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Title: Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme

Journal Article · · Structure
 [1];  [2];  [1];  [2]
  1. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
  2. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Howard Hughes Medical Inst.
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5-Aminolevulinic acid synthase (ALAS) catalyzes the first step in heme biosynthesis. We present herein the crystal structure of a eukaryotic ALAS from Saccharomyces cerevisiae. In this homodimeric structure, one ALAS subunit contains covalently bound cofactor, pyridoxal 5'-phosphate (PLP), whereas the second is PLP free. Comparison between the subunits reveals PLP-coupled reordering of the active site and of additional regions to achieve the active conformation of the enzyme. The eukaryotic C-terminal extension, a region altered in multiple human disease alleles, wraps around the dimer and contacts active-site-proximal residues. Mutational analysis demonstrates that this C-terminal region that engages the active site is important for ALAS activity. Our discovery of structural elements that change conformation upon PLP binding and of direct contact between the C-terminal extension and the active site thus provides a structural basis for investigation of disruptions in the first step of heme biosynthesis and resulting human disorders.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
The Jane Coffin Childs Memorial Fund for Medical Research; Burroughs Wellcome Postdoctoral Enrichment Program Fellowship; National Institutes of Health (NIH); NIH Ruth L. Kirschstein National Research Service Award; Howard Hughes Medical Institute; National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC)
Grant/Contract Number:
1015092; F32DK095726; R01 DK115558; S10OD021527; AC02-06CH11357
OSTI ID:
1434743
Journal Information:
Structure, Vol. 26, Issue 4; ISSN 0969-2126
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 32 works
Citation information provided by
Web of Science

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Cited By (5)

Heme-dependent Inactivation of 5-Aminolevulinate Synthase from Caulobacter crescentus journal September 2018
Molecular expression, characterization and mechanism of ALAS2 gain-of-function mutants journal January 2019
RETRACTED ARTICLE: Role of aminolevulinic acid synthase 1 in doxorubicin-induced oxidative stress to the ardiomyocyte journal January 2020
Anti-Correlation between the Dynamics of the Active Site Loop and C-Terminal Tail in Relation to the Homodimer Asymmetry of the Mouse Erythroid 5-Aminolevulinate Synthase journal June 2018
Mitochondrial ClpX activates an essential biosynthetic enzyme through partial unfolding journal February 2020

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