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In humans, the gene encoding a reverse thymidylate synthase (rTS) is transcribed in the reverse direction of the gene encoding thymidylate synthase (TS) that is involved in DNA biosynthesis. Three isoforms are found: α, β, and γ, with the transcript of the α-isoform overlapping with that of TS. rTSβ has been of interest since the discovery of its overexpression in methotrexate and 5-fluorouracil resistant cell lines. Despite more than 20 years of study, none of the rTS isoforms have been biochemically or structurally characterized. In this study, we identified rTSγ as an l-fuconate dehydratase and determined its high-resolution crystal structure. Our data provide an explanation for the observed difference in enzymatic activities between rTSβ and rTSγ, enabling more informed proposals for the possible function of rTSβ in chemotherapeutic resistance.

Original publication

DOI

10.1021/bi500349e

Type

Journal article

Journal

Biochemistry

Publication Date

29/04/2014

Volume

53

Pages

2732 - 2738

Keywords

Crystallography, X-Ray, Fluorouracil, Humans, Hydro-Lyases, Isoenzymes, Methotrexate, Models, Molecular, Protein Conformation