Unknown

Dataset Information

0

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


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.

SUBMITTER: Bailey HJ 

PROVIDER: S-EPMC7272653 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC428484 | biostudies-literature
| S-EPMC4573335 | biostudies-literature
| S-EPMC2566939 | biostudies-literature
| S-EPMC4615937 | biostudies-literature
| S-EPMC6908770 | biostudies-literature
| S-EPMC6154995 | biostudies-literature
| S-EPMC2865267 | biostudies-literature
| S-EPMC1134779 | biostudies-other
| S-EPMC5207166 | biostudies-literature
| S-EPMC5027489 | biostudies-literature