化工进展 ›› 2021, Vol. 40 ›› Issue (4): 2251-2257.DOI: 10.16085/j.issn.1000-6613.2020-1653
收稿日期:
2020-08-18
出版日期:
2021-04-05
发布日期:
2021-04-14
通讯作者:
胡永红
作者简介:
李玲(1986—),女,讲师,研究方向为发酵工程制药。E-mail:基金资助:
LI Ling1(), YU Yong1, HU Yonghong2()
Received:
2020-08-18
Online:
2021-04-05
Published:
2021-04-14
Contact:
HU Yonghong
摘要:
利普司他汀(lipstatin)是一种β-内酯分子,能选择性抑制胰脂肪酶的活性,从而减少小肠脂肪的吸收。分析表明,一个利普司他汀分子与一个脂肪酶分子结合,通过活性部位丝氨酸残基的酰化来抑制胰脂肪酶的催化活性。利普司他汀由毒三链霉菌(Streptomyces toxytricini,简称S. toxytricini)生产的一种天然产物。本文综述了利普司他汀的结构特点,分析了利普司他汀市场应用现状,着重论述了发酵法生产利普司他汀的研究进展;提出生物合成利普司他汀的机制尚不清楚,但酰基辅酶A羧化酶(ACCase)复合物在利普司他汀生物合成中起着关键作用。最后,指出当前存在的问题并对代谢工程在利普司他汀产生菌发酵中的应用进行概述,对今后的研究趋势进行了展望。
中图分类号:
李玲, 于泳, 胡永红. 发酵法生产利普司他汀的研究进展[J]. 化工进展, 2021, 40(4): 2251-2257.
LI Ling, YU Yong, HU Yonghong. Research progress in production of lipstatinfermentation[J]. Chemical Industry and Engineering Progress, 2021, 40(4): 2251-2257.
菌株 | 育种、优化方法 | 效价 /mg·L-1 | 研究团队 | 年份 |
---|---|---|---|---|
S.toxytricini NRRL 15443 | 6.23 | Paul等[ | 1985 | |
S.toxytricini NRRL 15443 | 43.17 | Weibel等[ | 1987 | |
S.toxytricini CCM 7349 | 70L发酵罐补料发酵,约34h补加亚油酸、L-亮氨酸混合溶液 | 3290 | Varga等[ | 2007 |
S.toxytricini | 补料添加0.3%亚油酸、1%豆油 | 4773 | Gasparic等[ | 2007 |
S.toxytricini | 培养20h后补加亚油酸和L-亮氨酸,控制亚油酸体积分数0.3%~0.5% | 4400 | Fujs等[ | 2010 |
S.toxytricini NRRL 15443 | Plackett-Burman法优化发酵种子、发酵培养基 | 1980 | Kumar等[ | 2011 |
S.toxytricini ATCC 19813 | UV和NTG联合诱变,全因子试验设计优化发酵培养条件,大豆粉35g/L和豆油25g/L | 3290 | Luthra等[ | 2013 |
S.toxytricini NRRL B-5426 | 调节碳氮比例、补充金属辅因子、维生素、TCA循环中间产物,有机酸和NADH | 2242.63 | Kumar等[ | 2016 |
S.toxytricini NRRL B-5426 | 紫外、甲磺酸乙酯、甲基甲烷磺酸盐和NTG复合诱变结合前体物添加 | 2387 | Kumar等[ | 2018 |
S.toxytricini srn7 | 添加前体:亚油酸0.02~0.1mg/g,油酸0.02~0.15mg/g,L-亮氨酸1.5%,大豆粉10% | 5886 | Khushboo等[ | 2020 |
S.toxytricini HCCB-2 | 紫外和微波复合诱变,培养条件优化 | 663 | 王栋海[ | 2004 |
S.toxytricini XC-lp-69 | 紫外和微波复合诱变,补料发酵 | 1400 | 韩俊如等[ | 2006 |
S.toxytricini SIPI-UN-21 | 紫外、NTG复合诱变,培养条件优化 | 3.25倍 | 黄娟等[ | 2006 |
S.toxytricini | 正交设计优化发酵培养基,补料油酸/辛酸补料、L-亮氨酸和豆油 | 1.2倍 | 王永青[ | 2013 |
S.toxytricini zjut011 | 正交试验法,添加前体L-亮氨酸,首次发现二价阳离子Mg2+、Co2+和Zn2+对提高效价有显著作用 | 4208 | Zhu等[ | 2014 |
S.toxytricini FIM-1015 | 考察溶氧和剪切力因素,10L发酵罐补料发酵 | 6446 | 孙菲[ | 2014 |
S.toxytricini LIPS-352 | 紫外-微波复合诱变,添加前体葵花籽油,Box-Behnken设计优化 | 8122.9 | 刘顺娜等[ | 2017 |
S.toxytricini FIM-17-16 | 发酵条件优化 | 9667 | 陈洲琴等[ | 2020 |
表1 国内外研究团队研究概况
菌株 | 育种、优化方法 | 效价 /mg·L-1 | 研究团队 | 年份 |
---|---|---|---|---|
S.toxytricini NRRL 15443 | 6.23 | Paul等[ | 1985 | |
S.toxytricini NRRL 15443 | 43.17 | Weibel等[ | 1987 | |
S.toxytricini CCM 7349 | 70L发酵罐补料发酵,约34h补加亚油酸、L-亮氨酸混合溶液 | 3290 | Varga等[ | 2007 |
S.toxytricini | 补料添加0.3%亚油酸、1%豆油 | 4773 | Gasparic等[ | 2007 |
S.toxytricini | 培养20h后补加亚油酸和L-亮氨酸,控制亚油酸体积分数0.3%~0.5% | 4400 | Fujs等[ | 2010 |
S.toxytricini NRRL 15443 | Plackett-Burman法优化发酵种子、发酵培养基 | 1980 | Kumar等[ | 2011 |
S.toxytricini ATCC 19813 | UV和NTG联合诱变,全因子试验设计优化发酵培养条件,大豆粉35g/L和豆油25g/L | 3290 | Luthra等[ | 2013 |
S.toxytricini NRRL B-5426 | 调节碳氮比例、补充金属辅因子、维生素、TCA循环中间产物,有机酸和NADH | 2242.63 | Kumar等[ | 2016 |
S.toxytricini NRRL B-5426 | 紫外、甲磺酸乙酯、甲基甲烷磺酸盐和NTG复合诱变结合前体物添加 | 2387 | Kumar等[ | 2018 |
S.toxytricini srn7 | 添加前体:亚油酸0.02~0.1mg/g,油酸0.02~0.15mg/g,L-亮氨酸1.5%,大豆粉10% | 5886 | Khushboo等[ | 2020 |
S.toxytricini HCCB-2 | 紫外和微波复合诱变,培养条件优化 | 663 | 王栋海[ | 2004 |
S.toxytricini XC-lp-69 | 紫外和微波复合诱变,补料发酵 | 1400 | 韩俊如等[ | 2006 |
S.toxytricini SIPI-UN-21 | 紫外、NTG复合诱变,培养条件优化 | 3.25倍 | 黄娟等[ | 2006 |
S.toxytricini | 正交设计优化发酵培养基,补料油酸/辛酸补料、L-亮氨酸和豆油 | 1.2倍 | 王永青[ | 2013 |
S.toxytricini zjut011 | 正交试验法,添加前体L-亮氨酸,首次发现二价阳离子Mg2+、Co2+和Zn2+对提高效价有显著作用 | 4208 | Zhu等[ | 2014 |
S.toxytricini FIM-1015 | 考察溶氧和剪切力因素,10L发酵罐补料发酵 | 6446 | 孙菲[ | 2014 |
S.toxytricini LIPS-352 | 紫外-微波复合诱变,添加前体葵花籽油,Box-Behnken设计优化 | 8122.9 | 刘顺娜等[ | 2017 |
S.toxytricini FIM-17-16 | 发酵条件优化 | 9667 | 陈洲琴等[ | 2020 |
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