Thymidylate Synthase Structure, Function and Implication in Drug Discovery

Abstract

Recent methodologies applied to the drug discovery process, such as genomics and proteomics, have greatly implemented our basic understanding of drug action and are giving more input to medicinal chemists, in finding genuinely new targets and opportunities for the development of drugs with original mechanisms of action. In this paper, an example of the successful application of some new techniques to the target enzymes with the Thymidylate Synthase (TS) function is given. The improved knowledge of the complex mechanism of the biological pathways in which thymidylate synthase is involved represents a unique chance to find new mechanism-based inhibitors, aimed to treat not only cancerous diseases, but also infectious pathologies. Thymidylate synthase (TS or ThyA) has long been considered as one of the best-known drug targets in the anti-cancer area, after which old and new drugs, such as 5-fluoro uracil and the anti-folate ZD1694, have been introduced into chemotherapy to treat solid tumours. Only a few attempts have been made to find non-classical anti-folate inhibitors that are dissimilar to the folate co-factor, with the aim of finding unshared protein target domains on the enzyme structure, in order to specifically inhibit TS enzymes from pathogens. Only recently from omic studies, a new Thymidylate Synthase Complementing Protein (TSCP or ThyX) has been identified in a number of pathogens, showing a different structure with respect to human TS, thus opening new avenues to specific inhibitions. A depiction of the most recent progress in the study of Thymidylate Synthase enzymes is presented in the following sections.

3R Variant of Thymidylate Synthase 5'-untranslated Enhanced Region Contributes to Colorectal Cancer Risk: A Meta-analysis

“…Epidemiological studies have revealed that smoking, diets and other environmental risk factors play important roles in the development of CRC (Chan and Giovannucci, 2010;Park et al, 2011). However, only a small proportion of individuals exposed to the known risk factors develop CRC, while many cases develop CRC among individuals without those risk factors, which suggest genetic factors also play an important role in the colorectal carcinogenesis (Markowitz and Bertagnolli,metabolism, and thymidylate synthase (TYMS) catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) in the DNA synthesis by using 5, 10-methylenetetrahydrofolate as a methyl donor (Costi et al, 2005). This process above is essential for the synthesis of thymidine which is a nucleotide needed for DNA synthesis and repair (Costi et al, 2005).…”

Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase

“…For this reason, TS has been investigated widely and currently is considered among the best known drug targets in the anticancer area. 5 Several studies clearly showed the efficacy of the evaluation of intratumoral expression of TS mRNA in predicting the response to 5-FU therapy in patients with breast cancer, 6 colorectal cancer, 7 head and neck cancer, 8 pancreatic cancer, 9 and NSCLC. 10 This association was not reported invariably 11,12 ; however, in most of those studies, an adverse effect of higher TS levels on prognosis was documented in different types of human cancers.…”

Functional Analysis of the Mycobacterium tuberculosis FAD-Dependent Thymidylate Synthase, ThyX, Reveals New Amino Acid Residues Contributing to an Extended ThyX Motif

“…Like most eukaryotes, humans depend upon ThyA, so there has been special interest in the enzyme of ThyX-dependent pathogens such as Helicobacter pylori, Campylobacter jejuni, Borrelia burgdorferi, and Treponema pallidum (see reference 22 for a review). ThyX in these organisms is an attractive drug target (4,6,15,23). Eubacterial species in the corynebacterium group are unusual because they have retained the genes for both the ThyA/ DHFR and the ThyX pathways (22,23).…”