Structure of human erythrocyte 5-aminolaevulinic acid dehydratase, the second enzyme in the biosynthesis pathway of haem
Structure of human erythrocyte 5-aminolaevulinic acid dehydratase, the second enzyme in the biosynthesis pathway of haem
The X-ray structure human 5-aminolaevulinic acid dehydratase (ALAD), the second enzyme in the haem biosynthesis pathway, has been determined to a resolution of 2.8A. This is the first structure of an ALAD from any vertebrate. The ALAD monomer takes the form of an α8β8 barrel with an N-terminal arm extension. Two monomers interact with one another as dimers in which the N-terminal arms interact with the barrel of the adjacent monomer. Within each dimer in the native structure, the monomers, termed A and B, have very distinct structural differences. All four A monomers are located on one side of the octamer and are well ordered with the product porphobilinogen (PBG) bound and the zinc metal ion bound together in the catalytic site at the centre of the barrel, with an active site loop docking the PBG into place. In contrast, the B monomers have no porphobilinogen bound and are less well ordered, with the active site loops unresolved and the metal ions absent. The observed asymmetry contributes to a molecular explanation for the properties of half site reactivity, previously noted for mammalian enzymes. Lead is a powerful inactivating agent of human ALAD that causes severe anaemia. Lead displaces the zinc ion in monomer A, weakly coordinating with Cys with Cys 122 and recruiting Asp 169 as a metal ligand, with attendant disruption of the zinc-binding region. The structure of the human enzyme enables, for the first time, a detailed molecular description of the mutations that cause ALAD deficiency porphyria (Doss porphyria) and their likely implications for the structural integrity of the enzyme.
University of Southampton
Mills-Davies, Nicola Louise
edca62d4-c903-4f93-8af5-e1b92c127929
2000
Mills-Davies, Nicola Louise
edca62d4-c903-4f93-8af5-e1b92c127929
Mills-Davies, Nicola Louise
(2000)
Structure of human erythrocyte 5-aminolaevulinic acid dehydratase, the second enzyme in the biosynthesis pathway of haem.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
The X-ray structure human 5-aminolaevulinic acid dehydratase (ALAD), the second enzyme in the haem biosynthesis pathway, has been determined to a resolution of 2.8A. This is the first structure of an ALAD from any vertebrate. The ALAD monomer takes the form of an α8β8 barrel with an N-terminal arm extension. Two monomers interact with one another as dimers in which the N-terminal arms interact with the barrel of the adjacent monomer. Within each dimer in the native structure, the monomers, termed A and B, have very distinct structural differences. All four A monomers are located on one side of the octamer and are well ordered with the product porphobilinogen (PBG) bound and the zinc metal ion bound together in the catalytic site at the centre of the barrel, with an active site loop docking the PBG into place. In contrast, the B monomers have no porphobilinogen bound and are less well ordered, with the active site loops unresolved and the metal ions absent. The observed asymmetry contributes to a molecular explanation for the properties of half site reactivity, previously noted for mammalian enzymes. Lead is a powerful inactivating agent of human ALAD that causes severe anaemia. Lead displaces the zinc ion in monomer A, weakly coordinating with Cys with Cys 122 and recruiting Asp 169 as a metal ligand, with attendant disruption of the zinc-binding region. The structure of the human enzyme enables, for the first time, a detailed molecular description of the mutations that cause ALAD deficiency porphyria (Doss porphyria) and their likely implications for the structural integrity of the enzyme.
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Published date: 2000
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Local EPrints ID: 464322
URI: http://eprints.soton.ac.uk/id/eprint/464322
PURE UUID: 34bc8bed-0cd4-40be-967d-f7cc5d312ddf
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Date deposited: 04 Jul 2022 22:07
Last modified: 16 Mar 2024 19:25
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Author:
Nicola Louise Mills-Davies
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