National Center for
4A35: Crystal Structure Of Human Mitochondrial Enolase Superfamily Member 1 (enosf1)
Enzymatic and structural characterization of rTSgamma provides insights into the function of rTSbeta
Biochemistry (2014) 53 p.2732-2738
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: alpha, beta, and gamma, with the transcript of the alpha-isoform overlapping with that of TS. rTSbeta 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 rTSgamma 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 rTSbeta and rTSgamma, enabling more informed proposals for the possible function of rTSbeta in chemotherapeutic resistance.