Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The structures and spectra of mono and dianionic species derived from PhCH2CN under the action of an organic base LHMDS or n-BuLi in THF solution have been investigated by vibrational spectroscopy and DFT calculations. The assignments previously proposed for the monoanion, the bridged, linear and dimeric monoanionic ion pairs compare well with the calculated ones. The addition of HMPA to a THF solution of PhCHCNLi leads to the formation of an HMPA solvated linear ion pair, distinguishable from the bridged ion pair by the wave number of the 8a v(CC) phenyl ring mode. The calculated structure of the phenylacetonitrile anion in the (PhCHCNLi, CH3Li) mixed dimer or 'Quadac' is very similar to that in the linear ion pair or in the dimer and to that observed by X-ray in (PhCHCNLi, [CH(CH9)2]2NLi) 'Quadac'. The structure of the anion is planar, indicating a charge delocalization from the benzene ring to the -CHCN group. The calculated spectra of the free, mono and dilithiated dianionic species compare well with the experimental ones of the species formed under addition of more than one equivalent of n-BuLi. The structure of the >C-C-CN2- group is very close to that of an imine. The v(CN) bands of the free, mono and dilithiated dianionic species are located at 1912, 1930 and 1890 cm(-1), respectively. The large wave number shift observed between the free monoanion and dianion (approximately 176 cm(-1)), in good accordance with the calculated one (170 cm(-1)) allows differentiating mono and dianionic species. The shifts observed for the 8a and 19a v(CC) phenyl ring modes, although much smaller, also allows discriminating the different species. These small shifts indicate a small variation of the electronic delocalization in the benzene ring in agreement with the calculations.
Spectrochim Acta A Mol Biomol Spectrosc 2002 Jul
PMID:Structural and vibrational characterization of the mono and dilithiated species derived from phenylacetonitrile in THF by infrared and Raman spectroscopy and density functional theory calculations. 1216 96

Folate metabolism in Plasmodium falciparum is essential for cell growth and replication, and the target of important antimalarial agents. The pathway comprises a series of enzymes that convert GTP to derivatives of tetrahydrofolate, which are cofactors in one-carbon transfer reactions. We investigated the expression of five of the genes encoding these enzymes by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using a threshold detection technique. We followed changes in mRNA levels as parasites progress through the erythrocytic cell cycle and examined this process in two cloned lines of diverse origins, as well as under stress conditions, induced by either removal of important metabolites or challenge by folate enzyme inhibitors. Although conventionally regarded as performing housekeeping functions, these genes show disparate levels of and changes in expression through the cell cycle, but respond quite uniformly to folate pathway-specific stress factors, with no evidence of feedback at the transcriptional level. Overall, the two genes involved in the thymidylate cycle (encoding dihy-drofolate reductase-thymidylate synthase, dhfr-ts, and serine hydroxymethyltransferase, shmt) gave the most abundant transcripts. However, only the latter showed major variation across the cell cycle, with a peak around the time of onset of DNA replication, possibly indicative of a regulatory function.
Mol Microbiol 2002 Oct
PMID:Transcriptional analysis of genes encoding enzymes of the folate pathway in the human malaria parasite Plasmodium falciparum. 1236 41

The photophysical processes of copolymer formed by copolymerization of 2,2'-dimethacrylamido-1,1'-binaphthyl (DMBN) with vinylcarbazole (VCZ) have been carefully studied. The results show that when the solution of copolymer (DMBN-VCZ) in THF located in low concentration range (< 10(-3) mg/ml), the fluorescence emission is in good agreement with that of DMBN monomer and the excimer is formed with gradual increase in concentration of copolymer (DMBN-VCZ). The fluorescence of copolymer (DMBN-VCZ) can be quenched both by electron donors and acceptors where the quenching effects follow the Stern-Volmer equation. The dimolecular exciplex between copolymer (DMBN-VCZ) and N,N-dimethylaniline (DMA) are formed and the triple exciplexes are also observed in the same system.
Spectrochim Acta A Mol Biomol Spectrosc 2002 Nov
PMID:Photophysical processes of a copolymer containing 1,1'-binaphthyl-2,2'-diamino and carbazolyl units. 1247 33

Conformational polymorphism of solid tetramesityldisilene (1) has been studied by the methods of optical spectroscopy. The three known modifications of 1: orange unsolvated 1a and two 1:1 solvates with toluene (1b) and THF (1c) have been found to transform under specific conditions to a new, most thermodynamically stable polymorph, yellow unsolvated powder 1d. The latter has been characterized by the Raman, IR, UV-vis and fluorescence data. All forms of 1 exhibit Raman spectra differing in details, which reflect their different crystal and molecular structures. Unsolvated 1a and 1d differ significantly in electronic absorption and fluorescence emission. The yellow form 1d can be converted to the orange form 1a upon illumination with laser light in the region 514-457 nm. Similarity of the Raman and UV-vis spectra of 1d to those of the solutions of 1 provides some evidence for a quasi-trans conformation of 1d.
Spectrochim Acta A Mol Biomol Spectrosc 2003 Jul
PMID:Conformational polymorphism of solid tetramesityldisilene Mes2Si=SiMes2 (Raman, UV-vis, IR and fluorescence study). 1278 51

An efficient solid-phase synthesis of 2-substituted 4-aminopyrido[2,3-d]pyrimidines 12 by cyclization-assisted cleavage from resin is reported. The procedure starts by solid supporting an alpha,beta-unsaturated acid 8 to the Wang resin 13 by using DCC and 4-DMAP in THF. The resulting alpha,beta-unsaturated ester 14 is converted to the Michael adduct by treatment with malononitrile in NaOMe/THF. Such Michael addition constitutes the first example of a Michael reaction with malononitrile in solid-phase. Finally, the Michael adducts 15 are treated with an amidine system in MeOH to yield the corresponding pyridopyrimidines 12. Compounds 12 present three diversity centers R1, R2 and G. Having validated the chemistry on solid support, a 40-membered combinatorial library was obtained using this protocol.
Mol Divers 2003
PMID:Solid-phase synthesis of 2-substituted 4-amino-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines: an example of cyclization-assisted cleavage. 1294 36

Folate metabolism in Plasmodium falciparum is the target of important antimalarial agents. The biosynthetic pathway converts GTP to polyglutamated derivatives of tetrahydrofolate (THF), essential cofactors for DNA synthesis. Tetrahydrofolate can also be acquired by salvage mechanisms. Using a transfection system adapted to studying this pathway, we investigated modulation of dihydropteroate synthase (DHPS) activity on parasite phenotypes. Dihydropteroate synthase incorporates p-aminobenzoate (pABA) into dihydropteroate, the precursor of dihydrofolate. We were unable to obtain viable parasites where the dhps gene had been truncated. However, parasites where the protein was full-length but mutated at two key residues and having < 10% of normal activity were viable in folate-supplemented medium. Metabolic labelling showed that these parasites could still convert pABA to polyglutamated folates, albeit at a very low level, but they could not survive on pABA supplementation alone. This degree of disablement in DHPS also abolished the synergy of the antifolate combination pyrimethamine/sulfadoxine. These data indicate that DHPS activity above a low but critical level is essential regardless of the availability of salvageable folate and formally prove the role of this enzyme in antifolate drug synergy and folate biosynthesis in vivo. However, we found no evidence of a significant role for DHPS in folate salvage. Moreover, when biosynthesis was compromised by the absence of a fully functional DHPS, the parasite was able to compensate by increasing flux through the salvage pathway.
Mol Microbiol 2004 Mar
PMID:Transfection studies to explore essential folate metabolism and antifolate drug synergy in the human malaria parasite Plasmodium falciparum. 1498 35

T-protein, one of the components of the glycine cleavage complex, catalyses the formation of ammonia and methylene-tetrahydrofolate from H-protein-bound intermediate. Native T-protein of the glycine cleavage system from E. coli was efficiently purified using a combination of hydrophobic interaction, gel permeation and ion exchange chromatography. Synchrotron radiation small angle X-ray solution scattering indicates that T-protein has an extended structure in solution. A low resolution model of the protein was constructed ab initio and tentative models of the tertiary structure were built using prediction methods constrained by the scattering data.
Cell Mol Biol (Noisy-le-grand) 2003
PMID:Structural characterization of T-protein of the Escherichia coli glycine cleavage system by X-ray small angle scattering. 1499 75

All the members of pyridoxal-5'-phosphate-dependent enzymes are involved in the metabolism of amino acids. The sequence homology studies further divide this family into three distinct groups. A fine scrutiny of the reactions catalyzed by these enzymes shows their regio specificity; they have been considered as the largest group of enzymes having tendency to affect the valency of the same carbon atom that carries the amino group forming an amine linkage with the coenzyme. Thus, this group was named 'alpha-class of enzymes'. Serine hydroxymethyltransferase (SHMT) is a member of this alpha-class; it reversibly catalyses the conversion of serine into glycine while the hydroxymethyl group is transferred to 5,6,7,8-tetrahydrofolate. The resultant compound is the sole precursor of purine biosynthesis. Henceforth, this enzyme greatly affects nucleic acid biosynthesis in all the organisms. It is obvious that SHMT plays an indispensable role in nucleic acid biosynthesis; therefore, designing and developing a repressor/inhibitor of the SHMT gene/protein may resolve the problem of drug resistance to cancer chemotherapy. SHMT has been widely studied in many living systems (e.g. Escherichia coli, humans, sheep, rabbits, Trypanosoma, Arabidopsis, peas, tobacco) in terms of its structure, cloning, expression, purification and folding patterns. Such studies have enabled one to assess the pattern of overall kinetic and activity behaviour of the enzyme, which may further help in developing a suitable cancer therapeutic molecule.
J Mol Microbiol Biotechnol 2003
PMID:Cloning, expression, activity and folding studies of serine hydroxymethyltransferase: a target enzyme for cancer chemotherapy. 1504 25

Whole blood samples of known methylene tetrahydrofolate reductase (MTHFR) genotypes from 24 individuals were examined at site C677T. Their amplified DNA products were assessed by two-color fluorescence cross-correlation measurements and agarose gel electrophoresis/capillary gel electrophoresis. DNA subpopulations were identified which were not associated with the proper genotype by primer combinations and cycling conditions called multiplexes. We confirmed that DNA analysis by two-color fluorescence cross-correlation measurements allowed the detection of fluorescence signals specifically associated with the proper genotypes in a mixture of amplified nontarget DNA molecules without DNA sizing. The measurement approach does not require complex, follow-up mathematical analysis and is applicable to any single nucleotide polymorphisms. The simple immunogenetic model showed how the approach works to reveal specific DNA target by preventing detection of nontarget DNA. Under those experimental conditions, a new ultrasensitive, and specific method for clinical immunologists is born.
Exp Mol Pathol 2004 Jun
PMID:Specifically associated PCR products probed by coincident detection of two-color cross-correlated fluorescence intensities in human gene polymorphisms of methylene tetrahydrofolate reductase at site C677T: a novel measurement approach without follow-up mathematical analysis. 1512 3

Dihydroneopterin aldolase (DHNA) catalyses a retroaldol reaction yielding 6-hydroxymethyl-7,8-dihydropterin, a biosynthetic precursor of the vitamin, tetrahydrofolate. The enzyme is a potential target for antimicrobial and anti-parasite chemotherapy. A gene specifying a dihydroneopterin aldolase from Arabidopsis thaliana was expressed in a recombinant Escherichia coli strain. The recombinant protein was purified to apparent homogeneity and crystallised using polyethylenglycol as the precipitating agent. The crystal structure was solved by X-ray diffraction analysis at 2.2A resolution. The enzyme forms a D(4)-symmetric homooctamer. Each polypeptide chain is folded into a single domain comprising an antiparallel four-stranded beta-sheet and two long alpha-helices. Four monomers are arranged in a tetrameric ring, and two of these rings form a hollow cylinder. Well defined purine derivatives are found at all eight topologically equivalent active sites. The subunit fold of the enzyme is related to substructures of dihydroneopterin triphosphate epimerase, GTP cyclohydrolase I, and pyruvoyltetrahydropterin synthase, which are all involved in the biosynthesis of pteridine type cofactors, and to urate oxidase, although some members of that superfamily have no detectable sequence similarity. Due to structural and mechanistical differences of DHNA in comparison with class I and class II aldolases, a new aldolase class is proposed.
J Mol Biol 2004 Jun 11
PMID:Biosynthesis of tetrahydrofolate in plants: crystal structure of 7,8-dihydroneopterin aldolase from Arabidopsis thaliana reveals a novel adolase class. 1516 63


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