Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release

Henry J. Bailey, Gustavo A. Bezerra, Jason R. Marcero, Siladitya Padhi, William R. Foster, Elzbieta Rembeza, Arijit Roy, David F. Bishop, Robert J. Desnick, Gopalakrishnan Bulusu, Harry A. Dailey and Wyatt W. Yue ()
Additional contact information
Henry J. Bailey: Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford
Gustavo A. Bezerra: Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford
Jason R. Marcero: Department of Biochemistry and Molecular Biology, University of Georgia
Siladitya Padhi: TCS Innovation Labs-Hyderabad (Life Sciences Division), Tata Consultancy Services Ltd
William R. Foster: Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford
Elzbieta Rembeza: Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford
Arijit Roy: TCS Innovation Labs-Hyderabad (Life Sciences Division), Tata Consultancy Services Ltd
David F. Bishop: Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai
Robert J. Desnick: Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai
Gopalakrishnan Bulusu: TCS Innovation Labs-Hyderabad (Life Sciences Division), Tata Consultancy Services Ltd
Harry A. Dailey: Department of Biochemistry and Molecular Biology, University of Georgia
Wyatt W. Yue: Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16586-x

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