5TXR

Structure of ALAS from S. cerevisiae non-covalently bound to PLP cofactor

Summary for 5TXR

• Entry DOI: 10.2210/pdb5txr/pdb
• Related: 5TXT
• Descriptor: 5-aminolevulinate synthase, mitochondrial, FORMIC ACID, PYRIDOXAL-5'-PHOSPHATE, ... (6 entities in total)
• Functional Keywords: transferase, heme biosynthesis, 5-aminolevulinic acid, pyridoxal 5-phosphate
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)
• Total number of polymer chains: 2
• Total formula weight: 109025.95

Authors

Brown, B.L.,Grant, R.A.,Kardon, J.R.,Sauer, R.T.,Baker, T.A. (deposition date: 2016-11-17, release date: 2018-03-28, Last modification date: 2024-04-03)

Primary citation

Brown, B.L.,Kardon, J.R.,Sauer, R.T.,Baker, T.A.
Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme.
Structure, 26:580-589.e4, 2018

PubMed 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.

PubMed: 29551290
DOI: 10.1016/j.str.2018.02.012

Experimental method

X-RAY DIFFRACTION (1.9 Å)