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Metabolic engineering of Pichia pastoris for myo-inositol production by dynamic regulation of central metabolism

Microbial cell factories, 2022-06, Vol.21 (1), p.112-112, Article 112 [Peer Reviewed Journal]

2022. The Author(s). ;COPYRIGHT 2022 BioMed Central Ltd. ;2022. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;The Author(s) 2022 ;ISSN: 1475-2859 ;EISSN: 1475-2859 ;DOI: 10.1186/s12934-022-01837-x ;PMID: 35659241

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Title:
Metabolic engineering of Pichia pastoris for myo-inositol production by dynamic regulation of central metabolism
Author: Zhang, Qiquan ; Wang, Xiaolu ; Luo, Huiying ; Wang, Yaru ; Wang, Yuan ; Tu, Tao ; Qin, Xing ; Su, Xiaoyun ; Huang, Huoqing ; Yao, Bin ; Bai, Yingguo ; Zhang, Jie
Subjects: 6-Phosphofructokinase ; Analysis ; Biosynthesis ; Carbon ; Cell density ; Dehydrogenases ; Dissolved oxygen ; Dynamic regulation ; E coli ; Engineering ; Enzymes ; Ethanol ; Fermentation ; Fluctuations ; Genes ; Genomes ; Glucose ; Glucose 6 phosphate dehydrogenase ; Glucose isomerase ; Glucose-6-phosphate isomerase ; Glucosephosphate dehydrogenase ; Glycerol ; Glycerols ; Glycolysis ; Growth rate ; High-cell-density fermentation ; Inosine monophosphate ; Inositol ; Inositol-3-phosphate synthase ; Inositols ; Kinases ; Metabolic engineering ; Metabolic flux ; Metabolism ; Methods ; Mutants ; Myo-inositol ; myo-Inositol-1 (or 4)-monophosphatase ; Pentose ; Pentose phosphate pathway ; Phosphates ; Phosphofructokinase ; Pichia pastoris ; Production processes ; Substrates ; Yeast ; Yeasts
Is Part Of: Microbial cell factories, 2022-06, Vol.21 (1), p.112-112, Article 112
Description: The methylotrophic budding yeast Pichia pastoris GS115 is a powerful expression system and hundreds of heterologous proteins have been successfully expressed in this strain. Recently, P. pastoris has also been exploited as an attractive cell factory for the production of high-value biochemicals due to Generally Recognized as Safe (GRAS) status and high growth rate of this yeast strain. However, appropriate regulation of metabolic flux distribution between cell growth and product biosynthesis is still a cumbersome task for achieving efficient biochemical production. In this study, P. pastoris was exploited for high inositol production using an effective dynamic regulation strategy. Through enhancing native inositol biosynthesis pathway, knocking out inositol transporters, and slowing down carbon flux of glycolysis, an inositol-producing mutant was successfully developed and low inositol production of 0.71 g/L was obtained. The inositol production was further improved by 12.7% through introduction of heterologous inositol-3-phosphate synthase (IPS) and inositol monophosphatase (IMP) which catalyzed the rate-limiting steps for inositol biosynthesis. To control metabolic flux distribution between cell growth and inositol production, the promoters of glucose-6-phosphate dehydrogenase (ZWF), glucose-6-phosphate isomerase (PGI) and 6-phosphofructokinase (PFK1) genes were replaced with a glycerol inducible promoter. Consequently, the mutant strain could be switched from growth mode to production mode by supplementing glycerol and glucose sequentially, leading to an increase of about 4.9-fold in inositol formation. Ultimately, the dissolved oxygen condition in high-cell-density fermentation was optimized, resulting in a high production of 30.71 g/L inositol (~ 40-fold higher than the baseline strain). The GRAS P. pastoris was engineered as an efficient inositol producer for the first time. Dynamic regulation of cell growth and inositol production was achieved via substrate-dependent modulation of glycolysis and pentose phosphate pathways and the highest inositol titer reported to date by a yeast cell factory was obtained. Results from this study provide valuable guidance for engineering of P. pastoris for the production of other high-value bioproducts.
Publisher: England: BioMed Central Ltd
Language: English
Identifier: ISSN: 1475-2859
EISSN: 1475-2859
DOI: 10.1186/s12934-022-01837-x
PMID: 35659241
Source: Freely Accessible Journals
PubMed Central
Springer OA刊
ROAD: Directory of Open Access Scholarly Resources
ProQuest Central
DOAJ Directory of Open Access Journals

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Metabolic engineering of Pichia pastoris for myo-inositol production by dynamic regulation of central metabolism

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