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将代谢建模和群体异质性分析整合到优化 Komagataella (毕赤酵母) 表达系统生产重组蛋白中。

Integrating metabolic modeling and population heterogeneity analysis into optimizing recombinant protein production by Komagataella (Pichia) pastoris.

机构信息

Microbial Processes and Interactions, TERRA Teaching and Research Centre, University of Liège - Gembloux AgroBio Tech, Avenue de la Faculté, 2B, B-5030, Gembloux, Belgium.

School of Biochemical Engineering, Pontificia Universidad Católica de Valparaíso, Av. Brasil 2085, Valparaíso, Chile.

出版信息

Appl Microbiol Biotechnol. 2018 Jan;102(1):63-80. doi: 10.1007/s00253-017-8612-y. Epub 2017 Nov 14.

Abstract

The methylotrophic yeast Komagataella (Pichia) pastoris has become one of the most utilized cell factories for the production of recombinant proteins over the last three decades. This success story is linked to its specific physiological traits, i.e., the ability to grow at high cell density in inexpensive culture medium and to secrete proteins at high yield. Exploiting methanol metabolism is at the core of most P. pastoris-based processes but comes with its own challenges. Co-feeding cultures with glycerol/sorbitol and methanol is a promising approach, which can benefit from improved understanding and prediction of metabolic response. The development of profitable processes relies on the construction and selection of efficient producing strains from less efficient ones but also depends on the ability to master the bioreactor process itself. More specifically, how a bioreactor processes could be monitored and controlled to obtain high yield of production. In this review, new perspectives are detailed regarding a multi-faceted approach to recombinant protein production processes by P. pastoris; including gaining improved understanding of the metabolic pathways involved, accounting for variations in transcriptional and translational efficiency at the single cell level and efficient monitoring and control of methanol levels at the bioreactor level.

摘要

在过去的三十年中,甲醇营养型酵母巴斯德毕赤酵母(Komagataella(Pichia)pastoris)已成为生产重组蛋白的最有效细胞工厂之一。这一成功与它特殊的生理特性有关,即在廉价培养基中以高细胞密度生长和以高产率分泌蛋白质的能力。甲醇代谢的利用是大多数基于毕赤酵母的工艺的核心,但也带来了自身的挑战。用甘油/山梨醇和甲醇共培养是一种很有前途的方法,可以通过更好地理解和预测代谢反应从中受益。盈利工艺的开发依赖于从效率较低的菌株中构建和选择高效的生产菌株,还取决于掌握生物反应器工艺本身的能力。更具体地说,如何监测和控制生物反应器过程以获得高产率的生产。在这篇综述中,详细介绍了通过毕赤酵母生产重组蛋白的多方面方法的新观点;包括更好地理解所涉及的代谢途径,在单细胞水平上考虑转录和翻译效率的变化,以及在生物反应器水平上有效监测和控制甲醇水平。

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