Structural Genomics Identify Thymidylate Synthase Complementing Protein as a Novel Antibacterial Drug Target

The huge number of complete genome sequences are fueling large-scale bioinformatics, and structural and functional proteomics efforts aimed at accelerating the identification and characterization of new drug targets, a critical pre-requisite for the development of new therapeutics. The JCSG structural genomics effort is pursuing a full proteome analysis of Thermotoga maritima, and follow-on studies have already resulted in the identification of an antibacterial drug target. The identification of thymidylate synthase complementing protein (thyX/thy1) as a thymidylate synthase enzyme (Myllykallio et al., 2002) and its structure-based functional analysis lead to the characterization of TSCP as an antibacterial drug target (Kuhn et al., 2002; Mathews et al., 2003). In general, TSCPs complement the activity of thymidylate synthase (TS) enzymes in organisms without TS. Thymidylate synthase methylates 2'- deoxyuridine 5'-monophosphate (dUMP) to produce 2'-deoxythymidine 5'-monophosphate (dTMP), a nucleotide essential for synthesis of DNA. The cofactor 5,10-methylene-5,6,7,8- tetrahydrofolate (CH2H4folate) serves as both a methyl donor and reductant in the reaction. Thymidylate synthesis is the terminal step in the sole de novo synthetic pathway to dTMP. Consequently, TS inhibition stops DNA production, arresting the cell cycle and eventually leading to "thymineless" cell death. The medical community has long been turned to TS inhibitors as a possible source of anticancer drugs. Interfering with dTMP production is a seductive strategy for drug design because it can directly prevent DNA replication. Identification of TSCP enzymes, which share no sequence or structural homology to classical TS found in humans (Figure 1), offers the possibility of therapeutic intervention with low cross-reactivity against mammalian enzymes.