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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.

Original publication




Journal article


Nature communications

Publication Date





Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK.


Humans, Protoporphyria, Erythropoietic, Genetic Diseases, X-Linked, Heme, Acyl Coenzyme A, 5-Aminolevulinate Synthetase, Crystallography, X-Ray, Gene Expression Regulation, Enzymologic, Catalytic Domain, Protein Conformation, Protein Binding, Substrate Specificity, Kinetics, Catalysis, Molecular Dynamics Simulation, Protein Domains