ArticleBiochemistry2024
Elucidating the Role of Human ALAS2 C-terminal Mutations Resulting in Loss of Function and Disease.
Article in Biochemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- A case report of congenital sideroblastic anemia caused by a novel ALAS2 mutation in conjunction with thalassemia.Annals of hematology · 2026Article
- A diagnostic pitfall in iron-refractory microcytic hypochromic anemia with acquired ring sideroblasts initially treated as iron deficiency anemia-a case report.Frontiers in medicine · 2026Article
- Case Report: A Previously Healthy Young Woman With Lethal, Unremitting Metabolic Acidosis: Could a Novel Variant inCase reports in pathology · 2026Article
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Authors and funding
3 authors.
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Abstract
The conserved enzyme aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in certain bacteria and eukaryotes by catalyzing the condensation of glycine and succinyl-CoA to yield aminolevulinic acid. In humans, the ALAS isoform responsible for heme production during red blood cell development is the erythroid-specific ALAS2 isoform. Owing to its essential role in erythropoiesis, changes in human ALAS2 (hALAS2) function can lead to two different blood disorders. X-linked sideroblastic anemia results from loss of ALAS2 function, while X-linked protoporphyria results from gain of ALAS2 function. Interestingly, mutations in the ALAS2 C-terminal extension can be implicated in both diseases. Here, we investigate the molecular basis for enzyme dysfunction mediated by two previously reported C-terminal loss-of-function variants, hALAS2 V562A and M567I. We show that the mutations do not result in gross structural perturbations, but the enzyme stability for V562A is decreased. Additionally, we show that enzyme stability moderately increases with the addition of the pyridoxal 5'-phosphate (PLP) cofactor for both variants. The variants display differential binding to PLP and the individual substrates compared to wild-type hALAS2. Although hALAS2 V562A is a more active enzyme
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