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111.
The constrained backbone torsion angle of a proline (Pro) residue has usually been invoked to explain its three-dimensional context in proteins. Here we show that specific interactions involving the pyrrolidine ring atoms also contribute to its location in a given secondary structure and its binding to another molecule. It is adept at participating in two rather non-conventional interactions, C-H...pi and C-H...O. The geometry of interaction between the pyrrolidine and aromatic rings, vis-à-vis the occurrence of the C-H...pi interactions has been elucidated. Some of the secondary structural elements stabilized by Pro-aromatic interactions are beta-turns, where a Pro can interact with an adjacent aromatic residue, and in antiparallel beta-sheet, where a Pro in an edge strand can interact with an aromatic residue in the adjacent strand at a non-hydrogen-bonded site. The C-H groups at the Calpha and Cdelta positions can form strong C-H...O interactions (as seen from the clustering of points) and such interactions involving a Pro residue at C' position relative to an alpha-helix can cap the hydrogen bond forming potentials of the free carbonyl groups at the helix C terminus. Functionally important Pro residues occurring at the binding site of a protein almost invariably engage aromatic residues (with one of them being held by C-H...pi interaction) from the partner molecule in the complex, and such aromatic residues are highly conserved during evolution. 相似文献
112.
Hydroxylation of benzylic methyl carbon atoms on drugs and carcinogenic polycyclic aromatic hydrocarbons (PAHs) forms benzylic alcohols. Many carcinogenic and mutagenic PAHs bear a primary or secondary benzylic hydroxyl group attached to the meso-region of the molecule. According to the unified theory, PAHs bearing a benzylic hydroxyl group are proximate carcinogenic metabolites. This paper demonstrates that carcinogenic benz[a]anthracenes bearing a formyl group at the meso-region undergo enzymatic reductive metabolism to the corresponding carcinogenic benzylic alcohol in vitro and in vivo. The unified theory would then predict sulfuric acid esterification of such benzylic alcohols as the final common step in their metabolic activation to generate ultimate electrophilic benzylic carbocations. Finally, oxidative metabolism of 7-formylbenz[a]anthracenes gives rise to corresponding carboxylic acids and other oxygenated metabolites that are carcinogenically inert. Thus, oxidative metabolism of meso-region formyl compounds represents an avenue for the elimination of the carcinogen in a detoxified form. 相似文献
113.
V.?SorokerEmail author C.?Lucas T.?Simon A.?Hefetz D.?Fresneau J.?L.?Durand 《Insectes Sociaux》2003,50(3):212-217
Summary Within and between individuals hydrocarbon (HC)-circulation was studied in Pachycondyla apicalis workers, using radioactive labeling. Newly synthesized HCs occurred both in the PPG and on the epicuticle in appreciable amounts, lesser quantities were found in the crop. The front basitarsal brush contained a greater amount of radiolabeled HCs than could be predicted from its surface area, suggesting preferential secretion to these organs. We propose that the newly synthesized HCs are secreted primarily to the front basitarsal brushes and are thereafter either distributed throughout the body surface, or cleared via the PPG and the alimentary canal.Using labeled HCs as a model, we tracked the time-dependent dispersion of cuticular lipids among 11 workers, one of which was prelabeled for 24 hours. Distribution among the recipients became progressively uniform, reaching near homogenization between 5–10 days. The mean HCs transfer of P. apicalis to the PPG was substantially lower compared to that of Camponotus fellah or Aphaenogaster senilis. In contrast, transfer to the cuticle in this species was superior. We attribute the low transfer to the PPG to the inefficacy of passive body contact characteristic of P. apicalis, as opposed to trophallaxis and/or allogrooming that typify the other two species. The higher occurrence of radiolabeled HCs in P. apicalis cuticle can be attributed to their accumulation in the basitarsal brushes. The impact of cuticular lipid transfer and formation of uniform colony odour, as opposed to the maintenance of an idiosyncratic caste-specific composition, are discussed.Received 5 September 2002; revised 17 January 2003; accepted 10 February 2003. 相似文献
114.
Chlorothalonil (2,4,5,6-tetrachloroisophthalonitrile, TCIN, CAS 1897-45-6) is a broad range spectrum fungicide whose fungitoxic action has been associated with the rapid formation of conjugated chlorothalonil–cellular thiol derivatives, specifically with thiol-rich enzymes such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and with glutathione (GSH). The biotransformation reaction sequence between enzyme-activated glutathione (GSH) and chlorothalonil depletes cellular glutathione reserves. The conjugation of glutathione with chlorothalonil via nucleophilic aromatic substitution was modeled for an isolated reacting species using semiempirical self-consistent field molecular orbital (SCF-MO) theory at the PM3 level. The potential energy hypersurface at each of the three possible chlorinated attack sites on chlorothalonil was elaborated using a thiolate (CH3S–) anion as a model for an enzyme-activated glutathione molecule. Calculated free energies of activation for formation of mono-RSH conjugates suggest that the order of nucleophilic attack on chlorine positions in TCIN is 2>4, 6>5 although energy differences are small (on the order of 1–2 kcal mol–1). Meisenheimer or -complexes have been isolated as true intermediates on the hypersurface for each reaction, suggesting that the mechanism follows a two-step pathway.Electronic Supplementary Material available. 相似文献
115.
The role of aromatic residues in the hydrophobic core of the villin headpiece subdomain 总被引:1,自引:0,他引:1
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Frank BS Vardar D Buckley DA McKnight CJ 《Protein science : a publication of the Protein Society》2002,11(3):680-687
Small autonomously folding proteins are of interest as model systems to study protein folding, as the same molecule can be used for both experimental and computational approaches. The question remains as to how well these minimized peptide model systems represent larger native proteins. For example, is the core of a minimized protein tolerant to mutation like larger proteins are? Also, do minimized proteins use special strategies for specifying and stabilizing their folded structure? Here we examine these questions in the 35‐residue autonomously folding villin headpiece subdomain (VHP subdomain). Specifically, we focus on a cluster of three conserved phenylalanine (F) residues F47, F51, and F58, that form most of the hydrophobic core. These three residues are oriented such that they may provide stabilizing aromatic–aromatic interactions that could be critical for specifying the fold. Circular dichroism and 1D‐NMR spectroscopy show that point mutations that individually replace any of these three residues with leucine were destabilized, but retained the native VHP subdomain fold. In pair‐wise replacements, the double mutant that retains F58 can adopt the native fold, while the two double mutants that lack F58 cannot. The folding of the double mutant that retains F58 demonstrates that aromatic–aromatic interactions within the aromatic cluster are not essential for specifying the VHP subdomain fold. The ability of the VHP subdomain to tolerate mutations within its hydrophobic core indicates that the information specifying the three dimensional structure is distributed throughout the sequence, as observed in larger proteins. Thus, the VHP subdomain is a legitimate model for larger, native proteins. 相似文献
116.
Aromatic L-amino acid decarboxylase (AADC) is necessary for conversion of L-DOPA to dopamine. Therefore, AADC gene therapy has been proposed to enhance pharmacological or gene therapies delivering L-DOPA. However, addition of AADC to the grafts of genetically modified cells expressing tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1), which produce L-DOPA in parkinsonian rats, resulted in decreased production of L-DOPA and dopamine owing to feedback inhibition of TH by dopamine. End-product feedback inhibition has been shown to be mediated by the regulatory domain of TH, and site-specific mutation of serine 40 makes TH less susceptible to dopamine inhibition. Therefore, we investigated the efficacy of using TH with serine 40 mutated to leucine (mTH) in an ex vivo gene-therapy paradigm. Primary fibroblasts (PF) from Fischer 344 rats were transduced with retrovirus to express mTH or wild-type rat TH cDNA (wtTH). Both cell types were also transduced with GCH1 to provide the obligate TH cofactor, tetrahydrobiopterin. PF transfected with AADC were used as coculture and cografting partners. TH activities and L-DOPA production in culture were comparable between PFwtTHGC and PFmTHGC cells. In cocultures with PFAADC cells, PFmTHGC cells showed significant reduction in the inhibitory effect of dopamine compared with PFwtTHGC cells. In vivo microdialysis measurement showed that cografting PFAADC cells with PFmTHGC cells resulted in smaller decreases in L-DOPA and no reduction in dopamine levels compared with cografts of PFAADC cells with PFwtTHGC cells, which decreased both L-DOPA and dopamine levels. Maintenance of dopamine levels with lower levels of L-DOPA would result in more focused local delivery of dopamine and less potential side-effects arising from L-DOPA diffusion into other structures. These data support the hypothesis that mutation of serine 40 attenuates TH end-product inhibition in vivo and illustrates the importance of careful consideration of biochemical pathways and interactions between multiple genes in gene therapy. 相似文献
117.
Sesquiterpene constituents in Petasites hybridus 总被引:1,自引:0,他引:1
The essential oil of the rhizomes of Petasites hybridus (Asteraceae) was investigated by gas chromatography, mass spectrometry, 1- and 2-dimensional NMR techniques and chemical correlations. Two new sesquiterpene hydrocarbons, petasitene and pethybrene, could be identified. Petasitene is the parent sesquiterpene hydrocarbon to the known norsesquiterpene albene. The absolute configuration of petasitene could be assigned by conversion of natural albene to petasitene by partial synthesis. Pethybrene is a tricyclic sesquiterpene hydrocarbon, which rearranges to the structurally related alpha-isocomene under acidic conditions. Several sesquiterpenes were isolated from the hydrodistillation products of Petasites hybridus and investigated by spectroscopic methods and chemical correlations 相似文献
118.
We have collected all aromatic pairs (3152) involving an N-phenyl partner in a dataset of 593 proteins of the PDB: 728 of these pairs involve a partner residue less than 6 apart in the sequence. These near-sequence Phe-X pairs correspond to specific conformations that stabilize secondary structures, mainly alpha-helices when the residues are 1, 3, and 4 apart, and beta-strands when they are 2 apart in the sequence. These conformations are not spatially random and have been examined in detail. The remaining phenylalanine pairs (2424) are between partners more than 5 apart in the sequence. Of these far-sequence pairs, 34% of occurrences are in sheets. Next in frequencies are pairs that bridge a beta-strand to a helix (24%), followed by pairs that bridge a beta-strand to a random coiled structure (15%). Helix to helix pairs only constitute 12% of these far-sequence pairs. Analysis of the pairing frequency supports the hypothesis that aromatic interactions are late events of protein folding. 相似文献
119.
In a data set of 593 nonhomologous proteins from the PDB, we have analyzed the pairing of phenylalanine, tyrosine, tryptophan, and histidine residues with their closest aromatic partner. The frequency distribution of the shortest interatomic distance of partners is bimodal with a sharp peak at approximately 3.8 A and a wider one at a longer distance. Only the 3.8 A peak corresponds to direct ring-ring interactions thus aromatic pairs. The aromatic pairs were separated into two classes, near-sequence pairs and far-sequence pairs. Near sequence pairs stabilize local structure, and far-sequence pairs stabilize tertiary structure. Far-sequence pairs (74% of all pairs) mainly bridge two beta-strands, followed by pairs that bridge a beta-strand and a helix, and pairs that bridge a beta-strand and a random coil structure. Pairs that bridge helices are rare. The secondary structure of the near-sequence pairs depends on the partner distance in the sequence. When the partners are 1, 3, or 4 residues apart in the sequence, pairs are mostly found in helical structures. When the partners are two apart, pairs are mostly found in the same beta-strand. Analysis of the frequency of near sequence pairs supports the hypothesis that aromatic pairing occurs after, rather than before, the formation of secondary structures. 相似文献
120.
The function of the human nucleotide excision repair (NER) apparatus is to remove bulky adducts from damaged DNA. In an effort to gain insights into the molecular mechanisms involved in the recognition and excision of bulky lesions, we investigated a series of site specifically modified oligonucleotides containing single, well-defined polycyclic aromatic hydrocarbon (PAH) diol epoxide-adenine adducts. Covalent adducts derived from the bay region PAH, benzo[a]pyrene, are removed by human NER enzymes in vitro. In contrast, the stereochemically analogous N(6)-dA adducts derived from the topologically different fjord region PAH, benzo[c]phenanthrene, are resistant to repair. The evasion of DNA repair may play a role in the observed higher tumorigenicity of the fjord region PAH diol epoxides. We are elucidating the structural and thermodynamic features of these adducts that may underlie their marked distinction in biologic function, employing high-resolution nuclear magnetic resonance studies, measurements of thermal stabilities of the PAH diol epoxide-modified oligonucleotide duplexes, and molecular dynamics simulations with free energy calculations. Our combined findings suggest that differences in the thermodynamic properties and thermal stabilities are associated with differences in distortions to the DNA induced by the lesions. These structural effects correlate with the differential NER susceptibilities and stem from the intrinsically distinct shapes of the fjord and bay region PAH diol epoxide-N(6)-adenine adducts. 相似文献