Megaloblastic Anemias
Harold R. Schumacher, William A. Rock, Sanford A. Stass in Handbook of Hematologic Pathology, 2019
The formation of methionine is central to DNA synthesis and requires both vitamin B12 and folate. Methylcobalamin, a form of vitamin Bi2 is an essential cofactor for methyltransferase in the conversion of homocysteine to methionine (Fig. 1). N5-methyltetrahydrofolate acts as the original methyl donor in this reaction. The methyl group is first transferred from N5-methyltetrahydrofolate to the enzyme-bound cobalamin to form methylcobalamin; methylcobalamin then transfers the methyl group to homocysteine to generate methionine. The importance of this reaction is that it generates tetrahydrofolate. Tetrahydrofolate is required (through its derivative N5, 10-methyltetrahydrofolate) for the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dUMP), an immediate precursor of DNA.
Nanomaterials for Theranostics: Recent Advances and Future Challenges *
Valerio Voliani in Nanomaterials and Neoplasms, 2021
MTX inhibits the action of the FA reductase, which is responsible for conversion of FA to tetrahydrofolic acid [362, 363]. In the absence of tetrahydrofolic acids, DNA, RNA, and proteins cannot be synthesized, leading to blockage of cell division. Hydroxyurea (hyhdroxycarbamide) reduces production of deoxyribonucleotides through inhibition of the enzyme ribonucleotidereductase [361–366]. This enzyme catalyzes the reduction of ribonucleotide into their corresponding deoxyribonucleotides, which are required for DNA synthesis. 5-FU, a thymidylate synthase inhibitor, is widely used in the treatment of patients with breast or gastrointestinal tract cancer. Interrupting the action of this enzyme blocks the synthesis of pyrimidine thymidine, which is a nucleoside required for DNA replication, in the S phase of the cell cycle [367]. Thymidylate synthase converts deoxyuridine monophosphate (dUMP) into deoxythymidine monophosphate (dTMP), which is crucial in production of pyrimidine base for synthesis of DNA; thus, it is a viable target for cancer chemotherapy [367]. 5-FU causes a scarcity of dTMP. Therefore, rapidly dividing cancer cells undergo apoptosis via thymine-less death. 5-FU can arrest unlimited proliferation of cancer cells and also lead to production of faulty rRNA [368, 369]. The immunosuppressive drug 6-MP alters the synthesis and function of DNA and RNA by inhibiting purine nucleotide synthesis and metabolism and interferes with nucleotide interconversion and glycoprotein synthesis [370, 371].
Precision medicine for colorectal cancer
Debmalya Barh in Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Thymidylate synthase (TYMS) is crucial enzyme for providing essential nucleotide precursors (de novo pyrimidine synthesis) in order to maintain DNA synthesis and repair. Respectively, TYMS is implicated in the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) (Carreras and Santi, 1995). Hence, TYMS expression is a rate-limiting step for cell proliferation as well as for cancer growth (Rustum, 2004). Compelling evidence from several clinical studies have demonstrated that TYMS protein and mRNA levels were higher in different cancers (Berger and Berger, 2006), including breast cancer, lung cancer, gastric cancer, and CRC (Yamada et al., 2001; Kamoshida et al., 2004; Popat et al., 2006), and this increase in TYMS levels has been associated with poor clinical outcome in these cancers. It is also shown that TYMS expression correlates closely with transcription factor E2F1 expression in colon cancer specimens. In accordance with this TYMS—E2F1 correlation TYMS could be considered as an E2F1-regulated enzyme, which is essential for DNA synthesis and repair (Kasahara et al., 2000; Rahman et al., 2004). Additionally, an in vitro study in immortalized NIH/3T3 mouse fibroblast cells underlined oncogene-like activity of TYMS that suggests a connection between TYMS-regulated DNA synthesis and the induction of a neoplastic phenotype (Rahman et al., 2004; Bertino and Banerjee, 2004).
Design, synthesis and in vitro antiproliferative activity of new thiazolidinedione-1,3,4-oxadiazole hybrids as thymidylate synthase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Zohor Mohammad Mahdi Alzhrani, Mohammad Mahboob Alam, Thikryat Neamatallah, Syed Nazreen
Despite the availability of various chemotherapeutic agents, cancer is the second highest cause of deaths next to cardiovascular diseases.1,2 Thymidylate synthase (TS) has become an area of interest in cancer chemotherapy due to their important role in DNA biosynthesis.3,4 TS is responsible for the formation of deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP) which is further phosphorylated to triphosphate group (dTTP), a direct precursor for DNA synthesis.5–7 TS inhibition causes inhibition of thymidylate biosynthesis which in turn causes cessation of cell growth and proliferation.8,9 Research on TS has been going on since many years, but still it is a challenge for medicinal chemists to develop new, safe and effective chemotherapeutic agents as TS inhibitor.
Levels of Folate and Vitamin B12, and Genetic Polymorphisms Involved in One-Carbon Metabolism May Increase the Risk of Cervical Cytological Abnormalities
Published in Nutrition and Cancer, 2022
Nayara Nascimento Toledo Silva, Ana Carolina Silva Santos, Maria de Fátima Dias de Sousa Brito, Diama Bradha Andrade Peixoto do Vale, Cláudia Martins Carneiro, Angélica Alves Lima
TS enzyme catalyzes the conversion of deoxyuridine monophosphate (dUMP) into deoxythymidine monophosphate (dTMP), through methylene transfer from folate, being the only de novo source of thymidine for DNA synthesis and repair. TS acts as a protein that binds to RNA for translation repression of its messenger RNA (mRNA) or other proteins, and can regulate cell cycle progression (15, 16). High levels of TS activity may to increase DNA synthesis, as well as the accumulation of genetic alterations, due to imbalance of deoxyribonucleotide triphosphates (dNTPs) pool. Therefore, TS enzyme is a potential target of several chemotherapeutic agents in treatment of cancer, besides the analysis of its levels to be useful in evaluation of tumor cell sensitivity to radiation (17). Many polymorphisms in untranslated regions (UTRs) were identified in TS gene, which is located on chromosome 18p11.32. The polymorphisms most frequently studied are double or triple 28 bp tandem repeat in 5′-untranslated enhanced region (TSER), and 6 bp deletion/insertion at nucleotide 1494 in TS 3′-untranslated region (TS3’UTR). These two genetic variations may influence the TS gene expression and the stability of its mRNA, respectively (15).
Clinical implications of lung neuroendocrine neoplasm classification
Published in Expert Review of Anticancer Therapy, 2021
Jasna Metovic, Marco Barella, Sergio Harari, Linda Pattini, Adriana Albini, Angelica Sonzogni, Giulia Veronesi, Mauro Papotti, Giuseppe Pelosi
Thymidylate synthase (TS), which converts deoxyuridine monophosphate to deoxythymidine monophosphate and participate in DNA synthesis, is a well-recognized predictor of chemotherapy response with antifolate drugs in NSCLC patients. However, it has been also implied as a diagnostic marker in the distinction between high-grade and low-grade lung NENs, as well as a possible predictor of antifolate drug sensitivity in the same tumor types [73]. A recent paper by Ibe et al. [74], comparing NECs of the lung (13 LCNECs and 8 SCLCs) with NSCLCs, revealed significantly higher TS expression in the NE group compared to squamous cell carcinomas. In addition, TS mRNA expression in SCLC cell lines was significantly higher than in NSCLC cell lines, suggesting helpfulness in predicting the effects of TS‐interfering agents.
Related Knowledge Centers
- Adenosine Diphosphate
- Deoxyribonucleotide
- Nucleotide
- Pyrimidine
- Uridine Monophosphate
- Conjugate
- Hydroxy Group
- Nucleoside-Phosphate Kinase
- Adenosine Triphosphate
- Uridine Diphosphate