Enhancing intracellular NADPH bioavailability through improving pentose phosphate pathway flux and its application in biocatalysis asymmetric reduction reaction

Ye, Lin; Qin, Yan-Li; Zou, Zhi-Cheng; Appiah, Bright; Huang, Hao; Yang, Zhangqi; Qun, Can

doi:10.1016/j.jbiosc.2022.08.010

Cited by 11 publications

(11 citation statements)

References 23 publications

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“…The PPP can provide tumor cells with the cellular reductants NADPH and ribose-5-phosphate. NADPH is required for fatty acid synthesis and ROS scavenging [ 7 , 26 ]. Meanwhile, ribose-5-phosphate provides the building blocks for nucleic acid biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

The p52-ZER6/G6PD axis alters aerobic glycolysis and promotes tumor progression by activating the pentose phosphate pathway

Tang

Qiu

et al. 2023

Oncogenesis

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Abnormal glucose metabolism is a highlight of tumor metabolic reprogramming and is closely related to the development of malignancies. p52-ZER6, a C2H2-type zinc finger protein, promotes cell proliferation and tumorigenesis. However, its role in the regulation of biological and pathological functions remains poorly understood. Here, we examined the role of p52-ZER6 in tumor cell metabolic reprogramming. Specifically, we demonstrated that p52-ZER6 promotes tumor glucose metabolic reprogramming by positively regulating the transcription of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP). By activating the PPP, p52-ZER6 was found to enhance the production of nucleotides and nicotinamide adenine dinucleotide phosphate, thereby providing tumor cells with the building blocks of ribonucleic acids and cellular reductants for reactive oxygen species scavenging, which subsequently promotes tumor cell proliferation and viability. Importantly, p52-ZER6 promoted PPP-mediated tumorigenesis in a p53-independent manner. Taken together, these findings reveal a novel role for p52-ZER6 in regulating G6PD transcription via a p53-independent process, ultimately resulting in tumor cell metabolic reprogramming and tumorigenesis. Our results suggest that p52-ZER6 is a potential target for the diagnosis and treatment of tumors and metabolic disorders.

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Section: Discussionmentioning

confidence: 99%

The p52-ZER6/G6PD axis alters aerobic glycolysis and promotes tumor progression by activating the pentose phosphate pathway

Tang

Qiu

et al. 2023

Oncogenesis

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“…Insufficient intracellular NAD(P)H is a major issue limiting the reduced product synthesis by whole cell biocatalysis or microbial cell factory. Yuan et al (2022) improved the PPP by overexpressing additional G6PDH encoding gene zwf and glucokinase encoding gene glk , thereby increasing the supply of NADPH, and intracellular NADPH content increased significantly from 150.3 to 681.8 mol/L, which was 4.5-fold higher than the control. It was applied to enhance the reduction process of 4-chloroacetoacetate to generate ethyl S-4-chloro-3-hydroxybutyrate, resulting in a 2.8-fold improvement in reaction yield.…”

Section: Regulation Of Cofactor Metabolic Balance and Its Applicationmentioning

confidence: 95%

“…By blocking the glycolytic pathway and overexpressing the PPP in lysineproducing strains and knocking out the gene Cgl2680, Cgl2680deficient strains of C. glutamicum showed increased production of L-lysine and L-leucine as well as increased H 2 O 2 tolerance. Insufficient intracellular NAD(P)H is a major issue limiting the reduced product synthesis by whole cell biocatalysis or microbial cell factory Yuan et al (2022). improved the PPP by overexpressing additional G6PDH encoding gene zwf and glucokinase encoding gene glk, thereby increasing the supply of NADPH, and intracellular NADPH content increased significantly from 150.3 to 681.8 mol/L, which was 4.5-fold higher than the control.…”

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confidence: 99%

Application of cofactors in the regulation of microbial metabolism: A state of the art review

Sun

Zhang

et al. 2023

Front. Microbiol.

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Cofactors are crucial chemicals that maintain cellular redox balance and drive the cell to do synthetic and catabolic reactions. They are involved in practically all enzymatic activities that occur in live cells. It has been a hot research topic in recent years to manage their concentrations and forms in microbial cells by using appropriate techniques to obtain more high-quality target products. In this review, we first summarize the physiological functions of common cofactors, and give a brief overview of common cofactors acetyl coenzyme A, NAD(P)H/NAD(P)+, and ATP/ADP; then we provide a detailed introduction of intracellular cofactor regeneration pathways, review the regulation of cofactor forms and concentrations by molecular biological means, and review the existing regulatory strategies of microbial cellular cofactors and their application progress, to maximize and rapidly direct the metabolic flux to target metabolites. Finally, we speculate on the future of cofactor engineering applications in cell factories. Graphical Abstract

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“…As the electron donors or acceptors, the reduced form of nicotinamide cofactors (NADH/NADPH) and its oxidized form (NAD(H)/NADP+) participate in many catabolic and anabolic reactions in the industrial microorganism's metabolic network, [22] including the pentose phosphate pathway (PP pathway), [10] tricarboxylic acid cycle (TCA cycle), and the glycolytic pathway. [23] Recently, studies reported that the intracellular NADP(H) supply strategy through metabolic engineering technology had been successfully applied in the practical synthesis of bulk chemicals, for instance, chiral alcohols, chiral amino acids, biofuel, [24][25][26] and so on.…”

Section: Introductionmentioning

confidence: 99%

Design of a cofactor self‐sufficient whole‐cell biocatalyst for enzymatic asymmetric reduction via engineered metabolic pathways and multi‐enzyme cascade

Zou,

Zhang,

Han

et al. 2024

Biotechnology Journal

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NAD(P)H‐dependent oxidoreductases are crucial biocatalysts for synthesizing chiral compounds. Yet, the industrial implementation of enzymatic redox reactions is often hampered by an insufficient supply of expensive nicotinamide cofactors. Here, a cofactor self‐sufficient whole‐cell biocatalyst was developed for the enzymatic asymmetric reduction of 2‐oxo‐4‐[(hydroxy)(‐methyl)phosphinyl] butyric acid (PPO) to L‐phosphinothricin (L‐PPT). The endogenous NADP+ pool was significantly enhanced by regulating Preiss‐Handler pathway toward NAD(H) synthesis and, in the meantime, introducing NAD kinase to phosphorylate NAD(H) toward NADP+. The intracellular NADP(H) concentration displayed a 2.97‐fold increase with the strategy compared with the wild‐type strain. Furthermore, a recombinant multi‐enzyme cascade biocatalytic system was constructed based on the Escherichia coli chassis. In order to balance multi‐enzyme co‐expression levels, the strategy of modulating rate‐limiting enzyme PmGluDH by RBS strengths regulation successfully increased the catalytic efficiency of PPO conversion. Finally, the cofactor self‐sufficient whole‐cell biocatalyst effectively converted 300 mM PPO to L‐PPT in 2 h without the need to add exogenous cofactors, resulting in a 2.3‐fold increase in PPO conversion (%) from 43% to 100%, with a high space‐time yield of 706.2 g L−1 d−1 and 99.9% ee. Overall, this work demonstrates a technological example for constructing a cofactor self‐sufficient system for NADPH‐dependent redox biocatalysis.

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Enhancing intracellular NADPH bioavailability through improving pentose phosphate pathway flux and its application in biocatalysis asymmetric reduction reaction

Cited by 11 publications

References 23 publications

The p52-ZER6/G6PD axis alters aerobic glycolysis and promotes tumor progression by activating the pentose phosphate pathway

The p52-ZER6/G6PD axis alters aerobic glycolysis and promotes tumor progression by activating the pentose phosphate pathway

Application of cofactors in the regulation of microbial metabolism: A state of the art review

Design of a cofactor self‐sufficient whole‐cell biocatalyst for enzymatic asymmetric reduction via engineered metabolic pathways and multi‐enzyme cascade

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