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PDBsum entry 2uuv
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References listed in PDB file
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Key reference
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Title
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The crucial step in ether phospholipid biosynthesis: structural basis of a noncanonical reaction associated with a peroxisomal disorder.
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Authors
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A.Razeto,
F.Mattiroli,
E.Carpanelli,
A.Aliverti,
V.Pandini,
A.Coda,
A.Mattevi.
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Ref.
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Structure, 2007,
15,
683-692.
[DOI no: ]
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PubMed id
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Abstract
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Ether phospholipids are essential constituents of eukaryotic cell membranes.
Rhizomelic chondrodysplasia punctata type 3 is a severe peroxisomal disorder
caused by inborn deficiency of alkyldihydroxyacetonephosphate synthase (ADPS).
The enzyme carries out the most characteristic step in ether phospholipid
biosynthesis: formation of the ether bond. The crystal structure of ADPS from
Dictyostelium discoideum shows a fatty-alcohol molecule bound in a narrow
hydrophobic tunnel, specific for aliphatic chains of 16 carbons. Access to the
tunnel is controlled by a flexible loop and a gating helix at the
protein-membrane interface. Structural and mutagenesis investigations identify a
cluster of hydrophilic catalytic residues, including an essential tyrosine,
possibly involved in substrate proton abstraction, and the arginine that is
mutated in ADPS-deficient patients. We propose that ether bond formation might
be orchestrated through a covalent imine intermediate with the flavin,
accounting for the noncanonical employment of a flavin cofactor in a nonredox
reaction.
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Figure 5.
Figure 5. Electrostatic Potentials of the ADPS Dimer Surface
Red, blue, and white show potentials at −8, +8, and 0
k[B]T e^−1, respectively. The basic amino acids forming the
membrane-binding region are labeled.
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Figure 7.
Figure 7. Structural Framework for ADPS Catalysis
(A) A
structural framework for the reaction cycle of ADPS. Step 1,
ADPS binds the acyl-DHAP substrate; the HHH loop becomes ordered
and the gating helix closes the tunnel. Step 2, the fatty-acid
product (R[1]COOH) is generated and released, whereas the DHAP
moiety remains trapped in the active site. Step 3, the fatty
alcohol (R[2]OH) binds in the tunnel. Step 4, the alkyl-DHAP
product is formed and released.
(B) Working hypothesis for
the reaction mechanism of ADPS.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2007,
15,
683-692)
copyright 2007.
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