Chapter category: Cell Metabolism
5-Aminolaevulinic Acid Dehydratase, Porphobilinogen Deaminase and Uroporphyrinogen III Synthase
Tetrapyrroles: Birth, Life and Death
Edited by: Martin J. Warren and Alison G. SmithISBN: 978-0-387-78517-2
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Chapter authors:
Heidi L. Schubert, Peter T. Erskine and Jonathan B. Cooper
The three enzymes 5-aminolaevulinic acid dehydratase (ALAD, E.C.4.2.1.24; sometimes referred to as porphobilinogen synthase), porphobilinogen deaminase (EC 4.3.1.8; also known as hydroxymethylbilane synthase) and uroporphyrinogen III synthase (U3S; E.C.4.2.1.75) together convert 5-aminolaevulinic acid (ALA) into uroporphyrinogen III, from which all tetrapyrroles are synthesized. The X-ray structures of several ALADs have been determined showing that the enzyme forms a large homo-octameric structure with all eight active sites on the outer surface. Each subunit adopts the TIM barrel fold with an N-terminal arm which forms extensive inter-subunit interactions. The active site of each subunit is located in a pronounced cavity formed by loops at the C-terminal ends of the strands forming the TIM barrel. Current proposals for the catalytic mechanism involve the binding of both substrate moieties by formation of Schiff bases with two invariant active site lysine residues. Structural studies of porphobilinogen deaminase have shown that the enzyme has three domains, two of which show a strong structural resemblance to a number of periplasmic binding proteins. The reaction catalysed by uroporphyrinogen III synthase involves cyclization and ring inversion, predicted to proceed through a spirocyclic intermediate. X-ray structures of the enzyme from humans and a thermophilic bacterium have enabled models of the catalytic process to be proposed.
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