scholarly journals Microbial Biosynthesis of L-Malic Acid and Related Metabolic Engineering Strategies: Advances and Prospects

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhen Wei ◽  
Yongxue Xu ◽  
Qing Xu ◽  
Wei Cao ◽  
He Huang ◽  
...  
Keyword(s):  
Metabolic Engineering ◽  
Malic Acid ◽  
Acid Production ◽  
Large Scale ◽  
Rapid Development ◽  
Tca Cycle ◽  
Dominant Mode ◽  
Comprehensive Overview ◽  
Recent Developments ◽  
Microbial Biosynthesis

Malic acid, a four-carbon dicarboxylic acid, is widely used in the food, chemical and medical industries. As an intermediate of the TCA cycle, malic acid is one of the most promising building block chemicals that can be produced from renewable sources. To date, chemical synthesis or enzymatic conversion of petrochemical feedstocks are still the dominant mode for malic acid production. However, with increasing concerns surrounding environmental issues in recent years, microbial fermentation for the production of L-malic acid was extensively explored as an eco-friendly production process. The rapid development of genetic engineering has resulted in some promising strains suitable for large-scale bio-based production of malic acid. This review offers a comprehensive overview of the most recent developments, including a spectrum of wild-type, mutant, laboratory-evolved and metabolically engineered microorganisms for malic acid production. The technological progress in the fermentative production of malic acid is presented. Metabolic engineering strategies for malic acid production in various microorganisms are particularly reviewed. Biosynthetic pathways, transport of malic acid, elimination of byproducts and enhancement of metabolic fluxes are discussed and compared as strategies for improving malic acid production, thus providing insights into the current state of malic acid production, as well as further research directions for more efficient and economical microbial malic acid production.

scholarly journals Investigation of Malic Acid Production in Aspergillus oryzae under Nitrogen Starvation Conditions

2013 ◽  
Vol 79 (19) ◽  
pp. 6050-6058 ◽  
Author(s):  
Christoph Knuf ◽  
Intawat Nookaew ◽  
Stephen H. Brown ◽  
Michael McCulloch ◽  
Alan Berry ◽  
...  
Keyword(s):  
Malic Acid ◽  
Acid Production ◽  
Large Scale ◽  
High Capacity ◽  
Nitrogen Sources ◽  
Building Blocks ◽  
Close Relative ◽  
Biotechnological Production ◽  
Content Type ◽  
The One

ABSTRACTMalic acid has great potential for replacing petrochemical building blocks in the future. For this application, high yields, rates, and titers are essential in order to sustain a viable biotechnological production process. Natural high-capacity malic acid producers like the malic acid producerAspergillus flavushave so far been disqualified because of special growth requirements or the production of mycotoxins. AsA. oryzaeis a very close relative or even an ecotype ofA. flavus, it is likely that its high malic acid production capabilities with a generally regarded as safe (GRAS) status may be combined with already existing large-scale fermentation experience. In order to verify the malic acid production potential, two wild-type strains, NRRL3485 and NRRL3488, were compared in shake flasks. As NRRL3488 showed a volumetric production rate twice as high as that of NRRL3485, this strain was selected for further investigation of the influence of two different nitrogen sources on malic acid secretion. The cultivation in lab-scale fermentors resulted in a higher final titer, 30.27 ± 1.05 g liter−1, using peptone than the one of 22.27 ± 0.46 g liter−1obtained when ammonium was used. Through transcriptome analysis, a binding site similar to the one of theSaccharomyces cerevisiaeyeast transcription factor Msn2/4 was identified in the upstream regions of glycolytic genes and the cytosolic malic acid production pathway from pyruvate via oxaloacetate to malate, which suggests that malic acid production is a stress response. Furthermore, the pyruvate carboxylase reaction was identified as a target for metabolic engineering, after it was confirmed to be transcriptionally regulated through the correlation of intracellular fluxes and transcriptional changes.

scholarly journals Metabolic engineering of Ustilago trichophora TZ1 for improved malic acid production

2017 ◽  
Vol 4 ◽  
pp. 12-21 ◽  
Author(s):  
Thiemo Zambanini ◽  
Hamed Hosseinpour Tehrani ◽  
Elena Geiser ◽  
Christiane K. Sonntag ◽  
Joerg M. Buescher ◽  
...  
Keyword(s):  
Metabolic Engineering ◽  
Malic Acid ◽  
Acid Production

scholarly journals Metabolic Engineering of Actinobacillus succinogenes Provides Insights into Succinic Acid Biosynthesis

2017 ◽  
Vol 83 (17) ◽  
Author(s):  
Michael T. Guarnieri ◽  
Yat-Chen Chou ◽  
Davinia Salvachúa ◽  
Ali Mohagheghi ◽  
Peter C. St. John ◽  
...  
Keyword(s):  
Metabolic Engineering ◽  
Succinic Acid ◽  
Acid Production ◽  
Tca Cycle ◽  
Economic Feasibility ◽  
High Yield ◽  
Actinobacillus Succinogenes ◽  
Acid Biosynthesis ◽  
Content Type ◽  
Succinic Acid Production

ABSTRACT Actinobacillus succinogenes, a Gram-negative facultative anaerobe, exhibits the native capacity to convert pentose and hexose sugars to succinic acid (SA) with high yield as a tricarboxylic acid (TCA) cycle intermediate. In addition, A. succinogenes is capnophilic, incorporating CO2 into SA, making this organism an ideal candidate host for conversion of lignocellulosic sugars and CO2 to an emerging commodity bioproduct sourced from renewable feedstocks. In this work, we report the development of facile metabolic engineering capabilities in A. succinogenes, enabling examination of SA flux determinants via knockout of the primary competing pathways—namely, acetate and formate production—and overexpression of the key enzymes in the reductive branch of the TCA cycle leading to SA. Batch fermentation experiments with the wild-type and engineered strains using pentose-rich sugar streams demonstrate that the overexpression of the SA biosynthetic machinery (in particular, the enzyme malate dehydrogenase) enhances flux to SA. Additionally, removal of competitive carbon pathways leads to higher-purity SA but also triggers the generation of by-products not previously described from this organism (e.g., lactic acid). The resultant engineered strains also lend insight into energetic and redox balance and elucidate mechanisms governing organic acid biosynthesis in this important natural SA-producing microbe. IMPORTANCE Succinic acid production from lignocellulosic residues is a potential route for enhancing the economic feasibility of modern biorefineries. Here, we employ facile genetic tools to systematically manipulate competing acid production pathways and overexpress the succinic acid-producing machinery in Actinobacillus succinogenes. Furthermore, the resulting strains are evaluated via fermentation on relevant pentose-rich sugar streams representative of those from corn stover. Overall, this work demonstrates genetic modifications that can lead to succinic acid production improvements and identifies key flux determinants and new bottlenecks and energetic needs when removing by-product pathways in A. succinogenes metabolism.

scholarly journals The opportunities and challenges of mobile and ubiquitous learning for future schools: A context of Thailand

2018 ◽  
pp. 485-506
Keyword(s):  
Mobile Devices ◽  
Large Scale ◽  
Rapid Development ◽  
Mobile Technologies ◽  
Learning Approach ◽  
Traditional Teaching ◽  
Ubiquitous Learning ◽  
Case Examples ◽  
Recent Developments ◽  
Innovative Learning

Today’s new digital technologies and the spread of the internet have created numerous new opportunities and challenges for the education of the future. The rapid development of mobile and ubiquitous computing technology offered more chances to design and develop innovative learning approach with mobile devices in preparing schools and students for a future. In this paper we present case examples and the research results and reflections based on our recent developments and experiences in Thailand regarding how novel pedagogical applications, mobile technologies and software tools can be combined to enhanced students’ learning at all level of education. To the end, we propose a possible direction for the transformation of traditional teaching in science to a novel of mobile and ubiquitous learning in an on-going large-scale educational project in Thailand. This is a challenge of our educational improvement to introduce the novel mobile-assisted learning approach, with the support of mobile devices, into classroom settings, innovative instructional practices and sustainability as the way of future schools in context of Thailand.

scholarly journals Metabolic engineering of Saccharomyces cerevisiae for enhanced production of caffeic acid

2020 ◽  
Author(s):  
Pingping Zhou ◽  
Chunlei Yue ◽  
Bin Shen ◽  
Yi Du ◽  
Nannan Xu ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Metabolic Engineering ◽  
Caffeic Acid ◽  
Acid Production ◽  
De Novo ◽  
Feedback Inhibition ◽  
Biological Activities ◽  
Acid Product ◽  
Enhanced Production ◽  
Microbial Biosynthesis

Abstract Background As a natural phenolic acid product of plant source, caffeic acid displays diverse biological activities and acts as an important precursor for the synthesis of other valuable compounds. Limitations in chemical synthesis or plant extraction of caffeic acid trigger interest in its microbial biosynthesis. Recently, Saccharomyces cerevisiae has been reported sporadically for biosynthesis of caffeic acid via free plasmid‑mediated pathway assembly. However, the production was far from satisfactory and even relied on the addition of precursor. Results In this study, we first established a controllable caffeic acid pathway by employing a modified GAL regulatory system in S. cerevisiae and realized de novo biosynthesis of 313.8 mg/L caffeic acid from glucose. Combinatorial engineering strategies including eliminating the tyrosine-induced feedback inhibition, deleting genes involved in competing pathways and overexpressing rate-limiting enzymes led to about 2.5-fold improvement in the caffeic acid production, reaching up to 769.3 mg/L in shake-flask cultures. To our knowledge, this is the highest ever reported titer of caffeic acid de novo synthesized by engineered yeast. Conclusions Caffeic acid production in S. cerevisiae strain was successfully improved by adopting a glucose-regulated GAL system and comprehensive metabolic engineering strategies. This work showed the prospect for microbial biosynthesis of caffeic acid and laid the foundation for constructing biosynthetic pathways of its derived metabolites.

scholarly journals GeneReg: A constraint-based approach for design of feasible metabolic engineering strategies at the gene level

2020 ◽  
Author(s):  
Zahra Razaghi-Moghadam ◽  
Zoran Nikoloski
Keyword(s):  
Gene Expression ◽  
Metabolic Engineering ◽  
Large Scale ◽  
Metabolic Networks ◽  
Tca Cycle ◽  
Growth Conditions ◽  
Knock Out ◽  
Cell Factories ◽  
Gene Level ◽  
Tca Cycle Intermediates

Abstract Motivation Large-scale metabolic models are widely used to design metabolic engineering strategies for diverse biotechnological applications. However, the existing computational approaches focus on alteration of reaction fluxes and often neglect the manipulations of gene expression to implement these strategies. Results Here we find that the association of genes with multiple reactions leads to infeasibility of engineering strategies at the flux level, since they require contradicting manipulations of gene expression. Moreover, we identify that all of the existing approaches to design gene knock-out strategies do not ensure that the resulting design may also require other gene alterations, such as up- or down-regulations, to match the desired flux distribution. To address these issues, we propose a constraint-based approach, termed GeneReg, that facilitates the design of feasible metabolic engineering strategies at the gene level and that is readily applicable to large-scale metabolic networks. We show that GeneReg can identify feasible strategies to overproduce ethanol in Escherichia coli and lactate in Saccharomyces cerevisiae, but overproduction of the TCA cycle intermediates is not feasible in five organisms used as cell factories under default growth conditions. Therefore, GeneReg points at the need to couple gene regulation and metabolism to design rational metabolic engineering strategies. Availability https://github.com/MonaRazaghi/GeneReg

Metabolic engineering of Pichia pastoris for malic acid production from methanol

2020 ◽  
Vol 118 (1) ◽  
pp. 357-371
Author(s):  
Feng Guo ◽  
Zhongxue Dai ◽  
Wenfang Peng ◽  
Shangjie Zhang ◽  
Jie Zhou ◽  
...  
Keyword(s):  
Metabolic Engineering ◽  
Pichia Pastoris ◽  
Malic Acid ◽  
Acid Production

Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease

2020 ◽  
Vol 17 (2) ◽  
pp. 141-157 ◽  
Author(s):  
Dubravka S. Strac ◽  
Marcela Konjevod ◽  
Matea N. Perkovic ◽  
Lucija Tudor ◽  
Gordana N. Erjavec ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Therapeutic Potential ◽  
Relevant Literature ◽  
Comprehensive Overview ◽  
Brain Functions ◽  
Specific Effects ◽  
And Behavior

Background: Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease. Objective: The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer’s disease. Method: PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles. Results: We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer’s disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications. Conclusion: Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer’s disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice.

Recent Developments in the Downstream Processing of Phycobiliproteins from Algae: A Review

2021 ◽  
Vol 06 ◽  
Author(s):  
Ayekpam Chandralekha Devi ◽  
G. K. Hamsavi ◽  
Simran Sahota ◽  
Rochak Mittal ◽  
Hrishikesh A. Tavanandi ◽  
...  
Keyword(s):  
Cell Wall ◽  
Large Scale ◽  
Downstream Processing ◽  
Review Article ◽  
Current Status ◽  
Wall Structure ◽  
Scale Production ◽  
Cell Wall Disruption ◽  
Recent Developments ◽  
Macro Algae

Abstract: Algae (both micro and macro) have gained huge attention in the recent past for their high commercial value products. They are the source of various biomolecules of commercial applications ranging from nutraceuticals to fuels. Phycobiliproteins are one such high value low volume compounds which are mainly obtained from micro and macro algae. In order to tap the bioresource, a significant amount of work has been carried out for large scale production of algal biomass. However, work on downstream processing aspects of phycobiliproteins (PBPs) from algae is scarce, especially in case of macroalgae. There are several difficulties in cell wall disruption of both micro and macro algae because of their cell wall structure and compositions. At the same time, there are several challenges in the purification of phycobiliproteins. The current review article focuses on the recent developments in downstream processing of phycobiliproteins (mainly phycocyanins and phycoerythrins) from micro and macroalgae. The current status, the recent advancements and potential technologies (that are under development) are summarised in this review article besides providing future directions for the present research area.

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