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

• Main Authors: Brown, Breann L. (Author), Kardon, Julia R. (Author), Sauer, Robert T (Author), Baker, Tania (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor)
• Format: Article
• Language: English
• Published: Elsevier BV, 2020-06-22T20:21:20Z.
• Subjects: Article
• Online Access: Get fulltext

 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.