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Figure 8.
Fig. 8. Schematic diagrams illustrating how cerulenin and
TLM mimic substrates in the active site of FabB. Upper panel,
the thiolactone ring of TLM mimics the bent conformation of the
thiomalonate, and this is emphasized by the shaded atoms. The
O-1s form hydrogen bonds with His-298 and His-333, and the C-1,
C-2, and C-3s of malonate are mimicked by the C-1, C-2, and C-9s
of TLM. The O-2 of TLM points out the active site tunnel that
would be occupied by the pantetheine arm of the malonyl-ACP
substrate. Lower panel, cerulenin mimics the condensation
transition state and spans the two halves of the active site.
The O-3 of cerulenin lies in the oxyanion hole formed by the
amides of Cys-163 and Phe-392 enclosed by the phenyl side chain
of Phe-392. This structure mimics the postulated location of the
oxyanion of the tetrahedral transition state. The side chain of
Cys-163 rotates in the cerulenin structure to form a covalent
bond with C-2, but in the transition state, it is postulated to
reside in the location observed in the native enzyme. The acyl
chain of cerulenin feeds into the hydrophobic groove that
accommodates the long chain acyl-enzyme intermediate.
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