张立新
主要致力于从海洋微生物天然产物资源库中筛选互动活性化合物,内容集中在以下三方面:1.构建多样性的海洋微生物库及其天然产物库,降低其遗传和化学重复性。2.互动天然产物为基础的高通量活性筛选。互动天然产物研发的新药已经进入临床前阶段。3. 精确工程方法提高微生物次级代谢产物。
个性化签名
- 姓名:张立新
- 目前身份:
- 担任导师情况:
- 学位:
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学术头衔:
博士生导师
- 职称:-
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学科领域:
微生物学
- 研究兴趣:主要致力于从海洋微生物天然产物资源库中筛选互动活性化合物,内容集中在以下三方面:1.构建多样性的海洋微生物库及其天然产物库,降低其遗传和化学重复性。2.互动天然产物为基础的高通量活性筛选。互动天然产物研发的新药已经进入临床前阶段。3. 精确工程方法提高微生物次级代谢产物。
张立新 研究员,博士生导师。2006年科学院“百人计划”入选者,主编或者参与编写六部学术专著(其中英文著作三部),获得11项国际专利发明授权,在PNAS,Current Opinion In Microbilogy,Biochemistry,J.Biol.Chem.,Oncogene等杂志上发表了60多篇论文,在国际相关学术会议上应邀做了多次大会和特邀报告。是PNAS等九个杂志的审稿人,长期担任国际学术期刊《Applied Microbiology and Biotechnology》编辑和《Journal of Antibiotics》的编委(Editorial Board)。
张立新博士实验室主要致力于从海洋微生物天然产物资源库中筛选互动活性化合物,内容集中在以下三方面:
1.构建多样性的海洋微生物库及其天然产物库,降低其遗传和化学重复性。
2.互动天然产物为基础的高通量活性筛选。互动天然产物研发的新药已经进入临床前阶段。
3. 精确工程方法提高微生物次级代谢产物。
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434
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成果数
10
【期刊论文】Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins
张立新, LIXIN ZHANG, JING CHEN, HAIAN FU
Proc. Natl. Acad. Sci. USA Vol. 96, pp. 8511-8515, July 1999,-0001,():
-1年11月30日
Apoptosis signal-regulating kinase 1 (ASK1) is a pivotal component of a signaling pathway induced by many death stimuli, including tumor necrosis factor a, Fas, and the anticancer drugs cisplatin and paclitaxel. Here we report that ASK1 proapoptotic activity is antagonized by association with 14-3-3 proteins. We found that ASK1 specifically bound 14-3-3 proteins via a site involving Ser-967 of ASK1. Interestingly, overexpression of 14-3-3 in HeLa cells blocked ASK1-induced apoptosis whereas disruption of the ASK1/14-3-3 interaction dramatically accelerated ASK1-induced cell death. Targeting of ASK1 by a 14-3-3-mediated survival pathway may provide a novel mechanism for the suppression of apoptosis.
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【期刊论文】Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034
张立新, Katsunori Fujii, Erinn Hoag Goldman, Hae Ryoun Park, Lixin Zhang, Jing Chen, Haian Fu
Oncogene (2004) 23, 5099-5104,-0001,():
-1年11月30日
Apoptosis signal-regulating kinase 1 (ASK1) is a serine/ threonine kinase that mediates cell stress signaling initiatedby diverse stimuli, such as H2O2 andTNF a. Owing to its critical role in promoting apoptosis, ASK1 activity is highly controlledin cells. Phosphorylation of ASK1 at Thr-845 has been correlatedwith its activation, while phosphorylation at Ser-967 negatively controls its death promoting activity. Here, we report the identification of a novel phosphorylation site at Ser-1034 in the Cterminal regulatory domain of ASK1. Mutating Ser-1034 to an unphosphorylatable Ala ledto increased catalytic activity of ASK1 andenhancedproapop totic function of ASK1. Thus, the proapoptotic function of ASK1 is suppressedin part by phosphorylation at its C-terminal regulatory domain, which may couple upstream survival kinases to the death regulatory machinery.
ASK1, apoptosis, phosphorylation, 14-3-3, kinase, survival signaling
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【期刊论文】Raf-1 Kinase and Exoenzyme S Interact with 14-3-3ζ through a Common Site Involving Lysine 49
张立新, Lixin Zhang, Haining Wang, Dong Liu, Robert Liddington, Haian Fu
The Journal of Biological Chemistry Vol. 272, No. 21, Issue of May 23, pp. 13717-13724, 1997,-0001,():
-1年11月30日
14-3-3 proteins are a family of conserved dimeric molecules that bind to a range of cellular proteins involved in signal transduction and oncogenesis. Our solution of the crystal structure of 14-3-3ζrevealed a conserved amphipathic groove that may allow the association of 14-3-3 with diverse ligands (Liu, D., Bienkowska, J., Petosa, C., Collier, R. J., Fu, H., and Liddington, R. (1995) Nature 376, 191–194). Here, the contributions of three positively charged residues (Lys-49, Arg-56, and Arg-60) that lie in this Raf-binding groove were investigated. Two of the charge-reversal mutations greatly (K49E) or partially (R56E) decreased the interaction of 14-3-3ζwith Raf-1 kinase, whereas R60E showed only subtle effects on the binding. Interestingly, these mutations exhibited similar effects on the functional interaction of 14-3-3ζwith another target protein, exoenzyme S (ExoS), an ADPribosyltransferase from Pseudomonas aeruginosa. The EC50 values of 14-3-3ζrequired for ExoS activation increased by ;110-, 5-, and 2-fold for the K49E, R56E, and R60E mutants, respectively. The drastic reduction of 14-3-3ζ/ligand affinity by the K49E mutation is due to a local electrostatic effect, rather than the result of a gross structural alteration, as evidenced by partial proteolysis and circular dichroism analysis. This work identifies the first point mutation (K49E) that dramatically disrupts 14-3-3ζ/ligand interactions. The parallel effects of this single point mutation on both Raf-1 binding and ExoS activation strongly suggest that diverse associated proteins share a common structural binding determinant on 14-3-3ζ.
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【期刊论文】Exploring novel bioactive compounds from marine microbes
张立新, Lixin Zhang, , Rong An, Jinping Wang, Nuo Sun, Si Zhang, Jiangchun Hu, Jun Kuai
Current Opinion in Mirobiology 2005, 8: 276-281,-0001,():
-1年11月30日
The historical paradigm of the deep ocean as a biological ‘desert’ has shifted to one of a ‘rainforest’ owing to the isolation of many novel microbes and their associated bioactive compounds. Recently, there has been an explosion of information about novel bioactive compounds that have been isolated from marine microbes in an effort to further explore the relatively untapped marine microbes and their secondary metabolites for drug discovery. The microbes are recovered and purified from the ocean by both conventional and innovative isolation methods to obtain those previously thought to be ‘uncultivable’. To overcome the difficulties and limitations associated with cultivation techniques, several DNA-based molecular methods have been developed to bypass the culture-dependent bottleneck. Bioactive compounds isolated using the above strategies have not only shown importance in biotechnological and pharmaceutical applications but have also increased our understanding of the diversity of marine microbiota, ecosystem functions and the exploitable biology.
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张立新, Zheng Xu, Li-Xin Zhang, Jun-Dong Zhang, Yong-Bing Cao, Yuan-Yuan Yu, De-Jun Wang, Kang Ying, Wan-Sheng Chen, Yuan-Ying Jiang
International Journal of Medical Microbiology 296 (2006) 421-434,-0001,():
-1年11月30日
Fungi have emerged as the fourth most common pathogens isolated in nosocomial bloodstream infections, and Candida albicans is the most common human fungal pathogen. Only a few antibiotics are effective in the treatment of fungal infections. In addition, the repetition and lengthy duration of fluconazole therapy has led to an increased incidence of azole resistance and treatment failure associated with C. albicans. To investigate the mechanism of drug resistance and explore new targets to treat clinically resistant fungal pathogens, we examined the large-scale gene expression profile of two sets of matched fluconazole-susceptible and -resistant bloodstream C. albicans isolates from bone marrow transplanted (BMT) patients for the first time by microarray analysis. More than 198 differentially expressed genes were identified and they were confirmed and validated by RT-PCR independently. Not surprisingly, the resistant phenotype is associated with increased expression of CDR mRNA, as well as some common genes involved in drug resistance such as CaIFU5, CaRTA2 and CaIFD6. Meanwhile, some special functional groups of genes, including ATP binding cassette (ABC) transporter genes (IPF7530, CaYOR1, CaPXA1), oxidative stress response genes (CaALD5, CaGRP1, CaSOD2, IPF10565), copper transport and iron mobilization-related genes (CaCRD1/2, CaCTR1/2, CaCCC2, CaFET3) were found to be differentially expressed in the resistant isolates. Furthermore, among these differentially expressed genes, some co-regulated with CaCDR1, CaCDR2 and CaIFU5, such as CaPDR16 and CaIFD6, have a DRE-like element and may interact with TAC1 in the promoter region. These findings may shed light on mechanisms of azole resistance in C. albicans and clinical antifungal therapy.
Candida albicans, Microarray, Drug resistance, Bone marrow transplant, Differential gene expression
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【期刊论文】Residues of 14-3-3ξ Required for Activation of Exoenzyme S of Pseudomonas aeruginosa
张立新, Lixin Zhang, Haining Wang, Shane C. Masters, Bingcheng Wang, Joseph T. Barbieri, Haian Fu
Biochemistry 1999, 38, 12159-12164,-0001,():
-1年11月30日
Exoenzyme S (ExoS) is a mono-ADP-ribosyltransferase secreted by the opportunistic pathogen Pseudomonas aeruginosa. ExoS requires a eukaryotic factor, the 14-3-3 protein, for enzymatic activity. Here, two aspects of the activation of the ADP-ribosyltransferase activity of ExoS by 14-3-3 proteins are examined. Initial studies showed that several isoforms of 14-3-3, including β, ξ, η, σ, and ô, activated ExoS with similar efficiency. This implicates a conserved structure in 14-3-3 that contributes to the interaction between 14-3-3 and ExoS. One candidate structure is the conserved amphipathic groove that mediates the 14-3-3/Raf-1 interaction. The next series of experiments examined the role of individual amino acids of the amphipathic groove of 14-3-3ξ in ExoS activation and showed that ExoS activation required the basic residues lining the amphipathic groove of 14-3-3ξ without extensive involvement of the hydrophobic residues. Strikingly, mutations of Val-176 of 14-3-3ξ that disrupted its interaction with Raf-1 did not affect the binding and activation of ExoS by 14-3-3. Thus, ExoS selectively employs residues in the Raf-binding groove for its association with 14-3-3 proteins.
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【期刊论文】Inhibition of Vibrio biofilm formation by a marine actinomycete strain A66
张立新, JianLan You, , XiaoLi Xue, LiXiang Cao, Xin Lu, Jian Wang, LiXin Zhang, ShiNing Zhou
Appl Microbiol Biotechnol (2007) 76: 1137-1144,-0001,():
-1年11月30日
China remains by far the largest aquaculture producer in the world. However, biofilms formed by pathogenic Vibrio strains pose serious problems to marine aquaculture. To provide a strategy for biofilm prevention, control, and eradication, extracts from 88 marine actinomycetes were screened. Thirty-five inhibited the biofilm formation of Vibrio harveyi, Vibrio vulnificus, and Vibrio anguillarum at a concentration of 2.5% (v/v). Thirty-three of the actinomycete extracts dispersed the mature biofilm. Six extracts inhibited the quorum-sensing system of V. harveyi by attenuating the signal molecules N-acylated homoserine lactones’ activity. Strain A66, which was identified as Steptomyces albus, both attenuated the biofilms and inhibited their quorum-sensing system. It is suggested that strain A66 is a promising candidate to be used in future marine aquaculture.
Vibrio biofilm, Quorum sensing, Biocontrol
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张立新, Yong Wang, YiGuang Wang, Ju Chu, Yingping Zhuang, Lixin Zhang, , Siliang Zhang
Appl Microbiol Biotechnol (2007) 75: 837-842,-0001,():
-1年11月30日
An S-adenosylmethionine synthetase (SAM-s) gene from Streptomyces spectabilis was integrated along with vector DNA into the chromosome of a Saccharopolyspora erythraea E2. Elevated production of SAM was observed in the recombinant strain Saccharopolyspora erythraea E1. The results from the bioassay showed that the titer of erythromycin was increased from 920 IU ml−1 by E2 to approximately 2,000 IU ml−1 by E1. High performance liquid chromatography (HPLC) analysis revealed that there was a 132% increase in erythromycin A compared with the original strain, while the erythromycin B, the main impurity component in erythromycin, was decreased by 30%. The sporulation process was inhibited, while the SAM-s gene was expressed. The addition of the exogenous SAM also inhibited sporulation and promoted an increase in erythromycin titers.
S-adenosylmethionine synthetase, Erythromycin A, Precision engineering, Saccharopolyspora erythraea
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【期刊论文】Secretory expression of a heterologous nattokinase in Lactococcus lactis
张立新, Xiaobo Liang, , Lixin Zhang, Jin Zhong, Liandong Huan
Appl Microbiol Biotechnol,-0001,():
-1年11月30日
Nattokinase has been reported as an oral health product for the prevention of atherosclerosis.We developed a novel strategy to express a nattokinase from Bacillus subtilis in a live delivery vehicle, Lactococcus lactis. Promoter PnisZ and signal peptide SPUsp were used for inducible and secretory expression of nattokinase in L. lactis. Western blotting analysis demonstrated that nattokinase was successfully expressed, and about 94% of the enzyme was secreted to the culture. The recombinant nattokinase showed potent fibrinolytic activity, equivalent to 41.7 urokinase units per milliliter culture. Expression and delivery of such a fibrinolytic enzyme in the food-grade vehicle L. lactis would facilitate the widespread application of nattokinase in the control and prevention of thrombosis diseases.
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张立新, Lixin Zhang, , Kezhi Yan, Yu Zhang, Ren Huang, Jiang Bian, Chuansen Zheng, Haixiang Sun, Zhihui Chen, Nuo Sun, Rong An, Fangui Min, Weibo Zhao, Ying Zhuo, Jianlan You, Yongjie Song, Zhenyan Yu, Zhiheng Liu, Keqian Yang, Hong Gao, Huanqin Dai, Xiaoli Zhang, Jian Wang, Chengzhang Fu, Gang Pei, Jintao Liu, Si Zhang, Michael Goodfellow, Yuanying Jiang, Jun Kuai, Guochun Zhou, Xiaoping Chen
PNAS March 13, 2007, Vol. 104, No. 11, 4606-4611,-0001,():
-1年11月30日
The high mortality rate of immunocompromised patients with fungal infections and the limited availability of highly efficacious and safe agents demand the development of new antifungal therapeutics. To rapidly discover such agents, we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products. Specifically, a microbial natural product library was screened for hits that synergize the effect of a low dosage of ketoconazole (KTC) that alone shows little detectable fungicidal activity. Through screening of ≈20,000 microbial extracts, 12 hits were identified with broadspectrum antifungal activity. Seven of them showed little cytotoxicity against human hepatoma cells. Fractionation of the active extracts revealed beauvericin (BEA) as the most potent component, because it dramatically synergized KTC activity against diverse fungal pathogens by a checkerboard assay. Significantly, in our immunocompromised mouse model, combinations of BEA (0.5 mg/kg) and KTC (0.5 mg/kg) prolonged survival of the host infected with Candida parapsilosis and reduced fungal colony counts in animal organs including kidneys, lungs, and brains. Such an effect was not achieved even with the high dose of 50 mg/kg KTC. These data support synergism between BEA and KTC and thereby a prospective strategy for antifungal therapy.
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