Metabolic Engineering Design Strategies for Increasing Acetyl-CoA Flux

Ku, Jason T.; Chen, Arvin Y.; Lan, Ethan I.

doi:10.3390/metabo10040166

Cited by 44 publications

(25 citation statements)

References 79 publications

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“…β-OHB increases the intracellular content of acetyl-CoA, indirectly altering histone acetylation by promoting acetyltransferase activity via an acetyl-CoA flux (Ku et al, 2020 ; Xie et al, 2012 ). Furthermore, histone hyperacetylation triggered by β-OHB results in the increased expression of forkhead box O3 (FOXO3) (Kenyon, 2010 ).…”

Section: Diet Microbiome Metabolites and Epigenetic Changesmentioning

confidence: 99%

The remodel of the “central dogma”: a metabolomics interaction perspective

2021

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Background In 1957, Francis Crick drew a linear diagram on a blackboard. This diagram is often called the “central dogma.” Subsequently, the relationships between different steps of the “central dogma” have been shown to be considerably complex, mostly because of the emerging world of small molecules. It is noteworthy that metabolites can be generated from the diet through gut microbiome metabolism, serve as substrates for epigenetic modifications, destabilize DNA quadruplexes, and follow Lamarckian inheritance. Small molecules were once considered the missing link in the “central dogma”; however, recently they have acquired a central role, and their general perception as downstream products has become reductionist. Metabolomics is a large-scale analysis of metabolites, and this emerging field has been shown to be the closest omics associated with the phenotype and concomitantly, the basis for all omics. Aim of review Herein, we propose a broad updated perspective for the flux of information diagram centered in metabolomics, including the influence of other factors, such as epigenomics, diet, nutrition, and the gut- microbiome. Key scientific concepts of review Metabolites are the beginning and the end of the flux of information.

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Section: Diet Microbiome Metabolites and Epigenetic Changesmentioning

confidence: 99%

The remodel of the “central dogma”: a metabolomics interaction perspective

2021

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“…Therefore, the ability to increase product formation with targeting phytochemical pathway gene will logically be quickly limited by the metabolite flux of upstream precursors ( Balcke et al, 2017 ). In this scenario, metabolic engineering to increase precursor of synthetic pathway has been demonstrated to progressively increase downstream products ( Ku et al, 2020 ). For the engineering of cannabinoid synthesis genes, the supply of the high amount of geranyldiphosphate (GPP), which is a substrate to synthesize CBGA is essential.…”

Section: Strategies Of Target Gene Selection For Enhancing Phytochemimentioning

confidence: 99%

Metabolic Engineering Strategies of Industrial Hemp (Cannabis sativa L.): A Brief Review of the Advances and Challenges

et al. 2020

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Industrial hemp (Cannabis sativa L.) is a diploid (2n = 20), dioecious plant that is grown for fiber, seed, and oil. Recently, there has been a renewed interest in this crop because of its panoply of cannabinoids, terpenes, and other phenolic compounds. Specifically, hemp contains terpenophenolic compounds such as cannabidiol (CBD) and cannabigerol (CBG), which act on cannabinoid receptors and positively regulate various human metabolic, immunological, and physiological functions. CBD and CBG have an effect on the cytokine metabolism, which has led to the examination of cannabinoids on the treatment of viral diseases, including COVID-19. Based on genomic, transcriptomic, and metabolomic studies, several synthetic pathways of hemp secondary metabolite production have been elucidated. Nevertheless, there are few reports on hemp metabolic engineering despite obvious impact on scientific and industrial sectors.In this article, recent status and current perspectives on hemp metabolic engineering are reviewed. Three distinct approaches to expedite phytochemical yield are discussed. Special emphasis has been placed on transgenic and transient gene delivery systems, which are critical for successful metabolic engineering of hemp. The advent of new tools in synthetic biology, particularly the CRISPR/Cas systems, enables environment-friendly metabolic engineering to increase the production of desirable hemp phytochemicals while eliminating the psychoactive compounds, such as tetrahydrocannabinol (THC).

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“…As such, metabolic rewiring designs are necessary to increase flux towards essential metabolites, for example, overexpressing native pathways [ 2 , 3 ], inhibition of competing pathways [ 4 ], increasing Coenzyme A (CoA) availability [ 5 ], and construction of pyruvate dehydrogenase bypass. Many strategies have been applied to improve production of chemicals [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Fine tuning the glycolytic flux ratio of EP-bifido pathway for mevalonate production by enhancing glucose-6-phosphate dehydrogenase (Zwf) and CRISPRi suppressing 6-phosphofructose kinase (PfkA) in Escherichia coli

Liu

Xian

et al. 2021

Microb Cell Fact

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Background Natural glycolysis encounters the decarboxylation of glucose partial oxidation product pyruvate into acetyl-CoA, where one-third of the carbon is lost at CO2. We previously constructed a carbon saving pathway, EP-bifido pathway by combining Embden-Meyerhof-Parnas Pathway, Pentose Phosphate Pathway and “bifid shunt”, to generate high yield acetyl-CoA from glucose. However, the carbon conversion rate and reducing power of this pathway was not optimal, the flux ratio of EMP pathway and pentose phosphate pathway (PPP) needs to be precisely and dynamically adjusted to improve the production of mevalonate (MVA). Result Here, we finely tuned the glycolytic flux ratio in two ways. First, we enhanced PPP flux for NADPH supply by replacing the promoter of zwf on the genome with a set of different strength promoters. Compared with the previous EP-bifido strains, the zwf-modified strains showed obvious differences in NADPH, NADH, and ATP synthesis levels. Among them, strain BP10BF accumulated 11.2 g/L of MVA after 72 h of fermentation and the molar conversion rate from glucose reached 62.2%. Second, pfkA was finely down-regulated by the clustered regularly interspaced short palindromic repeats interference (CRISPRi) system. The MVA yield of the regulated strain BiB1F was 8.53 g/L, and the conversion rate from glucose reached 68.7%. Conclusion This is the highest MVA conversion rate reported in shaken flask fermentation. The CRISPRi and promoter fine-tuning provided an effective strategy for metabolic flux redistribution in many metabolic pathways and promotes the chemicals production.

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Metabolic Engineering Design Strategies for Increasing Acetyl-CoA Flux

Cited by 44 publications

References 79 publications

The remodel of the “central dogma”: a metabolomics interaction perspective

The remodel of the “central dogma”: a metabolomics interaction perspective

Metabolic Engineering Strategies of Industrial Hemp (Cannabis sativa L.): A Brief Review of the Advances and Challenges

Fine tuning the glycolytic flux ratio of EP-bifido pathway for mevalonate production by enhancing glucose-6-phosphate dehydrogenase (Zwf) and CRISPRi suppressing 6-phosphofructose kinase (PfkA) in Escherichia coli

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