Deoxythymidine-5 -monophosphate

Thymine Deoxythymidme Deoxythymidylic acid Deoxythymidine monophosphate (dTMP) Deoxythymidine diphosphate (dTDP) Deoxythymidine triphosphate (dTTP)... 

Fig. 14.1 Cellular pathway of methotrexate. ABCBl, ABCCl-4, ABC transporters ADA, adenosine deaminase ADP, adenosine diphosphate AICAR, aminoimidazole carboxamide ribonucleotide AMP, adenosine monophosphate ATIC, AICAR transformylase ATP, adenosine triphosphate SjlO-CH -THF, 5,10-methylene tetrahydrofolate 5-CHj-THF, 5-methyl tetrahydro-folate DHFR, dihydrofolate reductase dTMP, deoxythymidine monophosphate dUMP, deoxy-uridine monophosphate FAICAR, 10-formyl AICAR FH, dihydrofolate FPGS, folylpolyglutamyl synthase GGH, y-glutamyl hydrolase IMP, inosine monophosphate MTHFR, methylene tetrahydrofolate reductase MTR, methyl tetrahydrofolate reductase MTX-PG, methotrexate polyglutamate RFCl, reduced folate carrier 1 TYMS, thymidylate synthase. Italicized genes have been targets of pharmacogenetic analyses in studies published so far. (Reproduced from ref. 73 by permission of John Wiley and Sons Inc.)...

Figure 15.4 Four compounds that are methylated either by SAM or methyl FH4 (CH3 FH4). The processes are (i) cytidine bases in DNA (11) methylatlon of deoxyUMP to produce deoxythymidine monophosphate (111) formation of phosphatidylcholine from phos-phatldylethanolamlne (Chapter 17) (Iv) methylatlon of a protein In myelin. The base cytidine Is methylated In DNA to produce methylcytidine which. If deamlnated, produces methylthymidine In DNA. Methylatlon of the bases can modify gene transcription (see text). (PR 5 -phosphor1bose).

Figure 20.12 (a) Details of reaction catalysed by thymidylate synthase. Methylene FH4 represents N N methylene tetrahydro-folate (see Figure 15.2). (b) Reactions in the pathways in which either CDP or UDP gives rise to deoxythymidine monophosphate. Note that two processes can be involved in synthesis of deoxyuridine monophosphate. It is not known if one process dominates, but in (c) it is assumed that the pathway from CDP dominates formation of dTTP. (c) k summary of the reactions required for synthesis of deoxyribonucleotides required for DNA replication. 

The enzyme tetrahydrofolate reductase, which is essential for the synthesises deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate, a process essential for DNA synthesis. This enzyme catalyses formation of methylene tetrahydrofate (CH3-FH4) a necessary co-substrate for synthesis of d-TMP catalysed by thymidylate synthase (See Figure 20.12(a) and p. 477). 

Fig. 3. Metabolism of the fluoropyrimidines dTMP = deoxythymidine monophosphate, dUMP = deoxyuridine monophosphate, FdUDP = fluorodeoxyuridine diphosphate, FdUMP - fluoro-deoxyuridine monophosphate, FdUTP = fluorodeoxyuridine triphosphate, FU-DNA= fluorouracil-deoxyribonucleic acid, FUDP = fluorouracil diphosphate, FUMP = fluorouracil monophosphate, FU-RNA = fluorouracil-ribonucleic acid, FUTP = fluorouracil triphosphate.

Fig. 1. Folate-cobalamin interaction in the synthesis of purines and pyrimidines and, therefore, of DNA. (1) In gastrointestinal mucosa cells (2) in the liver (3) in peripheral tissues. C, cobalamine DAC, desoxyadenosylcobalamine HC, hydroxy cobalamine MC, methylcobalamine F, folic acid MTHF, methyltetrahydrofolic acid THF, tetrahydrofolic acid DHF, dihydrofolic acid dUMP, deoxyuridinemonophosphate dTMP, deoxythymidine-monophosphate. (Adapted from Far-...

Fig. 2. Target enzymes for methotrexate and 5FU. 5-FU = 5-Fluorouracil THF = tetrahydrofolic acid DHF = dihydrofolic acid dUMP = deoxyuridine-monophosphate dTMP = deoxythymidine-monophosphate.

Trifluridine (Viroptic) is a fluorinated pyrimidine nucleoside that has in vitro activity against HSV-1 and HSV-2, vaccinia, and to a lesser extent, some adenoviruses. Activation of trifluridine requires its conversion to the 5 monophosphate form by cellular enzymes. Trifluridine monophosphate inhibits the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) by thymidylate synthetase. In addition, it competes with deoxythymidine triphosphate (dTTP) for incorporation by both viral and cellular DNA polymerases. Trifluridine-resistant mutants have been found to have alterations in thymidylate synthetase specificity. 

The TS mediates the conversion of 2-deoxyuridine monophosphate (dUMP) into deoxythymidine monophosphate (dTMP). This enzymatic methylation reaction is a key step in the synthesis of DNA and involves a ternary complex between the substrate, the enzyme and the co-factor [methylene tetrahydrofolic acid (CH2FAH4)] (Fig. 24) [8,80,81], This transformation represents the sole de novo source of dTMP, a building block for DNA synthesis and repair [82]. 

The other major class of antimalarials are the folate synthesis antagonists. There is a considerable difference in the drug sensitivity and affinity of dihydrofolate reductase enzyme (DHFR) between humans and the Plasmodium parasite. The parasite can therefore be eliminated successfully without excessive toxic effects to the human host. DHFR inhibitors block the reaction that transforms deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) at the end of the pyrimidine-synthetic pathway. This reaction, a methylation, requires N °-methylene-tetrahydrofolate as a carbon carrier, which is oxidized to dihydrofolate. If the dihydrofolate cannot then be reduced back to tetrahydrofolate (THF), this essential step in DNA synthesis will come to a standstill. 

ADP adenosine diphosphate, ANP atrial natriuretic peptide, AP5DTPT(5 -adenosyl)P5-(5 -thymidyl)pentaphosphate, ATP adenosine triphosphate, AZTMP 3 -azido-3 -deoxythymidine monophosphate, dGMP deoxyguanosine monophosphate, P 4-(2-hydroxyethyl)-l-piperazine ethanesulfonic acid, HMD hymenialdisine, TMP thymidine monophosphate... 

Deoxythymidine monophosphate derivatives that inhibit thymidine monophosphate kinase 36 MFA Alignments performed with least-squares (predictive R2=0.70), pharmacophore (0.56), or docked conformations (0.72). Receptor-based alignment performed best Aparna et al. (42)... 

CMRL CMS CPE dAMP, dTMP Connaught Medical Research Laboratories Calgon metasilicate cytopathic effect deoxyadenosine monophosphate, deoxythymidine monophosphate, etc. 

The folic acid-dependent conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) carried out by thymidylate synthase is an absolute requirement for DNA synthesis. An unusually high demand for uracil (ura) by certain tumor cells suggested that such an inhibitor of this process could have tumor cell selectivity. 5-Fluorouracil (fl5ura) (80), along with 5-fluorocytosine (fl5cyt) (81) and 5-fluoroorotic acid (fl5oro) (82), were synthesized by Heidelberger in 1957 as part of a... 

Figure 7-16. The transfer of a one-carbon unit from serine to deoxyuridine monophosphate (dUMP) to form deoxythymidine monophosphate (dTMP). FH4 is oxidized to FH2 (dihydrofolate) in this reaction. FH2 is reduced to FH4 by dihydrofolate reductase. Hi indicate the steps at which the antimetabolites methotrexate and 5-fluo-rouracil (5-FU) act.

Folic acid serves as a carrier of one-carbon groups in many metabolic reactions. It is required for the biosynthesis of compounds such as choline, serine, glycine, purines, and deoxythymidine monophosphate (dTMP). 

The best-known example of this type of inhibition is 5 -fluorouracil, a rather old cytostatic agent. Fluorouracil is first converted metabolically into the corresponding phosphodeoxyriboside. This, in turn, blocks DNA biosynthesis by inhibiting thy-midylate synthase, an enzyme which methylates deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), one of the four building blocks of DNA [77]. 

Allelic loss of chromosome 18q, which is located on the DCC gene, is predictive of mortality, independent of tumor differentiation, vascular invasion, and TNM stage. Five-year smvival rates decrease by 39% and 14% in patients with allelic loss of chromosome 18q and stage II or III colorectal cancer, respectively. Tumors that overexpress TS, which is responsible for converting de-oxyuridine monophosphate to deoxythymidine monophosphate, an... 

One-carbon pool Folate derivatives that carry a single carbon in various oxidation states (formyl, methenyl, methylene, and methyl) for transfer to acceptor molecules that is, transfer to deoxyuridine monophosphate to form deoxythymidine monophosphate transfer to homocysteine to form methionine. 

All the pyrimidine nucleotides can proceed to the deoxy compounds as diphosphates, similar to the purines. However, uridine does not occur in DNA therefore, it must be converted to a thymine derivative. This occurs by the following basic pathway CDP is converted to dCDP. This is converted to dCMP, which can produce dUMP. The dUMP is then methylated in the number 5 position, via N5, N10-methylene tetrahydrofolate. This produces deoxythymidine monophosphate (dTMP) and dihydrofolate. The dTMP then can be converted to dTDP and dTTP, which can be incorporated into DNA (Fig. 20.9). 

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