伯克氏菌E264连续吸附耦合发酵生产Thailandepsin A的研究
|
摘要
伯克氏菌E264(Burkholderia thailandensis E264)是从泰国稻田中分离得到的,能够合成组蛋白去乙酰化酶抑制剂(HDACi)类抗癌物质Thailandepsin A。作为抗癌药物FK228的结构类似物,Thailandepsin A与FK228有不同的选择性抑制特点,尤其对皮肤T细胞淋巴瘤具显著抑制作用。尽管Thailandepsin A作为抗癌药物极具开发前景,但如何大量获取Thailandepsin A成为相关研究的瓶颈。目前,野生型菌株合成Thailandepsin A产量很低(10mg/L),在对培养基和培养条件进行优化后有一定提高。本论文在此基础上,通过培养基优化的方法提高Thailandepsin A的产量,同时将发酵过程放大至5L发酵罐,通过动态吸附耦合装置与发酵过程偶联,解除产物抑制,实现连续吸附耦合发酵,从而提高Thailandepsin A的产量和生产效率。
首先,通过摇瓶发酵方法,用单因素试验来进一步探索适合伯克氏菌E264菌株产Thailandepsin A的培养基成分,重点就不同种类和浓度的氨基酸前体、复合碳氮源、微量元素对Thailandepsin A产量的影响进行研究,得出结论:最适浓度的α-丙氨酸、L-半胱氨酸、L-苯丙氨酸和甘氨酸复合添加至培养基中,Thailandepsin A的产量较对照提高65.9%;葡萄糖和甘油复合作为碳源能显著提高伯克氏菌E264生产Thailandepsin A的产量,最高能较对照提高54.48%(配比100%/20%);胰蛋白胨和硫酸铵或氯化铵作为复合氮源,则不利于Thailandepsin A的高产;添加以下微量元素能提高Thailandepsin A产量:FeSO4·7H2O(最适添加浓度1mg/L)/ FeCl3(最适添加浓度1mg/L)、ZnSO4·7H2O(最适添加浓度2mg/L)、、MnCl2·4H2O(最适添加浓度0.1mg/L)。
其次,初步探索了在发酵过程中补糖对Thailandepsin A产量的影响,通过设计累进补糖策略,使Thailandepsin A的产量最高达到205.29mg/L,是未补糖对照组的2.28倍,是最初培养基产量的20.5倍。从而找出其最适补糖分批发酵的条件,为后续的放大优化奠定了基础。
再次,将伯克氏菌E264发酵生产Thailandepsin A的过程放大到5L发酵罐,通过摸索通气条件、树脂吸附、种源条件等条件,探索Thailandepsin A放大发酵的最优条件。在此基础上,设计和制作了外置式吸附耦合装置,使之与发酵罐形成吸附与发酵耦合的过程,从而实现伯克氏菌E264的连续发酵,同时配合不同的循环流速、开启时间、补糖策略的研究,以提高Thailandepsin A的产量。
通过优化,伯克氏菌E264吸附耦合放大发酵生产Thailandepsin A的最优生产条件确定为:(1)接种量1%,种源为三级发酵种子;(2)搅拌转速:150rpm;通气量:1.3L/min;(3)罐压0.01MPa,发酵温度28℃;(4)耦合吸附装置,装置中内添加4%预处理后树脂,装置在发酵36h后开始不间歇运转,循环流速20ml/min;(5)从60h起,每12h流加1g/L的葡萄糖,直至发酵结束;(6)发酵终点采用经验方法,也即菌体不再生长后的24h停止。经验证,Thailandepsin A的产量能够达到224.11mg/L,是发酵罐优化前的5.6倍,是最初培养基产量的22.4倍。生产效率达到1.10 mg/L*h~(-1),与发酵罐优化前相比大幅提高了65%,是最初培养基生产效率的6.6倍。通过以上研究,为伯克氏菌E264的进一步发酵研究和放大优化打下基础。
Burkholderia thailandensis E264 was isolated from the rice field in Thailand. It can produce an antitumor drug of histone deacetylase inhibitors (HDACi) type: Thailandepsin A. As a structural analogue of anti-cancer drug FK228, Thailandepsin A possesses distinctive selective inhibition towards different type of HDAC, thus especially demonstrates significant impact towards T-cell lymphoma. Despite of its prospect as a potential effective anti-cancer drug, the bottleneck lies in its low production capacity. Currently, Thailandepsin A yield produced by wild-type strain was very low (10mg/L) . Under optimization on culture medium and cultivation condition, The production capacity increased somewhat. In this research, we attempted to further employ fermentation medium optimization on this basis, and then scale-up the fermentation process to 5L fermentor and applied an absorption-coupled fermentation process, to remove product inhibition and thus increase the productivity of Thailandepsin A
Firstly, at the shake flask level, with the one-factor-at-a-time screening method, we investigated impact on Thailandepsin A yield of amino acid precursor, compound carbon source and nitrogen source, and trace elements of different kinds and concentration. The results were: with a compound addition ofα-alanine, L-cysteine, L-phenylalanine and Glycine under optimal concentration in culture meidum, Thailandepsin A yield increased by 65.9%. With the application of compound carbon source of glucose and glycerol, maximum Thailandepsin A yield increased by 54.48%. With the application of compound nitrogen source of trypton and ammonium sulfate/ ammonium chloride, Thailandepsin A yield decreased on the contrary. With the addition of FeSO_4·7H_2O/ FeCl_3 (1mg/L), ZnSO_4·7H_2O(2mg/L), MnCl_2·4H_2O(0.1mg/L) in culture meidum, Thailandepsin A yield could increase more or less.
Secondly, we investigated different fed-batch cultivation strategy on Thailandepsin A yield. By a progressive glucose fed-batch strategy, maximum Thailandepsin A yield increased to 205.29mg/L, which was 2.28-fold compared to control and 20.5-fold compared to initial yield, thus found an effective way to increase Thailandepsin A production capacity and lay down a foundation for further scale-up fermentation.
Thirdly, in a laboratory scale 5L stirred tank bioreactor with a working volume of 3 L, Thailandepsin A fermentation was preliminarily optimized by the investigation of cultivation condition of ventilation conditions, seed source conditions and absorption of HP-20 resin. On this basis, we designed and made an external absorbitor column to connect with bioreactor, thus realized the process of continuous absorption-coupled fermentation. With the investigation of certain parameters such as circulative velocities, initial absorption time and fed-batch strategy, Thailandepsin A yield increased significantly.
The maximum Thailandepsin A yield cultivation strategy was : (1) inoculum volume 1%; three-level seed source; (2) agitation speed 150rpm; air flow rate 1.3L/min; (3) cultivation pressure 0.01MPa; temperature 28℃; (4) coupled to continuous absorption with 4% pretreated HP-20 resin, initial absorption time 36h and circulative velocities 20ml/min; (5) glucose fed-batch 1g/L per 12h start from 60h; (6) fermentation end determined to 24h after dry cell weight reaches peak. The fermentation experiment under above condition demonstrated a Thailandepsin A yield of 224.11mg/L, which was 5.6-fold compared to control and 22.4-fold compared to initial yield; Thailandepsin A productivity of 1.10 mg/L*h~(-1), which increased by 65% compared to control and 6.6-fold compared to initial productivity; thus lay down solid foundation for further research on Thailandepsin A fermentation.
首先,通过摇瓶发酵方法,用单因素试验来进一步探索适合伯克氏菌E264菌株产Thailandepsin A的培养基成分,重点就不同种类和浓度的氨基酸前体、复合碳氮源、微量元素对Thailandepsin A产量的影响进行研究,得出结论:最适浓度的α-丙氨酸、L-半胱氨酸、L-苯丙氨酸和甘氨酸复合添加至培养基中,Thailandepsin A的产量较对照提高65.9%;葡萄糖和甘油复合作为碳源能显著提高伯克氏菌E264生产Thailandepsin A的产量,最高能较对照提高54.48%(配比100%/20%);胰蛋白胨和硫酸铵或氯化铵作为复合氮源,则不利于Thailandepsin A的高产;添加以下微量元素能提高Thailandepsin A产量:FeSO4·7H2O(最适添加浓度1mg/L)/ FeCl3(最适添加浓度1mg/L)、ZnSO4·7H2O(最适添加浓度2mg/L)、、MnCl2·4H2O(最适添加浓度0.1mg/L)。
其次,初步探索了在发酵过程中补糖对Thailandepsin A产量的影响,通过设计累进补糖策略,使Thailandepsin A的产量最高达到205.29mg/L,是未补糖对照组的2.28倍,是最初培养基产量的20.5倍。从而找出其最适补糖分批发酵的条件,为后续的放大优化奠定了基础。
再次,将伯克氏菌E264发酵生产Thailandepsin A的过程放大到5L发酵罐,通过摸索通气条件、树脂吸附、种源条件等条件,探索Thailandepsin A放大发酵的最优条件。在此基础上,设计和制作了外置式吸附耦合装置,使之与发酵罐形成吸附与发酵耦合的过程,从而实现伯克氏菌E264的连续发酵,同时配合不同的循环流速、开启时间、补糖策略的研究,以提高Thailandepsin A的产量。
通过优化,伯克氏菌E264吸附耦合放大发酵生产Thailandepsin A的最优生产条件确定为:(1)接种量1%,种源为三级发酵种子;(2)搅拌转速:150rpm;通气量:1.3L/min;(3)罐压0.01MPa,发酵温度28℃;(4)耦合吸附装置,装置中内添加4%预处理后树脂,装置在发酵36h后开始不间歇运转,循环流速20ml/min;(5)从60h起,每12h流加1g/L的葡萄糖,直至发酵结束;(6)发酵终点采用经验方法,也即菌体不再生长后的24h停止。经验证,Thailandepsin A的产量能够达到224.11mg/L,是发酵罐优化前的5.6倍,是最初培养基产量的22.4倍。生产效率达到1.10 mg/L*h~(-1),与发酵罐优化前相比大幅提高了65%,是最初培养基生产效率的6.6倍。通过以上研究,为伯克氏菌E264的进一步发酵研究和放大优化打下基础。
Burkholderia thailandensis E264 was isolated from the rice field in Thailand. It can produce an antitumor drug of histone deacetylase inhibitors (HDACi) type: Thailandepsin A. As a structural analogue of anti-cancer drug FK228, Thailandepsin A possesses distinctive selective inhibition towards different type of HDAC, thus especially demonstrates significant impact towards T-cell lymphoma. Despite of its prospect as a potential effective anti-cancer drug, the bottleneck lies in its low production capacity. Currently, Thailandepsin A yield produced by wild-type strain was very low (10mg/L) . Under optimization on culture medium and cultivation condition, The production capacity increased somewhat. In this research, we attempted to further employ fermentation medium optimization on this basis, and then scale-up the fermentation process to 5L fermentor and applied an absorption-coupled fermentation process, to remove product inhibition and thus increase the productivity of Thailandepsin A
Firstly, at the shake flask level, with the one-factor-at-a-time screening method, we investigated impact on Thailandepsin A yield of amino acid precursor, compound carbon source and nitrogen source, and trace elements of different kinds and concentration. The results were: with a compound addition ofα-alanine, L-cysteine, L-phenylalanine and Glycine under optimal concentration in culture meidum, Thailandepsin A yield increased by 65.9%. With the application of compound carbon source of glucose and glycerol, maximum Thailandepsin A yield increased by 54.48%. With the application of compound nitrogen source of trypton and ammonium sulfate/ ammonium chloride, Thailandepsin A yield decreased on the contrary. With the addition of FeSO_4·7H_2O/ FeCl_3 (1mg/L), ZnSO_4·7H_2O(2mg/L), MnCl_2·4H_2O(0.1mg/L) in culture meidum, Thailandepsin A yield could increase more or less.
Secondly, we investigated different fed-batch cultivation strategy on Thailandepsin A yield. By a progressive glucose fed-batch strategy, maximum Thailandepsin A yield increased to 205.29mg/L, which was 2.28-fold compared to control and 20.5-fold compared to initial yield, thus found an effective way to increase Thailandepsin A production capacity and lay down a foundation for further scale-up fermentation.
Thirdly, in a laboratory scale 5L stirred tank bioreactor with a working volume of 3 L, Thailandepsin A fermentation was preliminarily optimized by the investigation of cultivation condition of ventilation conditions, seed source conditions and absorption of HP-20 resin. On this basis, we designed and made an external absorbitor column to connect with bioreactor, thus realized the process of continuous absorption-coupled fermentation. With the investigation of certain parameters such as circulative velocities, initial absorption time and fed-batch strategy, Thailandepsin A yield increased significantly.
The maximum Thailandepsin A yield cultivation strategy was : (1) inoculum volume 1%; three-level seed source; (2) agitation speed 150rpm; air flow rate 1.3L/min; (3) cultivation pressure 0.01MPa; temperature 28℃; (4) coupled to continuous absorption with 4% pretreated HP-20 resin, initial absorption time 36h and circulative velocities 20ml/min; (5) glucose fed-batch 1g/L per 12h start from 60h; (6) fermentation end determined to 24h after dry cell weight reaches peak. The fermentation experiment under above condition demonstrated a Thailandepsin A yield of 224.11mg/L, which was 5.6-fold compared to control and 22.4-fold compared to initial yield; Thailandepsin A productivity of 1.10 mg/L*h~(-1), which increased by 65% compared to control and 6.6-fold compared to initial productivity; thus lay down solid foundation for further research on Thailandepsin A fermentation.
引文
[1] Miller, A., Hoogstraten, B., Staquet, M., et al. (1981). "Reporting results of cancer treatment." Cancer 47(1): 207-214.
[2] Boyle.P. , Levin B. (2008) . World Cancer Report 2008. World Helath Organization.
[3]陈清奇. (2009).美国抗癌药物化学合成速查.科学出版社.
[4]张玥,张立平. (2008). "抗癌药物的研究进展".中国实用医药3(012): 187-188.
[5] Jones, P. A., Baylin, S. B. (2007). "The epigenomics of cancer." Cell 128(4): 683-692.
[6] Yoo, C. B., Jones, P. A. (2006). "Epigenetic therapy of cancer: past, present and future." Nature Reviews Drug Discovery 5(1): 37-50.
[7] Ma, W. W., Adjei, A. A. (2009). "Novel agents on the horizon for cancer therapy." CA: a cancer journal for clinicians 59(2): 111-137.
[8] Piekarz, R. L., Bates, S. E. (2009). "Epigenetic modifiers: basic understanding and clinical development." Clinical Cancer Research 15(12): 3918.
[9] Vogelstein, B., Kinzler, K. W. (2002). The genetic basis of human cancer, McGraw-Hill Professional.
[10]檀琼,刘全海.(2010). "组蛋白去乙酰化酶抑制剂的研究进展".世界临床药物31(010): 616-620.
[11] Mai, A., Rotili, D., Tarantino, D., et al. (2009). "Identification of 4-hydroxyquinolines inhibitors of p300/CBP histone acetyltransferases." Bioorganic & Medicinal Chemistry Letters 19(4): 1132-1135.
[12] Kikuchi, H., Nakayama, T. (2008). "GCN5 and BCR signalling collaborate to induce pre-mature B cell apoptosis through depletion of ICAD and IAP2 and activation of caspase activities." Gene 419(1-2): 48-55.
[13] Khochbin, S., Verdel, A., Lemercier, C., et al. (2001). "Functional significance of histone deacetylase diversity." Current Opinion in Genetics & Development 11(2): 162-166.
[14] MacDonald, J. L., Roskams, A. J. (2009). "Epigenetic regulation of nervous system development by DNA methylation and histone deacetylation." Progress in neurobiology 88(3): 170-183.
[15] Gregoretti, I. V., Lee, Y. M., Goodson, H. V. (2004). "Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis." Journal of molecular biology 338(1): 17-31.
[16] Bolden, J. E., Peart, M. J., Johnstone, R. W. (2006). "Anticancer activities of histone deacetylase inhibitors." Nature Reviews Drug Discovery 5(9): 769-784.
[17] Rosato, R. R., Grant, S. (2003). "Histone deacetylase inhibitors in cancer therapy." Cancer biology & therapy 2(1): 30.
[18] Bots, M., Johnstone, R. W. (2009). "Rational combinations using HDAC inhibitors." Clinical Cancer Research 15(12): 3970.
[19] Schrump, D. S. (2009). "Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications." Clinical Cancer Research 15(12): 3947.
[20] Marks, P. A., Richon, V. M., Miller, T., et al. (2004). "Histone deacetylase inhibitors." Advances in cancer research 91: 137-168.
[21] Gao, L., Cueto, M. A., Asselbergs, F., et al. (2002). "Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family." Journal of Biological Chemistry 277(28): 25748.
[22] StatBite: (2010). FDA oncology drug product approvals in 2009. J. Natl. Cancer Inst. 102, 219.
[23] Lindemann, R., Newbold, A., Whitecross, K., et al. (2007). "Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma." Proceedings of the National Academy of Sciences 104(19): 8071.
[24] Glaser, K. B. (2007). "HDAC inhibitors: clinical update and mechanism-based potential." Biochemical pharmacology 74(5): 659-671.
[25] Wang, H., Dymock, B. W. (2009). "New patented histone deacetylase inhibitors." Expert Opinion on Therapeutic Patents 19(12): 1727-1757.
[26] Ezzeldin, H. H., Diasio, R. B. (2009). "Histone deacetylase inhibitors: current status andoverview of recent clinical trials." Drugs 69(14): 1911-1934.
[27] Armeanu, S., Pathil, A., Venturelli, S., et al. (2005). "Apoptosis on hepatoma cells but not on primary hepatocytes by histone deacetylase inhibitors valproate and ITF2357." Journal of hepatology 42(2): 210-217.
[28]陈国柱,于晓枕(2008). "组蛋白去乙酰化酶抑制剂诱导肿瘤细胞凋亡的机制".生物技术通讯19(6): 907-910.
[29] Kelly, W. K., O'Connor, O. A., Krug, L. M., et al. (2005). "Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer." Journal of clinical oncology 23(17): 3923.
[30] Han, S., Lu, J., Zhang, Y., et al. (2007). "HDAC inhibitors TSA and sodium butyrate enhanced the human IL-5 expression by altering histone acetylation status at its promoter region." Immunology letters 108(2): 143-150.
[31] Steele, N. L., Plumb, J. A., Vidal, L., et al. (2008). "A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors." Clinical Cancer Research 14(3): 804.
[32] Komatsu, Y., Tomizaki, K., Tsukamoto, M., et al. (2001). "Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity." Cancer research 61(11): 4459.
[33] Davis, F. J., Pillai, J. B., Gupta, M., et al. (2005). "Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of |á-MHC and cardiac tubulins: implication for gain in cardiac muscle contractility." American Journal of Physiology-Heart and Circulatory Physiology 288(3): H1477.
[34] Jung, J. W., Cho, S. D., Ahn, N. S., et al. (2005). "Ras/MAP kinase pathways are involved in Ras specific apoptosis induced by sodium butyrate." Cancer letters 225(2): 199-206.
[35] Ueda, H., Nakajima, H., Hori, Y., et al. (1994). "FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity." The Journal ofantibiotics 47(3): 301.
[36] Ueda, H., Nakajima, H., Hori, Y., et al. (1994). "Action of FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968, on Ha-ras transformed NIH3T3 cells." Bioscience, biotechnology, and biochemistry 58(9): 1579.
[37]吕敏,厉保秋,王凤山. (2007). "海洋缩酚酸肽类药物的研究进展",中国海洋药物. 26 (5). R931.77.
[38] Vigushin, D. M. (2002). "FR-901228 (Fujisawa/National Cancer Institute)." Current Opinion in Investigational Drugs 3(9): 1396-1402.
[39] Garber, K. (2007). "HDAC inhibitors overcome first hurdle." Nature Biotechnology 25(1): 17-19.
[40] NCI (2008). NCI Drug Dictionary: clinical trials of romidepsin (FK228, FR901228, NSC,630176), National Cancer Institute.
[41] Ballard, C., Yu, H., Wang, B. (2002). "Recent developments in depsipeptide research." Current medicinal chemistry 9(4): 471-498.
[42] Li, K. W., Wu, J., Xing, W., et al. (1996). "Total synthesis of the antitumor depsipeptide FR-901,228." Journal of the American Chemical Society 118(30): 7237-7238.
[43] Furumai, R., Matsuyama, A., Kobashi, N., et al. (2002). "FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases." Cancer research 62(17): 4916.
[44] Cheng, Y. (2010). SEQUENCES FOR FK228 BIOSYNTHESIS AND METHODS OF SYNTHESIZING FK228 AND FK228 ANALOGS, US Patent App. 20,100/261,878.
[45] Brett, P. J., DeShazer, D., Woods, D. E. (1998). "Note: Burkholderia thailandensis sp. nov., a Burkholderia pseudomallei-like species." International Journal of Systematic and Evolutionary Microbiology 48(1): 317.
[46] Wuthiekanun, V., Smith, M., Dance, D., et al. (1996). "Biochemical characteristics of clinical and environmental isolates of Burkholderia pseudomallei." Journal of medical microbiology 45(6): 408.
[47] Smith, M., Angus, B., Wuthiekanun, V., et al. (1997). "Arabinose assimilation defines anonvirulent biotype of Burkholderia pseudomallei." Infection and immunity 65(10): 4319.
[48] Lertpatanasuwan, N., Sermsri, K., Petkaseam, A., et al. (1999). "Arabinose-positive Burkholderia pseudomallei infection in humans: case report." Clinical infectious diseases 28(4): 927-928.
[49] Glass, M. B., Gee, J. E., Steigerwalt, A. G., et al. (2006). "Pneumonia and Septicemia caused by Burkholderia thailandensis from the United States." Journal of clinical microbiology: JCM. 01585-01506v01581.
[50] Caboche, S., Leclere, V., Pupin, M., et al. (2010). "Diversity of monomers in nonribosomal peptides: towards the prediction of origin and biological activity." Journal of bacteriology 192(19): 5143-5150.
[51]陈长华,宫衡,高淑红.(2009).发酵工程实验.高等教育出版社.
[52]俞俊棠.(2003)新编生物工艺学.化学工业出版社.
[53] Galbiati, S., Smid, M., Gambini, D., et al. (2005). "Fetal DNA detection in maternal plasma throughout gestation." Human genetics 117(2): 243-248.
[54] Sarica, S. (2005). "Addition of avilamycin, mannanoligosaccharide and organic acids mixture to corn-soybean meal based broiler diets." Indian Journal of Animal Sciences (India).
[55] Sun, Y., Cheng, J. (2002). "Hydrolysis of lignocellulosic materials for ethanol production: a review* 1." Bioresource technology 83(1): 1-11.
[56]蔡谨,孙章辉,王隽,等. (2005). "补料发酵工艺的应用及其研究进展".工业微生物35(1):42-48.
[57] Lennox, B., Montague, G., Hiden, H., et al. (2001). "Process monitoring of an industrial fed-batch fermentation." Biotechnology and bioengineering 74(2): 125-135.
[58] ban Impe, J., Bastin, G. (1995). "Optimal adaptive control of fed-batch fermentation processes." Control Engineering Practice 3(7): 939-954.
[59] Lee, J., Lee, S. Y., Park, S., et al. (1999). "Control of fed-batch fermentations." Biotechnology advances 17(1): 29-48.
[60]陈涛,武秋立,李晓静,等. (2006). "不同流加发酵方式对重组枯草芽孢杆菌生产维生素B2的影响."天津大学学报39(B06): 7-12.
[61]高桦,唐芳. (2002). "麦角固醇发酵不同流加方式的比较"化工学报. 53(012): 1233-1237.
[62] Manginot, C., Roustan, J., Sablayrolles, J. (1998). "Nitrogen demand of different yeast strains during alcoholic fermentation. Importance of the stationary phase." Enzyme and Microbial Technology 23(7-8): 511-517.
[63] Robbins Jr, J., Taylor, K. (1989). "Optimization of Escherichia coli growth by controlled addition of glucose." Biotechnology and bioengineering 34(10): 1289-1294.
[64] Yee, L., Blanch, H. (1993). "Recombinant trypsin production in high cell density fed-batch cultures in Escherichia coli." Biotechnology and bioengineering 41(8): 781-790.
[65] Yan, Q., Du, G., Chen, J. (2003). "Biosynthesis of polyhydroxyalkanoates (PHAs) with continuous feeding of mixed organic acids as carbon sources by Ralstonia eutropha." Process Biochemistry 39(3): 387-391.
[66] Bajpai, R., Reuss, M. (1981). "Evaluation of feeding strategies in carbon-regulated secondary metabolite production through mathematical modeling." Biotechnology and bioengineering 23(4): 717-738.
[67] Yoshida, F., Yamane, T., Nakamoto, K. I. (1973). "Fed-batch hydrocarbon fermentation with colloidal emulsion feed." Biotechnology and bioengineering 15(2): 257-270.
[68] James, S., Legge, R., Budman, H. (2002). "Comparative study of black-box and hybrid estimation methods in fed-batch fermentation." Journal of Process Control 12(1): 113-121.
[69] Berkholz, R., R hlig, D., Guthke, R. (2000). "Data and knowledge based experimental design for fermentation process optimization." Enzyme and Microbial Technology 27(10): 784-788.
[70] Shi, Z., Shimizu, K. (1992). "Neuro-fuzzy control of bioreactor systems with pattern recognition." Journal of fermentation and bioengineering 74(1): 39-45.
[71] Siimes, T., Linko, P., von Numers, C., et al. (1995). "Real-time fuzzy-knowledge-based control of Baker's yeast production." Biotechnology and bioengineering 45(2): 135-143.
[72] Kleman, G. L., Chalmers, J. J., Luli, G. W., et al. (1991). "A predictive and feedback control algorithm maintains a constant glucose concentration in fed-batch fermentations." Applied and environmental microbiology 57(4): 910.
[73] Kim, B. S., Lee, S. C., Lee, S. Y., et al. (1994). "Production of poly (3-hydroxybutyric acid) by fed-batch culture of Alcaligenes eutrophus with glucose concentration control." Biotechnology and bioengineering 43(9): 892-898.
[74] Lee, J., Woodard, J., Pagan, R., et al. (1981). "Vacuum fermentation for ethanol production using strains of Zymomonas mobilis." Biotechnology Letters 3(4): 177-182.
[75] Qureshi, N., Blaschek, H. (2001). "Recovery of butanol from fermentation broth by gas stripping." Renewable energy 22(4): 557-564.
[76] Qureshi, N., Maddox, I. S., Friedl, A. (1992). "Application of continuous substrate feeding to the ABE fermentation: relief of product inhibition using extraction, perstraction, stripping, and pervaporation." Biotechnology progress 8(5): 382-390.
[77] Lin, J., Ruan, S., Cen, P. (1998). "Mathematical model of L-lactic acid fermentation in a RDC coupled with product separation by ion exchange." Chemical Engineering Communications 168(1): 59-79.
[78] Tessier, L., Bouchard, P., Rahni, M. (2005). "Separation and purification of benzylpenicillin produced by fermentation using coupled ultrafiltration and nanofiltration technologies." Journal of biotechnology 116(1): 79-89.
[79] Huang, R. Y. M. (1991). Pervaporation membrane separation processes, Elsevier Science Ltd.
[80] Nagashima, M., Azuma, M., Noguchi, S., et al. (1984). "Continuous ethanol fermentation using immobilized yeast cells." Biotechnology and bioengineering 26(8): 992-997.
[81] Wasewar, K. L., Yawalkar, A. A., Moulijn, J. A., et al. (2004). "Fermentation of glucose to lactic acid coupled with reactive extraction: a review." Industrial & engineering chemistry research 43(19): 5969-5982.
[82]王建龙,文湘华.环境生物技术.清华大学出版社
[83]李善吉,伍胜军. (2005). "大孔树脂的应用研究概况."广东轻工职业技术学院学报4(002): 11-13.
[85] Inoue, H., Yajima, Y., Kawano, G., et al. (2004). "Isolation of Indole-3-Aldehyde As a Growth Inhibitor of Legionella pneumophila from Diaion HP-20 Resins Used to Culture the Bacteria."Biocontrol science 9(1): 39-41.
[86] Ryuji Uchida, M. I., Yong-Pil Kim, S. O. (2010). "Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. I: Fermentation, isolation and biological properties." The Journal of antibiotics 63(4): 151-155.
[87] He, X., Liu, R. H. (2008). "Phytochemicals of apple peels: isolation, structure elucidation, and their antiproliferative and antioxidant activities." Journal of agricultural and food chemistry 56(21): 9905-9910.
[88] Awa, Y., Iwai, N., Ueda, T., et al. (2005). "Isolation of a new antibiotic, alaremycin, structurally related to 5-aminolevulinic acid from Streptomyces sp. A012304." Bioscience, biotechnology, and biochemistry 69(9): 1721-1725.
[89] Wang, X., Tao, J., Wei, D., et al. (2004). "Development of an adsorption procedure for the direct separation and purification of prodigiosin from culture broth." Biotechnology and applied biochemistry 40(3): 277-280.
[90] Tolonen, M., Saris, P., Siika-Aho, M. (2004). "Production of nisin with continuous adsorption to Amberlite XAD-4 resin using Lactococcus lactis N8 and L. lactis LAC48." Applied microbiology and biotechnology 63(6): 659-665.
[91] Serp, D., Von Stockar, U., Marison, I. (2003). "Enhancement of 2-phenylethanol productivity by Saccharomyces cerevisiae in two-phase fed-batch fermentations using solvent immobilization." Biotechnology and bioengineering 82(1): 103-110.
[92] Beshay, U., Miksch, G., Friehs, K., et al. (2009). "Integrated bioprocess for the production and purification of recombinant proteins by affinity chromatography in Escherichia coli." Bioprocess and Biosystems Engineering 32(2): 149-158.
[93] Bae, J., Moon, H., Oh, K. K., et al. (2001). "A novel bioreactor with an internal adsorbent for integrated fermentation and recovery of prodigiosin-like pigment produced from Serratia sp. KH-95." Biotechnology Letters 23(16): 1315-1319.
[94] Miller, G. L. (1959). "Use of dinitrosalicylic acid reagent for determination of reducing sugar." Analytical chemistry 31(3): 426-428.
[95]张克旭,陈宁,张蓓,等.(1998).代谢控制发酵.中国轻工业出版社.
[96]李艳.(2000).发酵工业概论.高等教育出版社.
[97] Moat, A. G., Foster, J. W., Spector, M. P. (2002). Microbial physiology, LibreDigital.
[98]伦世仪.(1993).生化工程.中国轻工业出版社.1993.
[99] Namdev, P. K., Irwin, N., Thompson, B., et al. (1993). "Effect of oxygen fluctuations on recombinant Escherichia coli fermentation." Biotechnology and bioengineering 41(6): 666-670.
[100] Shu, C. H., Liao, C. C. (2002). "Optimization of L-phenylalanine production of Corynebacterium glutamicum under product feedback inhibition by elevated oxygen transfer rate." Biotechnology and bioengineering 77(2): 131-141.
[101] Sahoo, D. K., Agarwal, G. P. (2002). "Effect of oxygen transfer on glycerol biosynthesis by an osmophilic yeast Candida magnoliae I2B." Biotechnology and bioengineering 78(5): 545-555.
[102] Higashiyama, K., Murakami, K., Tsujimura, H., et al. (1999). "Effects of dissolved oxygen on the morphology of an arachidonic acid production by Mortierella alpina 1S-4." Biotechnology and bioengineering 63(4): 442-448.
[103] Clark, T., Hesketh, T., Seddon, T. (1985). "Automatic control of dissolved oxygen tension via fermenter agitation speed." Biotechnology and bioengineering 27(10): 1507-1511.
[104] Williams, D., Yousefpour, P., Wellington, E. (1986). "On-line adaptive control of a fed-batch fermentation of Saccharomyces cerevisiae." Biotechnology and bioengineering 28(5): 631-645.
[105]刘冰. (2011). Burkholderia thailandensis E264生产抗癌药物Thailandepsin A的研究.上海交通大学硕士学位论文.
[2] Boyle.P. , Levin B. (2008) . World Cancer Report 2008. World Helath Organization.
[3]陈清奇. (2009).美国抗癌药物化学合成速查.科学出版社.
[4]张玥,张立平. (2008). "抗癌药物的研究进展".中国实用医药3(012): 187-188.
[5] Jones, P. A., Baylin, S. B. (2007). "The epigenomics of cancer." Cell 128(4): 683-692.
[6] Yoo, C. B., Jones, P. A. (2006). "Epigenetic therapy of cancer: past, present and future." Nature Reviews Drug Discovery 5(1): 37-50.
[7] Ma, W. W., Adjei, A. A. (2009). "Novel agents on the horizon for cancer therapy." CA: a cancer journal for clinicians 59(2): 111-137.
[8] Piekarz, R. L., Bates, S. E. (2009). "Epigenetic modifiers: basic understanding and clinical development." Clinical Cancer Research 15(12): 3918.
[9] Vogelstein, B., Kinzler, K. W. (2002). The genetic basis of human cancer, McGraw-Hill Professional.
[10]檀琼,刘全海.(2010). "组蛋白去乙酰化酶抑制剂的研究进展".世界临床药物31(010): 616-620.
[11] Mai, A., Rotili, D., Tarantino, D., et al. (2009). "Identification of 4-hydroxyquinolines inhibitors of p300/CBP histone acetyltransferases." Bioorganic & Medicinal Chemistry Letters 19(4): 1132-1135.
[12] Kikuchi, H., Nakayama, T. (2008). "GCN5 and BCR signalling collaborate to induce pre-mature B cell apoptosis through depletion of ICAD and IAP2 and activation of caspase activities." Gene 419(1-2): 48-55.
[13] Khochbin, S., Verdel, A., Lemercier, C., et al. (2001). "Functional significance of histone deacetylase diversity." Current Opinion in Genetics & Development 11(2): 162-166.
[14] MacDonald, J. L., Roskams, A. J. (2009). "Epigenetic regulation of nervous system development by DNA methylation and histone deacetylation." Progress in neurobiology 88(3): 170-183.
[15] Gregoretti, I. V., Lee, Y. M., Goodson, H. V. (2004). "Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis." Journal of molecular biology 338(1): 17-31.
[16] Bolden, J. E., Peart, M. J., Johnstone, R. W. (2006). "Anticancer activities of histone deacetylase inhibitors." Nature Reviews Drug Discovery 5(9): 769-784.
[17] Rosato, R. R., Grant, S. (2003). "Histone deacetylase inhibitors in cancer therapy." Cancer biology & therapy 2(1): 30.
[18] Bots, M., Johnstone, R. W. (2009). "Rational combinations using HDAC inhibitors." Clinical Cancer Research 15(12): 3970.
[19] Schrump, D. S. (2009). "Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications." Clinical Cancer Research 15(12): 3947.
[20] Marks, P. A., Richon, V. M., Miller, T., et al. (2004). "Histone deacetylase inhibitors." Advances in cancer research 91: 137-168.
[21] Gao, L., Cueto, M. A., Asselbergs, F., et al. (2002). "Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family." Journal of Biological Chemistry 277(28): 25748.
[22] StatBite: (2010). FDA oncology drug product approvals in 2009. J. Natl. Cancer Inst. 102, 219.
[23] Lindemann, R., Newbold, A., Whitecross, K., et al. (2007). "Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma." Proceedings of the National Academy of Sciences 104(19): 8071.
[24] Glaser, K. B. (2007). "HDAC inhibitors: clinical update and mechanism-based potential." Biochemical pharmacology 74(5): 659-671.
[25] Wang, H., Dymock, B. W. (2009). "New patented histone deacetylase inhibitors." Expert Opinion on Therapeutic Patents 19(12): 1727-1757.
[26] Ezzeldin, H. H., Diasio, R. B. (2009). "Histone deacetylase inhibitors: current status andoverview of recent clinical trials." Drugs 69(14): 1911-1934.
[27] Armeanu, S., Pathil, A., Venturelli, S., et al. (2005). "Apoptosis on hepatoma cells but not on primary hepatocytes by histone deacetylase inhibitors valproate and ITF2357." Journal of hepatology 42(2): 210-217.
[28]陈国柱,于晓枕(2008). "组蛋白去乙酰化酶抑制剂诱导肿瘤细胞凋亡的机制".生物技术通讯19(6): 907-910.
[29] Kelly, W. K., O'Connor, O. A., Krug, L. M., et al. (2005). "Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer." Journal of clinical oncology 23(17): 3923.
[30] Han, S., Lu, J., Zhang, Y., et al. (2007). "HDAC inhibitors TSA and sodium butyrate enhanced the human IL-5 expression by altering histone acetylation status at its promoter region." Immunology letters 108(2): 143-150.
[31] Steele, N. L., Plumb, J. A., Vidal, L., et al. (2008). "A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors." Clinical Cancer Research 14(3): 804.
[32] Komatsu, Y., Tomizaki, K., Tsukamoto, M., et al. (2001). "Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity." Cancer research 61(11): 4459.
[33] Davis, F. J., Pillai, J. B., Gupta, M., et al. (2005). "Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of |á-MHC and cardiac tubulins: implication for gain in cardiac muscle contractility." American Journal of Physiology-Heart and Circulatory Physiology 288(3): H1477.
[34] Jung, J. W., Cho, S. D., Ahn, N. S., et al. (2005). "Ras/MAP kinase pathways are involved in Ras specific apoptosis induced by sodium butyrate." Cancer letters 225(2): 199-206.
[35] Ueda, H., Nakajima, H., Hori, Y., et al. (1994). "FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity." The Journal ofantibiotics 47(3): 301.
[36] Ueda, H., Nakajima, H., Hori, Y., et al. (1994). "Action of FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968, on Ha-ras transformed NIH3T3 cells." Bioscience, biotechnology, and biochemistry 58(9): 1579.
[37]吕敏,厉保秋,王凤山. (2007). "海洋缩酚酸肽类药物的研究进展",中国海洋药物. 26 (5). R931.77.
[38] Vigushin, D. M. (2002). "FR-901228 (Fujisawa/National Cancer Institute)." Current Opinion in Investigational Drugs 3(9): 1396-1402.
[39] Garber, K. (2007). "HDAC inhibitors overcome first hurdle." Nature Biotechnology 25(1): 17-19.
[40] NCI (2008). NCI Drug Dictionary: clinical trials of romidepsin (FK228, FR901228, NSC,630176), National Cancer Institute.
[41] Ballard, C., Yu, H., Wang, B. (2002). "Recent developments in depsipeptide research." Current medicinal chemistry 9(4): 471-498.
[42] Li, K. W., Wu, J., Xing, W., et al. (1996). "Total synthesis of the antitumor depsipeptide FR-901,228." Journal of the American Chemical Society 118(30): 7237-7238.
[43] Furumai, R., Matsuyama, A., Kobashi, N., et al. (2002). "FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases." Cancer research 62(17): 4916.
[44] Cheng, Y. (2010). SEQUENCES FOR FK228 BIOSYNTHESIS AND METHODS OF SYNTHESIZING FK228 AND FK228 ANALOGS, US Patent App. 20,100/261,878.
[45] Brett, P. J., DeShazer, D., Woods, D. E. (1998). "Note: Burkholderia thailandensis sp. nov., a Burkholderia pseudomallei-like species." International Journal of Systematic and Evolutionary Microbiology 48(1): 317.
[46] Wuthiekanun, V., Smith, M., Dance, D., et al. (1996). "Biochemical characteristics of clinical and environmental isolates of Burkholderia pseudomallei." Journal of medical microbiology 45(6): 408.
[47] Smith, M., Angus, B., Wuthiekanun, V., et al. (1997). "Arabinose assimilation defines anonvirulent biotype of Burkholderia pseudomallei." Infection and immunity 65(10): 4319.
[48] Lertpatanasuwan, N., Sermsri, K., Petkaseam, A., et al. (1999). "Arabinose-positive Burkholderia pseudomallei infection in humans: case report." Clinical infectious diseases 28(4): 927-928.
[49] Glass, M. B., Gee, J. E., Steigerwalt, A. G., et al. (2006). "Pneumonia and Septicemia caused by Burkholderia thailandensis from the United States." Journal of clinical microbiology: JCM. 01585-01506v01581.
[50] Caboche, S., Leclere, V., Pupin, M., et al. (2010). "Diversity of monomers in nonribosomal peptides: towards the prediction of origin and biological activity." Journal of bacteriology 192(19): 5143-5150.
[51]陈长华,宫衡,高淑红.(2009).发酵工程实验.高等教育出版社.
[52]俞俊棠.(2003)新编生物工艺学.化学工业出版社.
[53] Galbiati, S., Smid, M., Gambini, D., et al. (2005). "Fetal DNA detection in maternal plasma throughout gestation." Human genetics 117(2): 243-248.
[54] Sarica, S. (2005). "Addition of avilamycin, mannanoligosaccharide and organic acids mixture to corn-soybean meal based broiler diets." Indian Journal of Animal Sciences (India).
[55] Sun, Y., Cheng, J. (2002). "Hydrolysis of lignocellulosic materials for ethanol production: a review* 1." Bioresource technology 83(1): 1-11.
[56]蔡谨,孙章辉,王隽,等. (2005). "补料发酵工艺的应用及其研究进展".工业微生物35(1):42-48.
[57] Lennox, B., Montague, G., Hiden, H., et al. (2001). "Process monitoring of an industrial fed-batch fermentation." Biotechnology and bioengineering 74(2): 125-135.
[58] ban Impe, J., Bastin, G. (1995). "Optimal adaptive control of fed-batch fermentation processes." Control Engineering Practice 3(7): 939-954.
[59] Lee, J., Lee, S. Y., Park, S., et al. (1999). "Control of fed-batch fermentations." Biotechnology advances 17(1): 29-48.
[60]陈涛,武秋立,李晓静,等. (2006). "不同流加发酵方式对重组枯草芽孢杆菌生产维生素B2的影响."天津大学学报39(B06): 7-12.
[61]高桦,唐芳. (2002). "麦角固醇发酵不同流加方式的比较"化工学报. 53(012): 1233-1237.
[62] Manginot, C., Roustan, J., Sablayrolles, J. (1998). "Nitrogen demand of different yeast strains during alcoholic fermentation. Importance of the stationary phase." Enzyme and Microbial Technology 23(7-8): 511-517.
[63] Robbins Jr, J., Taylor, K. (1989). "Optimization of Escherichia coli growth by controlled addition of glucose." Biotechnology and bioengineering 34(10): 1289-1294.
[64] Yee, L., Blanch, H. (1993). "Recombinant trypsin production in high cell density fed-batch cultures in Escherichia coli." Biotechnology and bioengineering 41(8): 781-790.
[65] Yan, Q., Du, G., Chen, J. (2003). "Biosynthesis of polyhydroxyalkanoates (PHAs) with continuous feeding of mixed organic acids as carbon sources by Ralstonia eutropha." Process Biochemistry 39(3): 387-391.
[66] Bajpai, R., Reuss, M. (1981). "Evaluation of feeding strategies in carbon-regulated secondary metabolite production through mathematical modeling." Biotechnology and bioengineering 23(4): 717-738.
[67] Yoshida, F., Yamane, T., Nakamoto, K. I. (1973). "Fed-batch hydrocarbon fermentation with colloidal emulsion feed." Biotechnology and bioengineering 15(2): 257-270.
[68] James, S., Legge, R., Budman, H. (2002). "Comparative study of black-box and hybrid estimation methods in fed-batch fermentation." Journal of Process Control 12(1): 113-121.
[69] Berkholz, R., R hlig, D., Guthke, R. (2000). "Data and knowledge based experimental design for fermentation process optimization." Enzyme and Microbial Technology 27(10): 784-788.
[70] Shi, Z., Shimizu, K. (1992). "Neuro-fuzzy control of bioreactor systems with pattern recognition." Journal of fermentation and bioengineering 74(1): 39-45.
[71] Siimes, T., Linko, P., von Numers, C., et al. (1995). "Real-time fuzzy-knowledge-based control of Baker's yeast production." Biotechnology and bioengineering 45(2): 135-143.
[72] Kleman, G. L., Chalmers, J. J., Luli, G. W., et al. (1991). "A predictive and feedback control algorithm maintains a constant glucose concentration in fed-batch fermentations." Applied and environmental microbiology 57(4): 910.
[73] Kim, B. S., Lee, S. C., Lee, S. Y., et al. (1994). "Production of poly (3-hydroxybutyric acid) by fed-batch culture of Alcaligenes eutrophus with glucose concentration control." Biotechnology and bioengineering 43(9): 892-898.
[74] Lee, J., Woodard, J., Pagan, R., et al. (1981). "Vacuum fermentation for ethanol production using strains of Zymomonas mobilis." Biotechnology Letters 3(4): 177-182.
[75] Qureshi, N., Blaschek, H. (2001). "Recovery of butanol from fermentation broth by gas stripping." Renewable energy 22(4): 557-564.
[76] Qureshi, N., Maddox, I. S., Friedl, A. (1992). "Application of continuous substrate feeding to the ABE fermentation: relief of product inhibition using extraction, perstraction, stripping, and pervaporation." Biotechnology progress 8(5): 382-390.
[77] Lin, J., Ruan, S., Cen, P. (1998). "Mathematical model of L-lactic acid fermentation in a RDC coupled with product separation by ion exchange." Chemical Engineering Communications 168(1): 59-79.
[78] Tessier, L., Bouchard, P., Rahni, M. (2005). "Separation and purification of benzylpenicillin produced by fermentation using coupled ultrafiltration and nanofiltration technologies." Journal of biotechnology 116(1): 79-89.
[79] Huang, R. Y. M. (1991). Pervaporation membrane separation processes, Elsevier Science Ltd.
[80] Nagashima, M., Azuma, M., Noguchi, S., et al. (1984). "Continuous ethanol fermentation using immobilized yeast cells." Biotechnology and bioengineering 26(8): 992-997.
[81] Wasewar, K. L., Yawalkar, A. A., Moulijn, J. A., et al. (2004). "Fermentation of glucose to lactic acid coupled with reactive extraction: a review." Industrial & engineering chemistry research 43(19): 5969-5982.
[82]王建龙,文湘华.环境生物技术.清华大学出版社
[83]李善吉,伍胜军. (2005). "大孔树脂的应用研究概况."广东轻工职业技术学院学报4(002): 11-13.
[85] Inoue, H., Yajima, Y., Kawano, G., et al. (2004). "Isolation of Indole-3-Aldehyde As a Growth Inhibitor of Legionella pneumophila from Diaion HP-20 Resins Used to Culture the Bacteria."Biocontrol science 9(1): 39-41.
[86] Ryuji Uchida, M. I., Yong-Pil Kim, S. O. (2010). "Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. I: Fermentation, isolation and biological properties." The Journal of antibiotics 63(4): 151-155.
[87] He, X., Liu, R. H. (2008). "Phytochemicals of apple peels: isolation, structure elucidation, and their antiproliferative and antioxidant activities." Journal of agricultural and food chemistry 56(21): 9905-9910.
[88] Awa, Y., Iwai, N., Ueda, T., et al. (2005). "Isolation of a new antibiotic, alaremycin, structurally related to 5-aminolevulinic acid from Streptomyces sp. A012304." Bioscience, biotechnology, and biochemistry 69(9): 1721-1725.
[89] Wang, X., Tao, J., Wei, D., et al. (2004). "Development of an adsorption procedure for the direct separation and purification of prodigiosin from culture broth." Biotechnology and applied biochemistry 40(3): 277-280.
[90] Tolonen, M., Saris, P., Siika-Aho, M. (2004). "Production of nisin with continuous adsorption to Amberlite XAD-4 resin using Lactococcus lactis N8 and L. lactis LAC48." Applied microbiology and biotechnology 63(6): 659-665.
[91] Serp, D., Von Stockar, U., Marison, I. (2003). "Enhancement of 2-phenylethanol productivity by Saccharomyces cerevisiae in two-phase fed-batch fermentations using solvent immobilization." Biotechnology and bioengineering 82(1): 103-110.
[92] Beshay, U., Miksch, G., Friehs, K., et al. (2009). "Integrated bioprocess for the production and purification of recombinant proteins by affinity chromatography in Escherichia coli." Bioprocess and Biosystems Engineering 32(2): 149-158.
[93] Bae, J., Moon, H., Oh, K. K., et al. (2001). "A novel bioreactor with an internal adsorbent for integrated fermentation and recovery of prodigiosin-like pigment produced from Serratia sp. KH-95." Biotechnology Letters 23(16): 1315-1319.
[94] Miller, G. L. (1959). "Use of dinitrosalicylic acid reagent for determination of reducing sugar." Analytical chemistry 31(3): 426-428.
[95]张克旭,陈宁,张蓓,等.(1998).代谢控制发酵.中国轻工业出版社.
[96]李艳.(2000).发酵工业概论.高等教育出版社.
[97] Moat, A. G., Foster, J. W., Spector, M. P. (2002). Microbial physiology, LibreDigital.
[98]伦世仪.(1993).生化工程.中国轻工业出版社.1993.
[99] Namdev, P. K., Irwin, N., Thompson, B., et al. (1993). "Effect of oxygen fluctuations on recombinant Escherichia coli fermentation." Biotechnology and bioengineering 41(6): 666-670.
[100] Shu, C. H., Liao, C. C. (2002). "Optimization of L-phenylalanine production of Corynebacterium glutamicum under product feedback inhibition by elevated oxygen transfer rate." Biotechnology and bioengineering 77(2): 131-141.
[101] Sahoo, D. K., Agarwal, G. P. (2002). "Effect of oxygen transfer on glycerol biosynthesis by an osmophilic yeast Candida magnoliae I2B." Biotechnology and bioengineering 78(5): 545-555.
[102] Higashiyama, K., Murakami, K., Tsujimura, H., et al. (1999). "Effects of dissolved oxygen on the morphology of an arachidonic acid production by Mortierella alpina 1S-4." Biotechnology and bioengineering 63(4): 442-448.
[103] Clark, T., Hesketh, T., Seddon, T. (1985). "Automatic control of dissolved oxygen tension via fermenter agitation speed." Biotechnology and bioengineering 27(10): 1507-1511.
[104] Williams, D., Yousefpour, P., Wellington, E. (1986). "On-line adaptive control of a fed-batch fermentation of Saccharomyces cerevisiae." Biotechnology and bioengineering 28(5): 631-645.
[105]刘冰. (2011). Burkholderia thailandensis E264生产抗癌药物Thailandepsin A的研究.上海交通大学硕士学位论文.