Article
- The EMBO Journal (2005) 24, 3166 - 3177
- doi:10.1038/sj.emboj.7600792
Published online: 25 August 2005
Subject Category:
Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans
Isabel Astner1,a, Jörg O Schulze1,a, Joop van den Heuvel1, Dieter Jahn2, Wolf-Dieter Schubert1 and Dirk W Heinz1
- Division of Structural Biology, German Research Centre for Biotechnology, Braunschweig, Germany
- Institute of Microbiology, Technical University Braunschweig, Braunschweig, Germany
Correspondence to:
Wolf-Dieter Schubert, Division of Structural Biology, German Research Centre for Biotechnology, Mascheroder Weg 1, 38124 Braunschweig, Germany. Tel.: +49 531 6181 764; Fax: +49 531 6181 763; E-mail: wds@gbf.de or dih@gbf.de
aThese authors contributed equally to this work
Received 10 May 2005; Accepted 29 July 2005
Abstract
5-Aminolevulinate synthase (ALAS) is the first and rate-limiting enzyme of heme biosynthesis in humans, animals, other non-plant eukaryotes, and 
-proteobacteria. It catalyzes the synthesis of 5-aminolevulinic acid, the first common precursor of all tetrapyrroles, from glycine and succinyl-coenzyme A (sCoA) in a pyridoxal 5'-phosphate (PLP)-dependent manner. X-linked sideroblastic anemias (XLSAs), a group of severe disorders in humans characterized by inadequate formation of heme in erythroblast mitochondria, are caused by mutations in the gene for erythroid eALAS, one of two human genes for ALAS. We present the first crystal structure of homodimeric ALAS from Rhodobacter capsulatus (ALASRc) binding its cofactor PLP. We, furthermore, present structures of ALASRc in complex with the substrates glycine or sCoA. The sequence identity of ALAS from R. capsulatus and human eALAS is 49%. XLSA-causing mutations may thus be mapped, revealing the molecular basis of XLSA in humans. Mutations are found to obstruct substrate binding, disrupt the dimer interface, or hamper the correct folding. The structure of ALAS completes the structural analysis of enzymes in heme biosynthesis.
Keywords:
- aminolevulinic acid synthase,
- bacteriochlorophyll,
- PLP,
- tetrapyrrole biosynthesis,
- X-linked sideroblastic anemia
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