Design, synthesis and evaluation of potent thymidylate synthase X inhibitors

Onen, Fannie; Boum, Yap; Jacquement, Claire; Spanedda, Maria Vittoria; Jaber, Nada; Scherman, Daniel; Myllykallio, Hannu; Herscovici, Jean

doi:10.1016/j.bmcl.2008.04.080

Cited by 34 publications

(23 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies of FDTS enzymes in particular are still in their infancy, and many aspects of their catalysis need further elucidation, which is a major reason for the current scarcity of potent and selective FDTS inhibitors. 43, 44 Considering that FDTS represents an important but under-characterized antibiotic target, future investigation of its chemical mechanism and interactions with the substrates will likely provide the basis for rational design of mechanism-based inhibitors. To this date, the relevance of the folate/FAD-dependent tRNA methyltransferase (TrmFO) to the survival of pathogens has not been elucidated.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, a series of derivatives based on a thiazolidine core were synthesized and shown to inhibit FDTS activity. 43 This resulted in the identification of two classes of submicromolar inhibitors, which either competed with dUMP or inactivated FDTS independently of dUMP concentration. To date, none of these compounds have been demonstrated to be selective for FDTS lowering their potential to serve as drug leads.…”

Section: Classical Thymidylate Synthase (Tsase Ec 21145) and Fmentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms and inhibition of uracil methylating enzymes

Mishanina

Koehn

Kohen

2012

Bioorganic Chemistry

View full text Add to dashboard Cite

Uracil methylation is essential for survival of organisms and passage of information from generation to generation with high fidelity. Two alternative uridyl methylation enzymes, flavin-dependent thymidylate synthase and folate/FAD-dependent RNA methyltransferase, have joined the long-known classical enzymes, thymidylate synthase and SAM-dependent RNA methyltransferase. These alternative enzymes differ significantly from their classical counterparts in structure, cofactor requirements and chemical mechanism. This review covers the available structural and mechanistic knowledge of the classical and alternative enzymes in biological uracil methylation, and offers a possibility of using inhibitors specifically aiming at microbial thymidylate production as antimicrobial drugs.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Classical Thymidylate Synthase (Tsase Ec 21145) and Fmentioning

confidence: 99%

Mechanisms and inhibition of uracil methylating enzymes

Mishanina

Koehn

Kohen

2012

Bioorganic Chemistry

View full text Add to dashboard Cite

show abstract

“…11,12 Potent inhibitors of classical TSase, such as 5F-dUMP, produce moderate reversible inhibition of FDTS, and crystal structures of FDTS with 5F-dUMP (e.g. P.D.B accession 1tls) present non-covalently bound complexes that do not provide significant information about the catalytic mechanism or intermediate structures.…”

Section: Introductionmentioning

confidence: 99%

Trapping of an Intermediate in the Reaction Catalyzed by Flavin-Dependent Thymidylate Synthase

et al. 2012

View full text Add to dashboard Cite

Thymidylate is a DNA nucleotide that is essential to all organisms and is synthesized by the enzyme thymidylate synthase (TSase). Several human pathogens rely on an alternative flavin-dependent thymidylate synthase (FDTS), which differs from the human TSase both in structure and molecular mechanism. Recently it has been shown that FDTS catalysis does not rely on an enzymatic nucleophile and the proposed reaction intermediates are not covalently bound to the enzyme during catalysis, an important distinction from the human TSase. Here we report the chemical trapping, isolation, and identification of a derivative of such an intermediate in the FDTS-catalyzed reaction. The chemically modified reaction intermediate is consistent with currently proposed FDTS mechanisms that do not involve an enzymatic nucleophile, and has never been observed during any other TSase reaction. These findings establish the timing of the methylene transfer during FDTS catalysis. The presented methodology provides an important experimental tool for further studies of FDTS, which may assist the efforts to rationally design inhibitors as leads for future antibiotics.

show abstract

“…To date there are few inhibitors of FDTS activity [42], and none that show high specificity for FDTS over classical thymidylate synthase. As mentioned above, the chemical and kinetic mechanisms of FDTS have recently been greatly clarified; however, even with current knowledge of these enzymes, the scope of rationally designed inhibitors is limited.…”

Section: Mechanism-based Inhibition Of Fdtssmentioning

confidence: 99%

Flavin-dependent thymidylate synthase: A novel pathway towards thymine

Koehn

Kohen

2010

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

For several decades only one chemical pathway was known for the de novo biosynthesis of the essential DNA nucleotide, thymidylate. This reaction catalyzed by thyA or TYMS encoded thymidylate synthases is the last committed step in the biosynthesis of thymidylate and proceeds via the reductive methylation of uridylate. However, many microorganisms have recently been shown to produce a novel, flavin-dependent thymidylate synthase encoded by the thyX gene. Preliminary structural and mechanistic studies have shown substantial differences between these deoxyuridylatemethylating enzymes. Recently, both the chemical and kinetic mechanisms of FDTS have provided further insight into the distinctions between thyA and thyX encoded thymidylate synthases. Since FDTSs are found in several severe human pathogens their unusual mechanism offers a promising future for the development of antibiotic and antiviral drugs with little effect on human thymidylate biosynthesis.

show abstract

Design, synthesis and evaluation of potent thymidylate synthase X inhibitors

Cited by 34 publications

References 13 publications

Mechanisms and inhibition of uracil methylating enzymes

Mechanisms and inhibition of uracil methylating enzymes

Trapping of an Intermediate in the Reaction Catalyzed by Flavin-Dependent Thymidylate Synthase

Flavin-dependent thymidylate synthase: A novel pathway towards thymine

Contact Info

Product

Resources

About