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

DOI: 10.1038/s41467-020-16586-x DOI Help

Authors: Henry J. Bailey (Structural Genomics Consortium, University of Oxford) , Gustavo A. Bezerra (Structural Genomic Consortium, University of Oxford) , Jason R. Marcero (University of Georgia) , Siladitya Padhi (Tata Consultancy Services Ltd) , William R. Foster (Structural Genomics Consortium, University of Oxford) , Elzbieta Rembeza (Structural Genomics Consortium, University of Oxford) , Arijit Roy (Tata Consultancy Services Ltd) , David F. Bishop (Icahn School of Medicine at Mount Sinai) , Robert J. Desnick (Icahn School of Medicine at Mount Sinai) , Gopalakrishnan Bulusu (Tata Consultancy Services Ltd) , Harry A. Dailey (University of Georgia) , Wyatt W. Yue (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 11

State: Published (Approved)
Published: June 2020

Open Access Open Access

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.

Journal Keywords: Enzyme mechanisms; Transferases; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: XChem
Instruments: B21-High Throughput SAXS , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography