Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme
| Autor: | Tania A. Baker, Julia R. Kardon, Breann L. Brown, Robert T. Sauer |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Conformation alpha-Helical Saccharomyces cerevisiae Proteins Protein subunit Amino Acid Motifs Genetic Vectors Coenzymes Gene Expression Heme Saccharomyces cerevisiae Crystallography X-Ray Cofactor Article Substrate Specificity 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Structural Biology Catalytic Domain Escherichia coli Transferase Protein Interaction Domains and Motifs Pyridoxal phosphate Cloning Molecular Molecular Biology ATP synthase biology Chemistry Active site Aminolevulinic Acid Recombinant Proteins Mitochondria Kinetics Protein Subunits 030104 developmental biology Biochemistry Amino Acid Substitution 030220 oncology & carcinogenesis Pyridoxal Phosphate Aminolevulinic acid synthase Mutation biology.protein Protein Conformation beta-Strand Protein Multimerization 5-Aminolevulinate Synthetase Protein Binding |
| Zdroj: | PMC |
| Popis: | 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. Burroughs Wellcome Postdoctoral Enrichment Program (Award 1015092) National Institutes of Health (Award F32DK095726) National Institutes of Health (Grant R01 DK115558) |
| Databáze: | OpenAIRE |
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