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Biochim Biophys Acta. 2004 Jan 14;1696(1):15-22.
Effects of ligand binding and conformational
switching on intracellular stability of human thymidylate synthase.
Berger SH, Berger FG, Lebioda L.
Center for Colon Cancer Research, University of South Carolina,
Columbia, SC 29208, USA. berger@cop.sc.edu
Thymidylate
synthase (TS) is the target in colon cancer therapeutic protocols
utilizing such drugs as 5-fluorouracil and raltitrexed. The
effectiveness of these treatments is hampered by emerging drug
resistance, usually related to increased levels of TS. Human TS (hTS)
is unique among thymidylate synthases from all species examined as its
loop 181-197 can assume two main conformations related by rotation of
180 degrees. In one conformation, "active", the catalytic Cys-195 is
positioned in the active site; in the other conformation, "inactive",
it is at the subunit interface. Also, in the active conformation,
region 107-128 has one well-defined conformation while in the inactive
conformation this region assumes multiple conformations and is
disordered in crystals. The native protein exists in apparent
equilibrium between the two conformational states, while the enzyme
liganded with TS inhibitors assumes the active conformation. The native
protein has been reported to bind to several mRNAs, including its own
mRNA, but upon ligation, RNA binding activity is lost. Ligation of TS
by inhibitors also stabilizes it to turnover. Since currently used
TS-directed drugs stabilize the active conformation and slow down the
enzyme degradation, it is postulated that inhibitors of hTS stabilizing
the inactive conformation of hTS should cause a down-regulation in
enzyme levels as well as inactivate the enzyme.
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