ArticleBiochemistry2015
Human Erythroid 5-Aminolevulinate Synthase Mutations Associated with X-Linked Protoporphyria Disrupt the Conformational Equilibrium and Enhance Product Release.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 24 citations in OpenAlex.
- An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.Science (New York, N.Y.) · 2026Article
- A reversible feedback mechanism regulating mitochondrial heme synthesis.The Journal of biological chemistry · 2026Article
- A reversible feedback mechanism regulating mitochondrial heme synthesis.bioRxiv : the preprint server for biology · 2025Article
- The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation.Scientific reports · 2025Article
- Long-term iron supplementation in four patients with X-linked erythropoietic protoporphyria: associations with serum proteins and erythrocyte protoporphyrin levels-a single-centre retrospective study.Frontiers in molecular biosciences · 2025Article
- Article
- Elucidating the Role of Human ALAS2 C-terminal Mutations Resulting in Loss of Function and Disease.Biochemistry · 2024Article
- Protoporphyrin IX-induced phototoxicity: Mechanisms and therapeutics.Pharmacology & therapeutics · 2023Review
- The yeast ALA synthase C-terminus positively controls enzyme structure and function.Protein science : a publication of the Protein Society · 2023Article
- ABCB6 polymorphisms are not overly represented in patients with porphyria.Blood advances · 2022Article
- Structural Basis for Allostery in PLP-dependent Enzymes.Frontiers in molecular biosciences · 2022Review
- A mutation in the iron-responsive element ofHaematologica · 2021Article
- Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release.Nature communications · 2020Article
- Review
- Heme biosynthesis and the porphyrias.Molecular genetics and metabolism · 2019Review
- Results of a pilot study of isoniazid in patients with erythropoietic protoporphyria.Molecular genetics and metabolism · 2019Article
- 5-Aminolevulinate synthase catalysis: The catcher in heme biosynthesis.Molecular genetics and metabolism · 2019Review
- Molecular expression, characterization and mechanism of ALAS2 gain-of-function mutants.Molecular medicine (Cambridge, Mass.) · 2019Article
- The molecular genetics of sideroblastic anemia.Blood · 2019Review
- Heme-dependent Inactivation of 5-Aminolevulinate Synthase from Caulobacter crescentus.Scientific reports · 2018Article
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
Regulation of 5-aminolevulinate synthase (ALAS) is at the origin of balanced heme production in mammals. Mutations in the C-terminal region of human erythroid-specific ALAS (hALAS2) are associated with X-linked protoporphyria (XLPP), a disease characterized by extreme photosensitivity, with elevated blood concentrations of free protoporphyrin IX and zinc protoporphyrin. To investigate the molecular basis for this disease, recombinant hALAS2 and variants of the enzyme harboring the gain-of-function XLPP mutations were constructed, purified, and analyzed kinetically, spectroscopically, and thermodynamically. Enhanced activities of the XLPP variants resulted from increases in the rate at which the product 5-aminolevulinate (ALA) was released from the enzyme. Circular dichroism spectroscopy revealed that the XLPP mutations altered the microenvironment of the pyridoxal 5'-phosphate cofactor, which underwent further and specific alterations upon succinyl-CoA binding. Transient kinetic analyses of the variant-catalyzed reactions and protein fluorescence quenching upon binding of ALA to the XLPP variants demonstrated that the protein conformational transition step associated with product release was predominantly affected. Of relevance is the fact that XLPP could also be modeled in cell culture. We propose that (1) the XLPP mutations destabilize the succinyl-CoA-induced hALAS2 closed conformation and thus accelerate ALA release, (2) the extended C-terminus of wild-type mammalian ALAS2 provides a regulatory role that allows for allosteric modulation of activity, thereby controlling the rate of erythroid heme biosynthesis, and (3) this control is disrupted in XLPP, resulting in porphyrin accumulation.
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Registered trials
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