|
type |
Journal Article |
authors |
Brown BL, Kardon JR, Sauer RT, Baker TA |
title |
Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme |
journal |
Structure |
Activity |
2.3.1.37 |
Family |
2.3.1.37 |
sel |
selected |
ui |
29551290 |
year |
(2018) |
volume |
26 |
number |
4 |
pages |
580-589 |
| |
keywords |
AAA+ unfoldase; ClpX; XLPP; XLSA; porphyria; sideroblastic anemia; α-oxoamine family |
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. |
last changed |
2018/05/07 09:03 |
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