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121.
Plasmodium falciparum, the causative agent of the fatal form of malaria, synthesizes GMP primarily from IMP and, hence, needs active GMPS (GMP synthetase) for its survival. GMPS, a G-type amidotransferase, catalyses the amination of XMP to GMP with the reaction occurring in two domains, the GAT (glutamine amidotransferase) and ATPPase (ATP pyrophosphatase). The GAT domain hydrolyses glutamine to glutamate and ammonia, while the ATPPase domain catalyses the formation of the intermediate AMP-XMP from ATP and XMP. Co-ordination of activity across the two domains, achieved through channelling of ammonia from GAT to the effector domain, is the hallmark of amidotransferases. Our studies aimed at understanding the kinetic mechanism of PfGMPS (Plasmodium falciparum GMPS) indicated steady-state ordered binding of ATP followed by XMP to the ATPPase domain with glutamine binding in a random manner to the GAT domain. We attribute the irreversible, Ping Pong step seen in initial velocity kinetics to the release of glutamate before the attack of the adenyl-XMP intermediate by ammonia. Specific aspects of the overall kinetic mechanism of PfGMPS are different from that reported for the human and Escherichia coli enzymes. Unlike human GMPS, absence of tight co-ordination of activity across the two domains was evident in the parasite enzyme. Variations seen in the inhibition by nucleosides and nucleotide analogues between human GMPS and PfGMPS highlighted differences in ligand specificity that could serve as a basis for the design of specific inhibitors. The present study represents the first report on recombinant His-tagged GMPS from parasitic protozoa. 相似文献
122.
Stereochemical control of peptide folding 总被引:1,自引:0,他引:1
Stereochemically constrained amino acid residues that strongly favour specific backbone conformations may be used to nucleate and stabilize specific secondary structures in designed peptides. An overview of the use of alphaalpha-dialkyl amino acids in stabilizing helical structures in synthetic peptides is presented, with an emphasis on work carried out in the authors laboratory. Alpha-aminoisobutyric acid (Aib) and related achiral homologs facilitate stable helix formation in oligopeptides as exemplified by a large number of crystal structure determinations in the solid state. The ability to design conformationally rigid helical modules has been exploited in attempts to design structurally well characterized helix-linker helix, using potential nonhelical linking segments. Beta-hairpin design has been approached by exploiting the tendency of 'prime turns' to nucleate hairpin formation. The use of nucleating (D)Pro-Gly segments has resulted in the generation of several well characterized beta-hairpin structures, including the crystallographic observation of beta-hairpin in a synthetic apolar octapeptide. Extensions of this approach to three stranded beta-sheets and larger structures containing multiple (D)Pro-Gly segments appear readily possible. 相似文献
123.
Polo-like kinase 1 (Plk1) regulates DNA replication origin firing and interacts with Rif1 in Xenopus
Diletta Ciardo Olivier Haccard Hemalatha Narassimprakash David Cornu Ida
Chiara Guerrera Arach Goldar Kathrin Marheineke 《Nucleic acids research》2021,49(17):9851
The activation of eukaryotic DNA replication origins needs to be strictly controlled at multiple steps in order to faithfully duplicate the genome and to maintain its stability. How the checkpoint recovery and adaptation protein Polo-like kinase 1 (Plk1) regulates the firing of replication origins during non-challenged S phase remained an open question. Using DNA fiber analysis, we show that immunodepletion of Plk1 in the Xenopus in vitro system decreases replication fork density and initiation frequency. Numerical analyses suggest that Plk1 reduces the overall probability and synchrony of origin firing. We used quantitative chromatin proteomics and co-immunoprecipitations to demonstrate that Plk1 interacts with firing factors MTBP/Treslin/TopBP1 as well as with Rif1, a known regulator of replication timing. Phosphopeptide analysis by LC/MS/MS shows that the C-terminal domain of Rif1, which is necessary for its repressive action on origins through protein phosphatase 1 (PP1), can be phosphorylated in vitro by Plk1 on S2058 in its PP1 binding site. The phosphomimetic S2058D mutant interrupts the Rif1-PP1 interaction and modulates DNA replication. Collectively, our study provides molecular insights into how Plk1 regulates the spatio-temporal replication program and suggests that Plk1 controls origin activation at the level of large chromatin domains in vertebrates. 相似文献
124.
P. Balaram 《Protein science : a publication of the Protein Society》2004,13(10):2571-2572
125.
The effect of surfactants (two cationic, one anionic and three non-ionic) at 0.001, 0.01, 0.1 and 1.0 % concentrations on
aflatoxin production, ergosterol content and sugar consumption by Aspergillus parasiticus (NRRL 2999) in YES liquid culture medium is reported. At 0.01% concentration, the cationic surfactants, cetyl dimethyl ammonium
bromide (CDAB) and dodecyl trimethyl ammonium bromide (DTAB), and the anionic surfactant, sodium dodecyl sulfate (SDS), completely
inhibited spore germination, while DTAB also inhibited the production of ergosterol and toxin (p < 0.05). At a concentration of 0.001%, CDAB was found to enhance toxin production, while SDS was found to inhibit it when
compared with other surfactants. Non-ionic surfactants, polyoxyethylene sorbitan monolaurate (Tween-20), polyoxyethylene lauryl
ether (Brij-35) and ethoxylated p-tert-octylphenol (Triton X-100) delayed the spore germination up to day 5 at all concentrations and inhibited toxin and ergosterol
production at 0.001% concentration. The affect was found to be dose-dependent from 0.001% to 1%, for Triton X-100 only. Positive
correlation between ergosterol content and toxin production in the presence of different surfactants at various time periods
(3, 5, 7, 9 and 12 days) was found. Tween-20 was most effective in inhibiting toxin production on day 7, when aflatoxin production
was found to be maximal in control group. Sugar consumption was directly proportional to the ergosterol content, showing a
significant correlation with aflatoxin production. 相似文献
126.
The role of end groups in determining stereochemistry and packing in hydrophobic helical peptides has been investigated using an α-aminosobutyric acid (Aib) containing model nonapeptide sequence. In contrast to the Boc-analogue, Ac-(Aib-Val-Ala-Leu)2-Aib-OMe crystallizes with two independent molecules in a triclinic cell. The cell parameters are: space group P1, a=10.100(2)Å, b=15.194(4) Å, c=19.948(5) Å, α=63.12(2)°, β=88.03(2)°, γ=88.61(2)°, Z=2, R=7.96% for 5140 data where |Fo|>3σ(F). The two independent molecules alternate in infinite columns formed by head-to-tail hydrogen bonding. The helices in the two independent molecules are quite similar to each other but one molecule is rotated ≈?123° about its helix axis with respect to the other. All the helical columns pack parallel to each other in the crystal. Replacement of the bulky Boc group does not lead to any major changes in conformation. Packing characteristics are also similar to those observed for similar helical peptides. 相似文献
127.
Alamethicin and related α-aminoisobutyric acid peptides form transmembrane channels across lipid bilayers. This article briefly
reviews studies on the effect of alamethicin on lipid phase transitions in lipid bilayers and on mitochondrial oxidative phosphorylation.
Fluorescence polarization studies, employing 1,6-diphenyl-1,3,5-hexatriene as a probe, suggest that alamethicin fluidizes
lipid bilayers below the phase transition t-emperature, but has little effect above the gel-liquid crystal transition point.
Alamethicin is shown to function as an uncoupler of oxidative phosphorylation in rat liver mitochondria. The influence of
alamethicin on mitochondrial respiration is modulated by the phosphate ion concentration in the medium. Classical uncoupling
activity is evident at low phosphate levels while inhibitory effects set in at higher phosphate concentrations. Time-dependent
changes in respiration rates following peptide addition are rationalized in terms of alamethicin interactions with mitochondrial
membrane components. 相似文献
128.
K. Suguna S. Ramakumar N. Shamala B. V. Venkataram Prasad P. Balaram 《Biopolymers》1982,21(9):1847-1855
The crystal and molecular structures of two α-aminoisobutyric acid (Aib)-containing diketopiperazines, cyclo(Aib-Aib) 1 and cyclo(Aib-L -Ile) 2 , are reported. Cyclo(Aib-Aib) crystallizes in the space group P1 with a = 5.649(3), b = 5.865(2), c = 8.363(1), α = 69.89(6), β = 113.04(8), γ = 116.0(3), and Z = 1, while 2 occurs in the space group P212121 with a = 6.177(1), b = 10.791(1), c = 16.676(1), and Z = 4. The structures of 1 and 2 have been refined to final R factors of 0.085 and 0.086, respectively. In both structures the diketopiperazine ring shows small but significant deviation from planarity. A very flat chair conformation is adopted by 1, in which the Cα atoms are displaced by 0.07 Å on each side of the mean plane, passing through the other four atoms of the ring. Cyclo(Aib-Ile) favors a slight boat conformation, with Aib Cα and Ile Cα atoms displaced by 0.11 and 0.05 Å on the same side of the mean plane formed by the other ring atoms. Structural features in these two molecules are compared with other related diketopiperazines. 相似文献
129.
S. Vijayasarathy S. Shivaji P. Balaram 《Biochemical and biophysical research communications》1982,108(2):585-591
Bull sperm plasma and outer acrosomal membranes have been isolated by discontinuous sucrose density gradient centrifugation and Ca2+-ATPase activity has been determined for both the membranes. Pyrene excimer fluorescence and diphenylhexatriene fluorescence polarization studies show that the lipid phase of the sperm plasma membranes is more fluid than the lipids of the outer acrosomal membranes. Approximately, a three fold increase in the cholesterol content has been found in the outer acrosomal membranes as compared to that in the plasma membranes. 相似文献
130.
A.K. Francis Ch. Pulla Rao M. Iqbal R. Nagaraj M. Vijayan P. Balaram 《Biochemical and biophysical research communications》1982,106(4):1240-1247
The crystal structures of three pentapeptide fragments of suzukacillin-A have been determined. Boc-Aib-Pro-Val-Aib-Val-OMe (peptide 1–5) adopts a distorted helical conformation, stabilized by three intramolecular hydrogen bonds (two 5→1, one 4→1). Boc-Ala-Aib-Ala-Aib-Aib-OMe (peptide 6–10) and Boc-Leu-Aib-Pro-Val-Aib-OMe (peptide 16–20) adopt 310 helical structures stabilized by three and two 4→1 intramolecular hydrogen bonds, respectively. These structures provide substantial support for a largely helical conformation for the suzukacillin membrane channel. 相似文献