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41.
Genes homologous to 2-deoxystreptamine (DOS) biosynthetic genes were isolated from aminoglycoside producers, Micromonospora and Streptomyces spp., using PCR primers based on the core sequences of 2-deoxy-scyllo-inosose (DOI) synthase and L-glutamine: scyllo-inosose aminotransferase (GIA). Identities of 40-45% were observed for DOI synthases, and 65-75% were observed for GIAs. The gene cluster of tobramycin biosynthesis was isolated from the genomic library of Streptomyces tenebrarius using DOI synthase as a probe. Sequencing of 33.9 kb revealed 24 putative open reading frames including the tobramycin biosynthetic gene cluster (13.8 kb) and a transport protein. This cluster encodes proteins homologous to 2-deoxystreptamine biosynthetic enzymes, glycosyltransferase and other aminocyclitols biosynthetic enzymes. Sequence analysis revealed the evolution of DOI synthases from 3-dehydroquinate (DHQ) synthases in actinomycetes. DOI synthases and GIA are therefore useful for cloning biosynthetic genes of DOS-containing aminocyclitol antibiotics or for screening such metabolites producers. 相似文献
42.
Thangavelu M James AB Bankier A Bryan GJ Dear PH Waugh R 《Plant biotechnology journal》2003,1(1):23-31
HAPPY mapping is an in vitro approach for defining the order and spacing of DNA markers directly on native genomic DNA. This cloning-free technique is based on analysing the segregation of markers amplified from high molecular weight genomic DNA which has been broken randomly and 'segregated' by limiting dilution into subhaploid samples. It is a uniquely versatile tool, allowing for the construction of genome maps with flexible ranges and resolutions. Moreover, it is applicable to plant genomes, for which many of the techniques pioneered in animal genomes are inapplicable or inappropriate. We report here its demonstration in a plant genome by reconstructing the physical map of a 1.9 Mbp region around the FCA locus of Arabidopsis thaliana. The resulting map, spanning around 10% of chromosome 4, is in excellent agreement with the DNA sequence and has a mean marker spacing of 16 kbp. We argue that HAPPY maps of any required resolution can be made immediately and with relatively little effort for most plant species and, furthermore, that such maps can greatly aid the construction of regional or genome-wide physical maps. 相似文献
43.
Palta P Chandrasekhar T Prakash BS Madan ML 《Indian journal of experimental biology》2000,38(4):390-392
The effect of naloxone on GnRH-induced LH and FSH release was measured in buffaloes in luteal phase of estrous cycle. Animals were administered intravenously, naloxone/saline (50 mg/injection) every 15 min for 3 hr followed by GnRH (100 micrograms). Peripheral plasma LH and FSH concentrations were measured in blood samples collected at 15 min intervals from 1 hr prior to beginning of naloxone/saline treatment up to 3 hr post GnRH administration and every 30 min for the subsequent 3.5 hr. Between the animals of Group I administered naloxone and those of Group II given saline, GnRH-induced peak LH and FSH concentrations, the total LH and FSH released in response to GnRH, and the time to peak LH and FSH concentrations were not significantly different. The results of the present study suggest the absence of a direct effect of naloxone on pituitary responsiveness to GnRH. 相似文献
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45.
Wilna J. Moree Florence Jovic Timothy Coon Jinghua Yu Bin-Feng Li Fabio C. Tucci Dragan Marinkovic Raymond S. Gross Siobhan Malany Margaret J. Bradbury Lisa M. Hernandez Zhihong O’Brien Jianyun Wen Hua Wang Samuel R.J. Hoare Robert E. Petroski Aida Sacaan Ajay Madan Paul D. Crowe Graham Beaton 《Bioorganic & medicinal chemistry letters》2010,20(7):2316-2320
SAR of lead benzothiophene H1-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H1-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound. 相似文献
46.
Wilna J. Moree Bin-Feng Li Said Zamani-Kord Jinghua Yu Timothy Coon Charles Huang Dragan Marinkovic Fabio C. Tucci Siobhan Malany Margaret J. Bradbury Lisa M. Hernandez Jianyun Wen Hua Wang Samuel R.J. Hoare Robert E. Petroski Kayvon Jalali Chun Yang Aida Sacaan Ajay Madan Paul D. Crowe Graham Beaton 《Bioorganic & medicinal chemistry letters》2010,20(19):5874-5878
Analogs of the known H1-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study. 相似文献
47.
Non-structural poliovirus 2B protein induces plasma membrane permeabilization and has been recently implicated in triggering apoptosis via the mitochondrial pathway. Here we describe that the pore-forming P3 peptide, based on the 2B amphipathic domain, translocates through the plasma membrane of culture cells and targets mitochondria. Cell permeabilization by P3 versions of different lengths, together with peptide uptake analyses supported an internalization mechanism dependent on P3 capacity to interact physically with lipid bilayers and establish permeating pores therein. Internalized P3 was found associated with mitochondria, but contrary to the parental 2B protein, the short peptide did not affect the morphology or cell distribution of these organelles, nor induced apoptosis. We conclude that P3 constitutes a mitochondriotropic sequence, which is however devoid of 2B pro-apoptotic activity. 相似文献
48.
Structural characterization of AtmS13, a putative sugar aminotransferase involved in indolocarbazole AT2433 aminopentose biosynthesis 下载免费PDF全文
Shanteri Singh Youngchang Kim Fengbin Wang Lance Bigelow Michael Endres Madan K. Kharel Gyorgy Babnigg Craig A. Bingman Andrzej Joachimiak Jon S. Thorson George N. Phillips Jr. 《Proteins》2015,83(8):1547-1554
AT2433 from Actinomadura melliaura is an indolocarbazole antitumor antibiotic structurally distinguished by its unique aminodideoxypentose‐containing disaccharide moiety. The corresponding sugar nucleotide‐based biosynthetic pathway for this unusual sugar derives from comparative genomics where AtmS13 has been suggested as the contributing sugar aminotransferase (SAT). Determination of the AtmS13 X‐ray structure at 1.50‐Å resolution reveals it as a member of the aspartate aminotransferase fold type I (AAT‐I). Structural comparisons of AtmS13 with homologous SATs that act upon similar substrates implicate potential active site residues that contribute to distinctions in sugar C5 (hexose vs. pentose) and/or sugar C2 (deoxy vs. hydroxyl) substrate specificity. Proteins 2015; 83:1547–1554. © 2015 Wiley Periodicals, Inc. 相似文献
49.
Shanteri Singh Karolina Michalska Lance Bigelow Michael Endres Madan K. Kharel Gyorgy Babnigg Ragothaman M. Yennamalli Craig A. Bingman Andrzej Joachimiak Jon S. Thorson George N. Phillips Jr. 《The Journal of biological chemistry》2015,290(43):26249-26258
Classical UDP-glucose 6-dehydrogenases (UGDHs; EC 1.1.1.22) catalyze the conversion of UDP-α-d-glucose (UDP-Glc) to the key metabolic precursor UDP-α-d-glucuronic acid (UDP-GlcA) and display specificity for UDP-Glc. The fundamental biochemical and structural study of the UGDH homolog CalS8 encoded by the calicheamicin biosynthetic gene is reported and represents one of the first studies of a UGDH homolog involved in secondary metabolism. The corresponding biochemical characterization of CalS8 reveals CalS8 as one of the first characterized base-permissive UGDH homologs with a >15-fold preference for TDP-Glc over UDP-Glc. The corresponding structure elucidations of apo-CalS8 and the CalS8·substrate·cofactor ternary complex (at 2.47 and 1.95 Å resolution, respectively) highlight a notably high degree of conservation between CalS8 and classical UGDHs where structural divergence within the intersubunit loop structure likely contributes to the CalS8 base permissivity. As such, this study begins to provide a putative blueprint for base specificity among sugar nucleotide-dependent dehydrogenases and, in conjunction with prior studies on the base specificity of the calicheamicin aminopentosyltransferase CalG4, provides growing support for the calicheamicin aminopentose pathway as a TDP-sugar-dependent process. 相似文献