxal phosphate (PLP) cofactor essential for its catalytic activity.
• Domains: The enzyme consists of an N-terminal mitochondrial targeting sequence, a catalytic core, and a C-terminal region involved in dimerization and regulation.

Classification and Subtypes:

• Isoforms: ALAS has two isoforms:
• ALAS1: Ubiquitously expressed in various tissues.
• ALAS2: Erythroid-specific, expressed primarily in erythroid precursor cells.

Function and Biological Significance:

• Heme Biosynthesis: ALAS2 catalyzes the first and rate-limiting step of heme synthesis, which is critical for the production of hemoglobin in red blood cells.
• Erythropoiesis: The enzyme plays a pivotal role in erythropoiesis by ensuring a sufficient supply of heme for incorporation into hemoglobin.
• Regulation: ALAS2 activity is tightly regulated by intracellular heme levels, iron availability, and erythropoietin, ensuring balanced heme production during erythroid differentiation.

Interactions:

• Substrates and Cofactors: ALAS2 interacts with glycine, succinyl-CoA, and the cofactor PLP during the catalytic process.
• Regulatory Proteins: The enzyme is regulated by various proteins and factors, including heme-regulated inhibitor (HRI) kinase, which modulates its activity in response to heme levels.

Clinical Issues:

• X-linked Sideroblastic Anemia (XLSA): Mutations in the ALAS2 gene can lead to XLSA, characterized by ineffective erythropoiesis and iron overload in mitochondria, resulting in ring sideroblasts in the bone marrow.
• Iron Metabolism Disorders: Dysregulation of ALAS2 can contribute to disorders of iron metabolism, given its role in utilizing mitochondrial iron for heme synthesis.

Summary:

5-Aminolevulinate Synthase (ALAS2) is an erythroid-specific enzyme critical for heme biosynthesis in red blood cells. Localized in mitochondria, ALAS2 catalyzes the formation of ALA, the first step in the heme production pathway. Its activity is essential for erythropoiesis and is tightly regulated by heme levels and iron availability. Mutations in the ALAS2 gene can lead to X-linked sideroblastic anemia, highlighting its clinical significance in hematology and iron metabolism disorders. Understanding ALAS2’s structure, function, and regulation is vital for diagnosing and managing related hematologic conditions.