Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme
Name
nihms949366.pdf
Description
Accepted version
Size
2.15 MB
Format
Adobe PDF
Checksum (MD5)
5279f23606d3682c655f07a2f4140536
Author(s)
Brown, Breann L.
Kardon, Julia R.
Sauer, Robert T
Baker, Tania
Date Issued
April 2018
Journal
Structure
Publisher
Elsevier BV
Citation
Brown, Breann L. et al. "Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme." Structure 26, 4 (April 2018): 580-589 © 2018 Elsevier Ltd
Version
Author's final manuscript
Abstract
5-Aminolevulinic acid synthase (ALAS) catalyzes the first step in heme biosynthesis. We present 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. Brown et al. determine structures of ALAS, a heme biosynthetic enzyme, that reveal how its PLP cofactor orders the active site. These structures also reveal the positioning of the eukaryote-specific C-terminal extension, providing a framework for understanding the mechanism of erythroid disease-causing mutations.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.str.2018.02.012
