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Title
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Structural basis for channelling mechanism of a fatty acid beta-oxidation multienzyme complex.
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Authors
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M.Ishikawa,
D.Tsuchiya,
T.Oyama,
Y.Tsunaka,
K.Morikawa.
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Ref.
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EMBO J, 2004,
23,
2745-2754.
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PubMed id
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Abstract
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The atomic view of the active site coupling termed channelling is a major
subject in molecular biology. We have determined two distinct crystal structures
of the bacterial multienzyme complex that catalyzes the last three sequential
reactions in the fatty acid beta-oxidation cycle. The alpha2beta2
heterotetrameric structure shows the uneven ring architecture, where all the
catalytic centers of 2-enoyl-CoA hydratase (ECH), L-3-hydroxyacyl-CoA
dehydrogenase (HACD) and 3-ketoacyl-CoA thiolase (KACT) face a large inner
solvent region. The substrate, anchored through the 3'-phosphate ADP moiety,
allows the fatty acid tail to pivot from the ECH to HACD active sites, and
finally to the KACT active site. Coupling with striking domain rearrangements,
the incorporation of the tail into the KACT cavity and the relocation of
3'-phosphate ADP bring the reactive C2-C3 bond to the correct position for
cleavage. The alpha-helical linker specific for the multienzyme contributes to
the pivoting center formation and the substrate transfer through its
deformation. This channelling mechanism could be applied to other beta-oxidation
multienzymes, as revealed from the homology model of the human mitochondrial
trifunctional enzyme complex.
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