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Structure. 2018 Apr 3;26(4):580-589.e4. doi: 10.1016/j.str.2018.02.012. Epub 2018 Mar 15.

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

Author information

1
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: tabaker@mit.edu.

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.

KEYWORDS:

AAA+ unfoldase; ClpX; XLPP; XLSA; porphyria; sideroblastic anemia; α-oxoamine family

PMID:
29551290
PMCID:
PMC5894356
[Available on 2019-04-03]
DOI:
10.1016/j.str.2018.02.012
[Indexed for MEDLINE]

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