ArticleNature communications2020
Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release.
Article in Nature communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 41 citations in OpenAlex.
- Milestones in the Elucidation of Heme Biosynthesis.Chemical reviews · 2026Review
- An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.Science (New York, N.Y.) · 2026Article
- Updates to gene-disease classifications and inheritance patterns for porphyrias.Molecular genetics and metabolism · 2026Article
- A case report of congenital sideroblastic anemia caused by a novel ALAS2 mutation in conjunction with thalassemia.Annals of hematology · 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
- Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA-mediated silencing.Science (New York, N.Y.) · 2024Article
- A computational strategy to improve the activity of tyrosine phenol-lyase for the synthesis of L-DOPA.Scientific reports · 2024Article
- Article
- Elucidating the Role of Human ALAS2 C-terminal Mutations Resulting in Loss of Function and Disease.Biochemistry · 2024Article
- Classification of likely functional class for ligand binding sites identified from fragment screening.Communications biology · 2024Article
- A novel and apparentFrontiers in pediatrics · 2024Article
- Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype.Nature communications · 2023Article
- The yeast ALA synthase C-terminus positively controls enzyme structure and function.Protein science : a publication of the Protein Society · 2023Article
- New Avenues of Heme Synthesis Regulation.International journal of molecular sciences · 2022Review
- The alternative splicing landscape of a coral reef fish during a marine heatwave.Ecology and evolution · 2022Article
- An Extended C-Terminus, the Possible Culprit for Differential Regulation of 5-Aminolevulinate Synthase Isoforms.Frontiers in molecular biosciences · 2022Review
- Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins.Frontiers in cell and developmental biology · 2022Review
- Ferrochelatase: Mapping the Intersection of Iron and Porphyrin Metabolism in the Mitochondria.Frontiers in cell and developmental biology · 2022Review
- Structural Basis for Allostery in PLP-dependent Enzymes.Frontiers in molecular biosciences · 2022Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
5'-aminolevulinate synthase (ALAS) catalyzes the first step in heme biosynthesis, generating 5'-aminolevulinate from glycine and succinyl-CoA. Inherited frameshift indel mutations of human erythroid-specific isozyme ALAS2, within a C-terminal (Ct) extension of its catalytic core that is only present in higher eukaryotes, lead to gain-of-function X-linked protoporphyria (XLP). Here, we report the human ALAS2 crystal structure, revealing that its Ct-extension folds onto the catalytic core, sits atop the active site, and precludes binding of substrate succinyl-CoA. The Ct-extension is therefore an autoinhibitory element that must re-orient during catalysis, as supported by molecular dynamics simulations. Our data explain how Ct deletions in XLP alleviate autoinhibition and increase enzyme activity. Crystallography-based fragment screening reveals a binding hotspot around the Ct-extension, where fragments interfere with the Ct conformational dynamics and inhibit ALAS2 activity. These fragments represent a starting point to develop ALAS2 inhibitors as substrate reduction therapy for porphyria disorders that accumulate toxic heme intermediates.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.