Pharmaceutical case study
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Evolutionary Trace analysis of dihydro-
folate reductase (DHFR)
Accelrys European Headquarters
334 Cambridge Science Park
Cambridge, CB4 0WN, UK
Tel: +44 1223 228500
Accelrys Asia Headquarters
Nishi-shimbashi TS Bldg 11F
Nishi-shimbashi 3-3-1, Minato-ku,
Tokyo, 105-0003, Japan
Tel: 81 3 3578 3861
Accelrys Corporate Headquarters
9685 Scranton Road
San Diego, CA 92121-3752, USA
Tel: +1 858 799 5000
Dr. Teresa Lyons, Accelrys, demonstrates here that Evolutionary Trace is an
accurate and thorough application to highlight functionally important
residues in dihydrofolate reductase (DHFR).
Introduction
DHFR reduces dihydrofolic acid to tetrahydrofolic acid. Folate shuttles carbon
atoms to various enzymes that need them in their reactions. In one example,
DHFR is essential in the pathway for DNA synthesis. While the DHFR structure
is generally conserved throughout nature, the mammalian form is about
3000 Daltons larger than the bacterial form, most of the additional residues
occurring in loops. The amino acid sequences are quite diverse across species,
being as little as 30% identical between bacterial species. Eukaryotes and
prokaryotes only share about 30% identity at best. These distinctions have
made DHFR an excellent candidate for species-specific drugs such as the
antibiotic trimethoprim and the antimalarial pyrimethamine. DHFR is also
the target of the chemotherapeutic methotrexate as well as the first anti-
cancer drug aminopterin.
Evolutionary Trace, developed by Olivier Lichtarge from Baylor College of
Medicine (Lichtage et al. (1996), J. Mol. Biol., 257, 342-358), exploits the fact that
residues important to the structure or function of a protein strongly tend to
be conserved across species. The method uses a multiple sequence alignment
of a protein family to identify conserved residues within the family. The
Evolutionary Trace algorithm analyzes the conservation of amino acids within
a protein family and maps this information in the context of an atomic struc-
ture. Hence