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

Abstract

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.

Authors:
 [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.
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
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)
OSTI Identifier:
1434743
Grant/Contract Number:  
1015092; F32DK095726; R01 DK115558; S10OD021527; AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Structure
Additional Journal Information:
Journal Volume: 26; Journal Issue: 4; Journal ID: ISSN 0969-2126
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; porphyria; XLPP; sideroblastic anemia; XLSA; ClpXAAA+ unfoldase; α-oxoamine family

Citation Formats

Brown, Breann L., Kardon, Julia R., Sauer, Robert T., and Baker, Tania A. Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme. United States: N. p., 2018. Web. doi:10.1016/j.str.2018.02.012.
Brown, Breann L., Kardon, Julia R., Sauer, Robert T., & Baker, Tania A. Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme. United States. doi:10.1016/j.str.2018.02.012.
Brown, Breann L., Kardon, Julia R., Sauer, Robert T., and Baker, Tania A. Thu . "Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme". United States. doi:10.1016/j.str.2018.02.012. https://www.osti.gov/servlets/purl/1434743.
@article{osti_1434743,
title = {Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme},
author = {Brown, Breann L. and Kardon, Julia R. and Sauer, Robert T. and Baker, Tania A.},
abstractNote = {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.},
doi = {10.1016/j.str.2018.02.012},
journal = {Structure},
issn = {0969-2126},
number = 4,
volume = 26,
place = {United States},
year = {2018},
month = {3}
}

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