Disease relevance of DI-H-uracil

• The repair of dihydrouracil is initiated by E. coli endonuclease III and processed via the base excision repair pathway [1].
• Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors [2].

High impact information on DI-H-uracil

• All of the mutations that reduce competition involve base changes that decrease homology to a eucaryotic tRNA consensus sequence in the highly conserved D and T psi regions [3].
• RNA polymerase bypass at sites of dihydrouracil: implications for transcriptional mutagenesis [4].
• Complexes with dihydrouracil and N-carbamyl-beta-alanine obtained for the yeast dihydropyrimidinase reveal the mode of substrate and product binding and allow conclusions about what determines substrate specificity, stereoselectivity, and the reaction direction among cyclic amidohydrolases [5].
• Repair of dihydrouracil supported by base excision repair in mNTH1 knock-out cell extracts [6].
• In the present study we used an in vitro repair system to investigate the mechanism for the removal of 5,6-dihydrouracil from DNA by mNTH1-deficient cell-free extracts derived from testes of mNTH1 knock-out mice [6].

Chemical compound and disease context of DI-H-uracil

• The dihydrouracil residue at position 20 of Escherichia coli tRNAGly1 has been replaced by the photoaffinity reagent, N-(4-azido-2-nitrophenyl)glycyl hydrazide (AGH) [7].

Biological context of DI-H-uracil

• The enzyme preparations also catalyze the hydrolysis of 5-bromo-5,6-dihydrouracil, 5,6-dihydrouracil, and 5,6-dihydrothymine, the latter two of which are the natural substrates for dihydropyrimidine amidohydrolase [8].
• The enzymic general base with a pK of 7.5-8 is required to activate water for nucleophilic attack on the C-4 of 5,6-dihydrouracil which is directly coordinated to the active site zinc [9].
• Steady-state kinetics were measured with these mutant enzymes using substrates containing 5,6-dihydrouracil, two enantiomers of thymine glycol, 8-oxo-7,8-dihydroguanine, and an abasic site positioned opposite each of the four canonical DNA bases [10].
• Circadian rhythm of orotate phosphoribosyltransferase, pyrimidine nucleoside phosphorylases and dihydrouracil dehydrogenase in mouse liver. Possible relevance to chemotherapy with 5-fluoropyrimidines [11].
• Urinary dihydrouracil concentrations in the parents after the loading were several times higher than those in normal control persons, the finding being consistent with DHPuria heterozygotes [12].

Anatomical context of DI-H-uracil

• The catabolism of dCyd was highest in macrophages where 25% of the added dCyd (0.5 microM, 0.5 nmol/million cells) had been converted to dihydrouracil after 30 min, and 90% after 12 h [13].
• Cytoplasmic extracts from late passage fibroblasts also showed reduced activity with all three substrates suggesting that the residual hAPE, and activities that recognized dihydrouracil, were preferentially targeted to the nuclei [14].

Associations of DI-H-uracil with other chemical compounds

• Urinary dihydrouracil and uracil levels were determined by high-performance liquid chromatography with column switching [15].
• The fluorescence signal of proflavin replacing dihydrouracil at position 16 or 17 in yeast tRNA(Phe) was utilized to monitor changes of the conformation of the D loop [16].
• Dihydropyrimidine dehydrogenase catalyzes, in the rate-limiting step of the pyrimidine degradation pathway, the NADPH-dependent reduction of uracil and thymine to dihydrouracil and dihydrothymine, respectively [17].
• Of these, barbituric acid and 5, 6-dihydrouracil were more fully characterized with regard to pH, temperature, and concentration CEST effects [18].
• Both 5-FU and uracil (U) are catabolised by dihydropyrimidine dehydrogenase (DPD) to form dihydrofluorouracil (FUH(2)) and dihydrouracil (UH(2)), respectively [19].

Gene context of DI-H-uracil

• A series of dihydrouracil derivatives has been synthesized and investigated for their in vitro inhibitory activity toward human leukocyte elastase (HLE) and cathepsin G (Cath G) [20].
• However, with DNA containing a DHU that is closely opposed to a single strand break, Ku inhibited the nicking activity of human endonuclease III as well as the amount of free double strand breaks induced by the enzyme [21].
• Uracil to dihydrouracil ratio in plasma was evaluated as a surrogate marker for DPD deficiency, and showed values out of the range previously recorded from a reference, non-toxic population [22].
• A. tumefacins hydantoinase was most active on 5,6-dihydrouracil and DL-5-methylhydantoin with only slight activity on DL-benzylhydantoin [23].
• Like water, dihydrouracil does not bind to active charcoal, and its presence in the cell medium can result in an overestimation of the in situ thymidylate synthase activity [13].

Analytical, diagnostic and therapeutic context of DI-H-uracil

• Northern blot and primer extension analyses revealed that the pydBC genes are induced by dihydrouracil and regulated under the control of sigma(54) recognized promoter at transcriptional level as a polycistronic operon [24].
• A rapid, robust and sensitive HPLC method for analysis of uracil (U) and dihydrouracil (UH2) in plasma was developed using solid phase extraction and ultraviolet detection [25].

References