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Crystal structure of 5‐aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans
Author(s) -
Astner Isabel,
Schulze Jörg O,
van den Heuvel Joop,
Jahn Dieter,
Schubert WolfDieter,
Heinz Dirk W
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600792
Subject(s) - biology , heme , biosynthesis , enzyme , atp synthase , biochemistry
5‐Aminolevulinate synthase (ALAS) is the first and rate‐limiting enzyme of heme biosynthesis in humans, animals, other non‐plant eukaryotes, and α‐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 (ALAS Rc ) binding its cofactor PLP. We, furthermore, present structures of ALAS Rc 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.