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