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Human Aminolevulinate Synthase Structure Reveals a Eukaryotic-Specific Autoinhibitory Loop Regulating Substrate Binding and Product Release

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 Jr, Wyatt W Yue

Nat Commun. 2020 Jun 4;11(1):2813.

PMID: 32499479

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42414798	ALAS2 Active human			Price

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