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51.
Nitric oxide is a diatomic gas that has traditionally been viewed, particularly in the context of chemical fields, as a toxic, pungent gas that is the product of ammonia oxidation. However, nitric oxide has been associated with many biological roles including cell signaling, macrophage cytotoxicity, and vasodilation. More recently, a model for nitric oxide trafficking has been proposed where nitric oxide is regulated in the form of dinitrosyl-dithiol-iron-complexes, which are much less toxic and have a significantly greater half-life than free nitric oxide. Our laboratory has previously examined this hypothesis in tumor cells and has demonstrated that dinitrosyl-dithiol-iron-complexes are transported and stored by multi-drug resistance-related protein 1 and glutathione-S-transferase P1. A crystal structure of a dinitrosyl-dithiol-iron complex with glutathione-S-transferase P1 has been solved that demonstrates that a tyrosine residue in glutathione-S-transferase P1 is responsible for binding dinitrosyl-dithiol-iron-complexes. Considering the roles of nitric oxide in vasodilation and many other processes, a physiological model of nitric oxide transport and storage would be valuable in understanding nitric oxide physiology and pathophysiology. 相似文献
52.
Quantitative structure-activity relationships for herbicidal activity against rape of sulfonylurea and triazolopyrimidin-2-sulfonamide derivatives were examined three-dimensionally using comparative molecular field analysis (CoMFA). The CoMFA results show that the slopes in steric and electrostatic fields around the molecule were significant for both series in governing the potency variations in herbicidal activity. Based upon the successful superposition between the two series, the herbicidal activity was analyzable with a single equation for the combined set of compounds, which suggested that the two different series of compounds have a common region of the receptor site. 相似文献
53.
一氧化氮(nitric oxide,NO)在肿瘤病理生理过程中产生多方面的生化作用,诸如引起的某些核苷酸碱基的羟基化,参与免疫系统清除肿瘤细胞,促进肿瘤细胞凋亡和调节血管生成等.在此基础上,首次提出将NO供体(NO donor)或一氧化氮合酶(nitric oxide synthase,NOS)抑制剂分别连接到甲氨蝶呤(methotrexate,MTX,MTX本身就是NOS抑制剂)的α或γ位羧基上的设想,设计并合成出:(1)MTX-NO供体(3-羟甲基-4-苯基-1,2,5-噁二唑-2-氧化物,属于Furoxan衍生物,缩写为FU):1a(MTX-α-FU),2a(MTX-γ-FU);(2)MTX-NOS抑制剂(L-N^ω-硝基精氨酸或L-N^ω-硝基精氨酸甲酯):1b(MTX-α-L-N^ω-NO2-Arg),2b(MTX-γ-L-N^ω-NO2-Arg),1c(MTX-α-L-N^ω-NO2-Arg-OMe),2c(MTX-γ-L-N^ω-NO2-Arg-OMe).在生物活性测试中,我们选择耐MTX细胞株K-562(慢性粒细胞性白血病急性病变细胞株),进行抗肿瘤活性测试,得到以下结果:(1)脂溶性差的MTX衍生物1b,2b抗肿瘤活性低于MTX,其它1a,2a;1c,2c均优于MTX;(2)连接有NO供体的MTX明显增强了MTX衍生物的抗肿瘤活性;(3)MTX中谷氨酸γ位组合物抗肿瘤活性均高于相应的α位异构体的活性.以上初步结果,将对进一步研究NO抗肿瘤作用以及新的抗肿瘤药物设计提供新的思路,对肿瘤临床化疗也有一定的参考价值. 相似文献
54.
竹红菌素是我国特有的一类苝醌类光敏色素,在开发新型抗肿瘤抗病毒药物、光敏活性农药及新型光电转换材料等方面应用前景广阔.聚酮合酶( Polyketide synthase,PKS)是合成竹红菌素的一种关键酶,通过全基因组测序及分析发现在Shiraia sp. Slf14中存在一个III型聚酮合酶基因.利用RT-PCR技术,以其总RNA为模板,扩增得到目的片段,并成功构建表达载体pET-22b(+)-PKSIII,采用Ni-NTA亲和层析法纯化目的蛋白,在大肠杆菌BL21( DE3)中成功表达出了目的蛋白,SDS-PAGE结果显示表达重组产物分子质量约为43 kDa,与理论值一致,为III型聚酮合酶的催化活性研究提供理论依据. 相似文献
55.
Xing L Kurumbail RG Frazier RB Davies MS Fujiwara H Weinberg RA Gierse JK Caspers N Carter JS McDonald JJ Moore WM Vazquez ML 《Journal of computer-aided molecular design》2009,23(1):13-24
Inducible, microsomal prostaglandin E synthase 1 (mPGES-1), the terminal enzyme in the prostaglandin (PG) biosynthetic pathway,
constitutes a promising therapeutic target for the development of new anti-inflammatory drugs. To elucidate structure–function
relationships and to enable structure-based design, an mPGES-1 homology model was developed using the three-dimensional structure
of the closest homologue of the MAPEG family (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism), mGST-1.
The ensuing model of mPGES-1 is a homo-trimer, with each monomer consisting of four membrane-spanning segments. Extensive
structure refinement revealed an inter-monomer salt bridge (K26-E77) as well as inter-helical interactions within each monomer,
including polar hydrogen bonds (e.g. T78-R110-T129) and hydrophobic π-stacking (F82-F103-F106), all contributing to the overall
stability of the homo-trimer of mPGES-1. Catalytic co-factor glutathione (GSH) was docked into the mPGES-1 model by flexible
optimization of both the ligand and the protein conformations, starting from the initial location ascertained from the mGST-1
structure. Possible binding site for the substrate, prostaglandin H2 (PGH2), was identified by systematically probing the refined molecular structure of mPGES-1. A binding model was generated by induced
fit docking of PGH2 in the presence of GSH. The homology model prescribes three potential inhibitor binding sites per mPGES-1 trimer. This was
further confirmed experimentally by equilibrium dialysis study which generated a binding stoichiometric ratio of approximately
three inhibitor molecules to three mPGES-1 monomers. The structural model that we have derived could serve as a useful tool
for structure-guided design of inhibitors for this emergently important therapeutic target. 相似文献
56.
Marisa Freitas 《Analytica chimica acta》2009,649(1):8-8272
Neutrophils, also known as polymorphonuclear leukocytes (PMN), are the most common type of white blood cells, comprising about 50-70% of all white blood cells. In the event of inflammatory processes, neutrophils display increased mobility, tissue influx ability, prolonged life span, and an increased phagocytic capacity, constituting the initial participants in the cellular defense of the organism. One of the most important defense systems of neutrophils corresponds to their ability to mediate a strong oxidative burst through the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). While oxidative burst is important for the elimination of invading microorganisms, the overproduction of ROS and RNS or the impairment of endogenous antioxidant defenses may result to detrimental effects to the host. The nature and the extent of ROS and RNS production by neutrophils in response to different stimuli is, consequently, a matter of extensive research, with scientific reports showing an enormous variability on the detection methodologies employed. This review attempts to provide a critical assessment of the most common approaches to identify and quantify reactive species formed during the neutrophils’ oxidative burst. The detection mechanisms and performance, as well as advantages and limitations of the different methodologies, are scrutinized, focusing on the use of fluorimetric, chemiluminometric and colorimetric probes. 相似文献
57.
The title total synthesis was achieved by employing deconjugative asymmetric α-sulfenylation of the chiral 3-(α,β,γ,δ-unsaturated acyl)oxazolidin-2-one with a 3,3-dimethoxypropyl methanethiosulfonate as a key step. From the biological activity assay carried out using the title compounds, it appeared evident that in vitro antibacterial and mammalian type I FAS inhibitory activity can be cleanly separated by changing not only the substituent at the C3-position but also the absolute configuration at the C5-position, and that unnatural (S)-(−)-3-demethylthiolactomycin and its congeners might be usable as selective mammalian type I FAS inhibitors. 相似文献
58.
Although there are a number of existing assays for monitoring the activity of both isopenicillin N synthase (IPNS) and deacetoxycephalosporin C synthase (DAOCS), none have demonstrated the qualities required for screening a mutant library. Hence, enzyme-linked immunosorbent assays (ELISAs) for IPNS and DAOCS were developed based on the detection of the catalytic turnover products isopenicillin N and cephalexin/phenylacetyl-7-aminodeacetoxycephalosporanic acid (G-7-ADCA), respectively. These assays are relatively fast compared to existing assays, such as the hole-plate bioassay, and are amenable with high-throughput screening. Both the IPNS and DAOCS-ELISAs were optimised for use with crude protein extracts rather than purified protein, thereby eliminating any additional time required for purification. The ELISA developed for the detection of cephalexin had an IC50 value of 154 ± 9 ng mL−1 and LOD of 7.2 ± 2.2 ng mL−1 under conditions required for the assay. Good recoveries and correlation was observed for spiked samples when the concentration of crude protein was kept below 1 mg mL−1. The DAOCS-ELISA was found to have increased sensitivity compared to the hole-plate bioassay (10.3 μg mL−1). The IPNS-ELISA did not significantly increase the sensitivity (approximately 5 μg mL−1) compared to that of the hole-plate bioassay (16 μg mL−1) for isopenicillin N. The minimum amount of crude protein extract required for producing detectable amounts of product for both assays was below 0.5% of the maximum amount of protein that the assay could contain without any effect on the ELISA. This suggests that when screening a mutant library, mutants producing low amounts of the product could still be detected using these assays. 相似文献
59.
Jumiarti Agus Hideki Abe Yoshiharu Doi Takeharu Tsuge 《Polymer Degradation and Stability》2006,91(5):1138-1146
This study investigated the relationship of growth conditions, host strains and molecular weights of poly[(R)-3-hydroxybutyrate] [P(3HB)] synthesized by genetically engineered Escherichia coli. Various PHA synthases belonging to types I-IV enzymes were expressed in E. coli JM109 under the same experimental conditions, and the molecular weights of the polymers were characterized by gel permeation chromatography. The results demonstrate that P(3HB) polymers have varied molecular weights and polydispersities dependent on the characteristics of the individual PHA synthase employed. P(3HB) with high number-average molecular weights (Mn) [(1.5-4.0) × 106] and narrow polydispersities (1.6-1.8) were synthesized by PHA synthases from Ralstonia eutropha (type I), Delftia acidovorans (type I) and Allochromatium vinosum (type III). Contrary to these, P(3HB) with relatively low Mn [(0.17-0.79) × 106] and broad polydispersities (2.2-9.0) were synthesized by PHA synthases from Aeromonas caviae (type I), Pseudomonas sp. 61-3 (type II) and Bacillus sp. INT005 (type IV). Furthermore, the molecular weights of P(3HB) synthesized under various culture conditions, in various hosts of E. coli and by mutants of PHA synthase were characterized. It was found that, in addition to culture pH [Kusaka et al. Appl Microbiol Biotechnol 1997;47:140], other variances such as culture temperature, host strain and use of mutants are effective in changing polymer molecular weight. 相似文献
60.
生物法合成5-氨基乙酰丙酸(5-ALA)大多通过添加5-ALA脱水酶(ALAD)的抑制剂乙酰丙酸(LA)减少5-ALA的降解,造成生产成本增高,发酵工艺复杂.本文利用ALAD缺失的大肠杆菌ZSEc2作为出发菌株,通过紫外诱变的方法,获得可利用外源血红素恢复正常生长的大肠杆菌突变株ZGEc1,并过表达来自沼泽红假单胞菌的5-ALA合成酶(ALAS)基因,最终建立一条不需要添加ALAD抑制剂的5-ALA的生物合成新路线.经过培养基初步优化,重组菌可在胞外积累约1,g/L的5-ALA. 相似文献