Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetrahydrofolate (vitamin B9) and its folate derivatives are essential cofactors in one-carbon (C1) transfer reactions and absolutely required for the synthesis of a variety of different compounds including methionine and purines. Most plants, microbial eukaryotes, and prokaryotes synthesize folate de novo. We have characterized an important enzyme in this pathway, the Saccharomyces cerevisiae FOL1 gene. Expression of the budding yeast gene FOL1 in Escherichia coli identified the folate biosynthetic enzyme activities dihydroneopterin aldolase (DHNA), 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (HPPK), and dihydropteroate synthase (DHPS). All three enzyme activities were also detected in wild-type yeast strains, whereas fol1Delta deletion strains only showed background activities, thus demonstrating that Fol1p catalyzes three sequential steps of the tetrahydrofolate biosynthetic pathway and thus is the central enzyme of this pathway, which starting from GTP consists of seven enzymatic reactions in total. Fol1p is exclusively localized to mitochondria as shown by fluorescence microscopy and immune electronmicroscopy. FOL1 is an essential gene and the nongrowth phenotype of the fol1 deletion leads to a recessive auxotrophy for folinic acid (5'-formyltetrahydrofolate). Growth of the fol1Delta deletion strain on folinic acid-supplemented rich media induced a dimorphic switch with haploid invasive and filamentous pseudohyphal growth in the presence of glucose and ammonium, which are known suppressors of filamentous and invasive growth. The invasive growth phenotype induced by the depletion of C1 carrier is dependent on the transcription factor Ste12p and the flocullin/adhesin Flo11p, whereas the filamentation phenotype is independent of Ste12p, Tec1p, Phd1p, and Flo11p, suggesting other signaling pathways as well as other adhesion proteins.
Mol Biol Cell 2004 Aug
PMID:Characterization of the Saccharomyces cerevisiae Fol1 protein: starvation for C1 carrier induces pseudohyphal growth. 1516 67

An amide-based 1,10-phenanthroline (phen) derivative and its complexes with europium(III) and terbium(III) ions were synthesized. The complexes were characterized by elemental analysis, infrared spectra and conductivity. The europium and terbium ions were coordinated by O atoms of C=O, Ar-O-C and N atoms of phen. The fluorescence properties of the complexes in THF, dioxane, MeCN and DMF were investigated. Under the excitation of UV light, these complexes exhibited characteristic fluorescence of europium and terbium ions. The solvent factors influencing the fluorescent intensity were discussed.
Spectrochim Acta A Mol Biomol Spectrosc 2004 Jul
PMID:Synthesis and infrared and fluorescence spectra of new europium and terbium polynuclear complexes with an amide-based 1,10-phenanthroline derivative. 1524 41

Antifolate drugs that target the biosynthesis and processing of essential folate cofactors are widely used for treatment of chloroquine-resistant falciparum malaria. Salvage of pre-formed folate can strongly compromise the efficacy of these drugs in vitro and the availability of folate from the human host in natural infections also influences therapeutic outcomes. To investigate how different parasite lines respond to the presence of exogenous folate, we measured the effect of the latter on the susceptibility of parasites to sulfa-drug blockage of folate biosynthesis, utilising the parents and 22 progeny of the HB3-Dd2 genetic cross of Plasmodium falciparum, together with selected unrelated lines. Complete linkage of the folate utilisation phenotype was observed to a DNA sequence of 48.6 kb lying between nucleotide positions 738,489 and 787,058 of chromosome 4 and encompassing the dihydrofolate reductase-thymidylate synthase (dhfr-ts) gene locus. Examination of the putative ORFs on this fragment upstream (3) and downstream (4) of dhfr-ts revealed no plausible candidate genes for folate processing. Similarly, a marked heterogeneity in the 5'-UTR regions of Dd2 and HB3, manifest as a directly repeated 256 bp sequence in the former, also did not correlate with the folate utilisation phenotype nor apparently influence levels of dhfr-ts transcripts or protein products. By contrast, the nature of the coding sequence of the dhfr domain appeared to play a direct role, with the single mutant (S108N) HB3-type utilising folic acid much less efficiently than other allelic variants. We also compared the processing of exogenous folic acid, folinic acid and p-aminobenzoic acid (pABA) in metabolic labelling studies of HB3 and Dd2. These support the view that DHFR is likely to have a low-level folate reductase activity as well as its normal function of reducing dihydrofolate to tetrahydrofolate, and that a significant hurdle in the utilisation of exogenous folic acid is the initial reduction of fully oxidised folic acid to dihydrofolate, an activity that the single mutant enzyme found in HB3 is postulated to perform particularly poorly. This would mirror earlier studies indicating that the DHFR activity of HB3 is also compromised relative to other variants.
Mol Biochem Parasitol 2004 May
PMID:Genetic and metabolic analysis of folate salvage in the human malaria parasite Plasmodium falciparum. 1528 89

Clarithromycin (6-O-methylerythromycin A) is a 14-membered macrolide antibiotic which is active in vitro against clinically important gram-positive and gram-negative bacteria. The selectivity of the methylation of the C-6 OH group is studied on erythromycin A derivatives. To understand the effect of the solvent on the methylation process, detailed molecular dynamics (MD) simulations are performed in pure DMSO, pure THF and DMSO:THF (1:1) mixture by using the anions at the C-6, C-11 and C-12 positions of 2',4"-[O-bis(TMS)]erythromycin A 9-[O-(dimethylthexylsilyl)oxime] under the assumption that the anions are stable on the sub-nanosecond time scale. The conformations of the anions are not affected by the presence of the solvent mixture. The radial distribution functions are computed for the distribution of different solvent molecules around the 'O-' of the anions. At distances shorter than 5 A, DMSO molecules are found to cluster around the C-11 anion, whereas the anion at the C-12 position is surrounded by the THF molecules. The anion at the C-6 position is not blocked by the solvent molecules. The results are consistent with the experimental finding that the methylation yield at the latter position is increased in the presence of a DMSO:THF (1:1) solvent mixture. Thus, the effect of the solvent in enhancing the yield during the synthesis is not by changing the conformational properties of the anions, but rather by creating a suitable environment for methylation at the C-6 position.
J Comput Aided Mol Des 2004 Feb
PMID:Solvent effect on the synthesis of clarithromycin: a molecular dynamics study. 1528

A structural analysis for dibutoxyphosphoryl benzylisothiourea (DBBT) was carried out by mass spectrometry, 1H NMR, 13C NMR, infrared and Raman spectroscopy. The Fourier transform infrared and Fourier transform Raman spectra of liquid of DBBT were carried out with the purpose of studying the tautomerism (structures I and II) and the behavior of the more polar absorption's bands in different solvents, i.e., absorption's of the P=O and C=N bands. The results suggest the existence of tautomerism in the pure (liquid) compound and in solution of CHCl(3), CH(2)Cl(2), CHBr(3), and THF, C(2)H(4)Cl(2) and C(2)H(4)Br(2). The solvent interaction with the P=O band was characterized by the presence of a new band in the region of the O-H absorption. A vibrational assignment of the IR bands and Raman shifts was done and is proposed in this paper.
Spectrochim Acta A Mol Biomol Spectrosc 2004 Sep
PMID:Structural analysis and Fourier transform infrared and Raman spectra of dibutoxyphosphoryl benzylisothiourea. 1529 49

We have investigated the incidence of the C677T and A1298C methylene tetrahydrofolate reductase (MTHFR) gene single nucleotide polymorphisms (SNPs) in the South Indian Tamil Nadu population with a total number of 72 individuals. The MTHFR genotyping was performed using the polymerase chain reaction followed by restriction enzyme analysis. Homozygosity for the MTHFR A1298C SNP was detected in 15.3% (11/72) of the individuals tested, and 47.2% (34/72) were heterozygous for this SNP. Homozygosity for the C677T MTHFR SNP was detected in 1.38%(1/72), and the frequency of the C677T heterozygotes was 18.1%(13/72). When we analyzed the combined frequency of the two SNPs, the frequency of double heterozygosity was19.6%, and the frequency of double homozygosity was completely absent among the study group. The 'C' allele frequency for MTHFR A1298C was 0.389, and the 'T' allele frequency for C677T mutation was 0.104. Out of the 72 individuals included in the study, 52 were acute myocardial infarction (AMI) patients and 20 were healthy individuals with no documented history of heart disease. The results of this study indicate that the MTHFR A1298C SNP is more prevalent among the Tamilians when compared to the MTHFR C677T SNP, suggesting a possible role of MTHFR A1298C in the pathogenesis of heart diseases.
Exp Mol Pathol 2004 Oct
PMID:Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians. 1535 Dec 30

Colorectal carcinoma (CRC) remains a frequent cause of cancer-associated mortality in the UK and still has a relatively poor outcome. Single gene defects account for up to 2-6% of cases, but twin studies suggest a hereditary component in 35%. CRC represents a paradigm for cancer genetics. Almost all the major-gene influences on CRC have been identified, and the identification of the remaining susceptibility alleles is proving troublesome. Only a few low-penetrance alleles, such as methylene tetrahydrofolate reductase C677T, appear convincingly to be associated with CRC risk. To identify the remaining CRC genes, parallel approaches, including strategies based on linkage and association and complementary analyses such as searches for modifier genes, must be employed. To gain sufficient evidence to prove that a gene is involved in CRC predisposition, it is probably necessary for multiple, adequately-powered studies to demonstrate an association with the disease, especially if the allelic variants have only a small differential effect on risk. It may also be possible to show how genes interact with each other and the environment, although this will be even more difficult. Accurate quantitation of the allele-specific risks in different populations will be necessary, but problematic, especially if those risks combine in a fashion which is not of a straightforward additive or multiplicative type. Without any good prior evidence of the nature of the remaining genetic influence on CRC, the possibility remains that this is a truly polygenic trait or that multiple, rare variants contribute to the increased risk; in these cases, identification of the genes involved will be very difficult. Despite these potential problems, the effectiveness of preventive measures for CRC, especially in high-risk individuals, means that the search for new predisposition genes is justified.
Hum Mol Genet 2004 Oct 01
PMID:An update on the genetics of colorectal cancer. 1535 23

This study was designed to investigate, in the Turkish population, the association of methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism and left ventricular hypertrophy (LVH) in patients with type II diabetes mellitus. Our study included 249 patients with type II diabetes mellitus (102 men, 147 women) and 214 healthy volunteers as controls (91 men, 123 women). MTHFR C677T genotypes were determined by polymerase chain reaction, restriction fragment length polymorphism techniques. No differences were observed in the distribution of MTHFR genotypes or allele frequencies in the cases versus the controls. The frequency of the MTHFR-mutated allele (T) was 31.7% in the type II diabetes mellitus versus 31.1% of the controls. The homozygous mutation (T/T) in the MTHFR gene was identified in 12% of the type II diabetes mellitus versus 9.3% of the controls. Patients with the TT genotype showed a higher prevalence of LVH when compared to patients with the CC and CT genotypes (p = 0.01). The MTHFR gene C677T mutation may be a possible risk factor for the development of LVH in the type II diabetic patients.
J Biochem Mol Biol 2004 Mar 31
PMID:Methylene tetrahydrofolate reductase C677T mutation and left ventricular hypertrophy in Turkish patients with type II diabetes mellitus. 1546 1

Whereas tetrahydrofolate is an essential cofactor in all bacteria, the gene that encodes the enzyme dihydrofolate reductase (DHFR) could not be identified in many of the bacteria whose genomes have been entirely sequenced. In this communication we show that the halophilic archaea Halobacterium salinarum and Haloarcula marismortui contain genes coding for proteins with an N-terminal domain homologous to dihydrofolate synthase (FolC) and a C-terminal domain homologous to dihydropteroate synthase (FolP). These genes are able to complement a Haloferax volcanii mutant that lacks DHFR. We also show that the Helicobacter pylori dihydropteroate synthase can complement an Escherichia coli mutant that lacks DHFR. Activity resides in an N-terminal segment that is homologous to the polypeptide linker that connects the dihydrofolate synthase and dihydropteroate synthase domains in the haloarchaeal enzymes. The purified recombinant H. pylori dihydropteroate synthase was found to be a flavoprotein.
Mol Microbiol 2004 Dec
PMID:An alternative pathway for reduced folate biosynthesis in bacteria and halophilic archaea. 1555 70

The reactions between [M(3)(CO)(12)], M = Ru and Os, and salicylideneimine-2-thiophenol Schiff base in THF under reflux gave [Ru(CO)(4)(satpH)] and [Os(CO)(3)(satpH(2))] complexes. Structures of the two complexes were proposed on the basis of spectroscopic studies. Magnetic study of [Ru(CO)(4)(satpH)] suggested that a change in oxidation state of the ruthenium atom from zero to +1 was achieved via oxidative addition of the SH group with a proton displacement to give a low-spin d(7) electronic configuration. UV-Vis spectra of the two complexes in different solvents exhibited visible bands due to metal-to-ligand charge transfer. Electrochemical investigation of the free ligand and complexes showed some cathodic and anodic irreversible peaks due to interconversions through electron transfer.
Spectrochim Acta A Mol Biomol Spectrosc 2005 Jan 01
PMID:Spectroscopic and electrochemical studies of ruthenium and osmium complexes of salicylideneimine-2-thiophenol Schiff base. 1555 34


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