cell factories
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Author(s):  
Timothy C. Cairns ◽  
Xiaomei Zheng ◽  
Claudia Feurstein ◽  
Ping Zheng ◽  
Jibin Sun ◽  
...  

Submerged fermentation using filamentous fungal cell factories is used to produce a diverse portfolio of useful molecules, including food, medicines, enzymes, and platform chemicals. Depending on strain background and abiotic culture conditions, different macromorphologies are formed during fermentation, ranging from dispersed hyphal fragments to approximately spherical pellets several millimetres in diameter. These macromorphologies are known to have a critical impact on product titres and rheological performance of the bioreactor. Pilot productivity screens in different macromorphological contexts is technically challenging, time consuming, and thus a significant limitation to achieving maximum product titres. To address this bottleneck, we developed a library of conditional expression mutants in the organic, protein, and secondary metabolite cell factory Aspergillus niger. Thirteen morphology-associated genes transcribed during fermentation were placed via CRISPR-Cas9 under control of a synthetic Tet-on gene switch. Quantitative analysis of submerged growth reveals that these strains have distinct and titratable macromorphologies for use as chassis during strain engineering programs. We also used this library as a tool to quantify how pellet formation is connected with strain fitness and filamentous growth. Using multiple linear regression modelling, we predict that pellet formation is dependent largely on strain fitness, whereas pellet Euclidian parameters depend on fitness and hyphal branching. Finally, we have shown that conditional expression of the putative kinase encoding gene pkh2 can decouple fitness, dry weight, pellet macromorphology, and culture heterogeneity. We hypothesize that further analysis of this gene product and the cell wall integrity pathway in which it is embedded will enable more precise engineering of A. niger macromorphology in future.


2022 ◽  
Vol 12 ◽  
Author(s):  
Huijie Sun ◽  
Xinghua Cai ◽  
Bing Yan ◽  
Huashan Bai ◽  
Duotao Meng ◽  
...  

Investigating microbial lipid regulation contributes to understanding the lipid-dependent signal transduction process of cells and helps to improve the sensitivity of microorganisms to environmental factors by interfering with lipid metabolism, thus beneficial for constructing advanced cell factories of novel molecular drugs. Integrated omics technology was used to systematically reveal the lipid metabolism mechanism of a marine Meyerozyma guilliermondii GXDK6 under high NaCl stress and test the sensitivity of GXDK6 to antibiotics when its lipid metabolism transformed. The omics data showed that when GXDK6 perceived 10% NaCl stress, the expression of AYR1 and NADPH-dependent 1-acyldihydroxyacetone phosphate reductase was inhibited, which weaken the budding and proliferation of cell membranes. This finding was further validated by decreased 64.39% of OD600 under 10% NaCl stress when compared with salt-free stress. In addition, salt stress promoted a large intracellular accumulation of glycerol, which was also verified by exogenous addition of glycerol. Moreover, NaCl stress remarkably inhibited the expression of drug target proteins (such as lanosterol 14-alpha demethylase), thereby increasing sensitivity to fluconazole. This study provided new insights into the molecular mechanism involved in the regulation of lipid metabolism in Meyerozyma guilliermondii strain and contributed to developing new methods to improve the effectiveness of killing fungi with lower antibiotics.


Author(s):  
Yang Zhang ◽  
Xiao Guo ◽  
Huaiyi Yang ◽  
Shuobo Shi

Fatty acid alkyl esters have broad applications in biofuels, lubricant formulas, paints, coatings, and cosmetics. Traditionally, these esters are mostly produced through unsustainable and energy-intensive processes. In contrast, microbial production of esters from renewable and sustainable feedstocks may provide a promising alternative and has attracted widespread attention in recent years. At present, yeasts are used as ideal hosts for producing such esters, due to their availability for high-density fermentation, resistance to phage infection, and tolerance against toxic inhibitors. Here, we summarize recent development on the biosynthesis of alkyl esters, including fatty acid ethyl esters (FAEEs), fatty acid short-branched chain alkyl esters (FASBEs), and wax esters (WEs) by various yeast cell factories. We focus mainly on the enzyme engineering strategies of critical wax ester synthases, and the pathway engineering strategies employed for the biosynthesis of various ester products. The bottlenecks that limit productivity and their potential solutions are also discussed in this review.


2022 ◽  
Vol 8 (1) ◽  
pp. 51
Author(s):  
Maria Sousa-Silva ◽  
Pedro Soares ◽  
João Alves ◽  
Daniel Vieira ◽  
Margarida Casal ◽  
...  

The yeast Cyberlindnera jadinii has great potential in the biotechnology industry due to its ability to produce a variety of compounds of interest, including carboxylic acids. In this work, we identified genes encoding carboxylate transporters from this yeast species. The functional characterization of sixteen plasma membrane carboxylate transporters belonging to the AceTr, SHS, TDT, MCT, SSS, and DASS families was performed by heterologous expression in Saccharomyces cerevisiae. The newly identified C. jadinii transporters present specificity for mono-, di-, and tricarboxylates. The transporters CjAto5, CjJen6, CjSlc5, and CjSlc13-1 display the broadest substrate specificity; CjAto2 accepts mono- and dicarboxylates; and CjAto1,3,4, CjJen1-5, CjSlc16, and CjSlc13-2 are specific for monocarboxylic acids. A detailed characterization of these transporters, including phylogenetic reconstruction, 3D structure prediction, and molecular docking analysis is presented here. The properties presented by these transporters make them interesting targets to be explored as organic acid exporters in microbial cell factories.


2022 ◽  
pp. 985-1011
Author(s):  
Hemansi ◽  
Raj Kamal Vibhuti ◽  
Rishikesh Shukla ◽  
Rishi Gupta ◽  
Jitendra Kumar Saini

Nutraceuticals are the food ingredients which have a proven beneficial effect on human health. These include low calories sugars, proteins and vitamins B complex, etc. Microorganisms, such as Lactococcus lactis, are ideal microbial cell factories for the production of these nutraceuticals. Developments in the genetic engineering of food-grade microorganisms have been very helpful for enhanced production or overexpression of nutraceuticals. This chapter describes the use of food grade microorganisms in industrial production of nutraceuticals. The main emphasis is on industrial production of these beneficial nutraceuticals by food grade microorganism. The diversity of microbial cell types, various approaches for improved nutraceutical production through process optimization as well as strain improvement of the producing microorganisms are discussed.


eFood ◽  
2021 ◽  
Author(s):  
Haolin Zhang ◽  
Giovanni Caprioli ◽  
Hidayat Hussain ◽  
Nguyen Phan Khoi Le ◽  
Mohamed A. Farag ◽  
...  

Natural bioactive compounds present a better alternative to prevent and treat chronic diseases owing to their lower toxicity and abundant resources. (+)-Dihydromyricetin (DMY) is a flavanonol, possessing numerous interesting bioactivities with abundant resources. This review provides a comprehensive overview of the recent advances in DMY natural resources, stereoisomerism, physicochemical properties, extraction, biosynthesis, pharmacokinetics, and biotransformation. Stereoisomerism of DMY should be considered for better indication of its efficacy. Biotechnological approach presents a potential tool for the production of DMY using microbial cell factories. DMY high instability is related to its powerful antioxidant capacity due to pyrogallol moiety in ring B, and whether preparation of other analogues could demonstrate improved properties. DMY demonstrates poor bioavailability based on its low solubility and permeability with several attempts to improve its pharmacokinetics and efficacy. DMY possesses various pharmacological effects, which have been proven by many in vitro and in vivo experiments, while clinical trials are rather scarce, with underlying action mechanisms remaining unclear. Consequently, to maximize the usefulness of DMY in nutraceuticals, improvement in bioavailability, and better understanding of its actions mechanisms and drug interactions ought to be examined in the future along with more clinical evidence.


Author(s):  
Xiuyun Wu ◽  
Tao Wu ◽  
Ailin Huang ◽  
Yuanyuan Shen ◽  
Xuanyu Zhang ◽  
...  

Cordyceps militaris, a traditional medicinal ingredient with a long history of application in China, is regarded as a high-value fungus due to its production of various bioactive ingredients with a wide range of pharmacological effects in clinical treatment. Several typical bioactive ingredients, such as cordycepin, D-mannitol, cordyceps polysaccharides, and N6-(2-hydroxyethyl)-adenosine (HEA), have received increasing attention due to their antitumor, antioxidant, antidiabetic, radioprotective, antiviral and immunomodulatory activities. Here, we systematically sorted out the latest research progress on the chemical characteristics, biosynthetic gene clusters and pathways of these four typical bioactive ingredients. This summary will lay a foundation for obtaining low-cost and high-quality bioactive ingredients in large amounts using microbial cell factories in the future.


2021 ◽  
Vol 8 ◽  
Author(s):  
Peng-Wei Huang ◽  
Ying-Shuang Xu ◽  
Xiao-Man Sun ◽  
Tian-Qiong Shi ◽  
Yang Gu ◽  
...  

Schizochytrium sp. HX-308 is a marine microalga with fast growth and high lipid content, which has potential as microbial cell factories for lipid compound biosynthesis. It is significant to develop efficient genetic editing tool and discover molecular target in Schizochytrium sp. HX-308 for lipid compound biosynthesis. In this study, we developed an efficient gene editing tool in HX-308 which was mediated by Agrobacterium tumefaciens AGL-1. Results showed that the random integration efficiency reached 100%, and the homologous recombination efficiency reached about 30%. Furthermore, the metabolic pathway of lipid and terpenoid biosynthesis were engineered. Firstly, the acetyl-CoA c-acetyltransferase was overexpressed in HX-308 with a strong constitutive promoter. With the overexpression of acetyl-CoA c-acetyltransferase, more acetyl-CoA was used to synthesize terpenoids, and the production of squalene, β-carotene and astaxanthin was increased 5.4, 1.8, and 2.4 times, respectively. Interestingly, the production of saturated fatty acids and polyunsaturated fatty acids also changed. Moreover, three Acyl-CoA oxidase genes which catalyze the first step of β-oxidation were knocked out using homologous recombination. Results showed that the production of lipids increased in the three knock-out strains. Our results demonstrated that the A. tumefaciens-mediated transformation method will be of great use for the study of function genes, as well as developing Schizochytrium sp. as a strong cell factory for producing high value products.


2021 ◽  
Author(s):  
Bobo Liang ◽  
Rongzhan Fu ◽  
Yingqun Ma ◽  
Lizhen Hu ◽  
Qiang Fei ◽  
...  

Abstract BackgroundThe dramatic increase in emissions of greenhouse gases (GHGs) has led to an irreversible effect on the ecosystem, which in turn caused significant harm to human beings and other species. Exploring innovative and effective approaches to neutralizing GHGs is urgently needed. Considering the advancement of synthetic biology and the bioconversion process, C1-utilizing cell factories (CUCFs) have been modified to be able to effectively convert C1-gases includes biogas, natural gas, and carbon dioxide (CO2) into chemicals or fuels via biological routes, which greatly facilitates the inedible carbon sources used in biomanufacturing, increases the potential value of GHGs and meanwhile reduces the GHG emissions. Process design and resultsEven though the current experimental results are satisfactory in lab-scale research, the evaluation of economic feasibility as well as applications of CUCFs in industrial-scale still need to be analyzed. This study designed three scenarios of CUCFs-based conversion of biogas, natural gas, and CO2 into isobutanol, the detailed techno-economic analyses of these scenarios were conducted with the comparisons of capital cost, operating cost, and minimum isobutanol selling price (MISP). Results revealed that direct bio-conversion of CO2 by CUCFs into isobutanol exhibited the best economic performance with a MISP of $1.38/kg isobutanol. The single sensitivity analysis showed that the gas utilization rate, flow rate, and CO2 cost are the three most significant economic-driving forces on MISP of CO2-derived biological isobutanol. Multiple-point sensitivity analysis presented that the MISP for the long-term case can be as low as 0.99 $/kg with using ideal targets. ConclusionsOur findings provide a comprehensive assessment of bio-conversion of C1-gases via CUCFs to isobutanol in terms of the bioprocess design, mass/energy calculation, capital investment, operating expense, sensitivity analysis, and environmental impact. It is expected that this study may lead to the paradigm shift in isobutanol synthesis with C1-gases as substrates.


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