Cell Factories of Higher Fungi for Useful Metabolite Production

Qin, Hao; Xu, Junwei; Xiao, Jian‐Hui; Tang, Ya‐Jie; Xiao, Han; Zhong, Jian‐Jiang

doi:10.1007/10_2015_335

Cited by 7 publications

(26 citation statements)

References 186 publications

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“…The overexpression of multiple genes in the GA biosynthetic pathway may considerably increase GA production. , We investigated the effect of simultaneously overexpressing SE and HMGR genes on GA production in G. lingzhi . The pJW-EXP-HMGR and pJW-EXP-SE plasmids were cotransformed into G. lingzhi protoplasts.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Considerable efforts have been made to enhance GA production in the submerged cultivation of G. lucidum , such as the optimization of cultivation conditions, ,− addition of elicitors, − and development of bioprocessing strategies. − A highly productive G. lingzhi strain may allow for the sustainable and large-scale production of valuable secondary metabolites. Genetically engineering G. lucidum has been recently reported as an effective approach to increase GA production. ,, For instance, homologous overexpression of GA biosynthetic genes and the heterologous expression of the Vitreoscilla hemoglobin gene in G. lucidum significantly increased GA production. , HMGR, SQS, and LS gene overexpression implicate important roles of these genes in the regulation of GA biosynthesis in G. lingzhi . ,,, Genetic manipulation of GA biosynthetic genes is crucial in elucidating the regulation of GA biosynthesis and enhancement of GA production.…”

Section: Introductionmentioning

confidence: 99%

“…Genetically engineering G. lucidum has been recently reported as an effective approach to increase GA production. 10,27,29 For instance, homologous overexpression of GA biosynthetic genes and the heterologous expression of the Vitreoscilla hemoglobin gene in G. lucidum significantly increased GA production. 10,28 HMGR, SQS, and LS gene overexpression implicate important roles of these genes in the regulation of GA biosynthesis in G. lingzhi.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of the Squalene Epoxidase Gene Alone and in Combination with the 3-Hydroxy-3-methylglutaryl Coenzyme A Gene Increases Ganoderic Acid Production in Ganoderma lingzhi

Zhang

Lei

et al. 2017

J. Agric. Food Chem.

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The squalene epoxidase (SE) gene from the biosynthetic pathway of ganoderic acid (GA) was cloned and overexpressed in Ganoderma lingzhi. The strain that overexpressed the SE produced approximately 2 times more GA molecules than the wild-type (WT) strain. Moreover, SE overexpression upregulated lanosterol synthase gene expression in the biosynthetic pathway. These results indicated that SE stimulates GA accumulation. Then, the SE and 3-hydroxy-3-methylglutaryl coenzyme A (HMGR) genes were simultaneously overexpressed in G. lingzhi. Compared with the individual overexpression of SE or HMGR, the combined overexpression of the two genes further enhanced individual GA production. The overexpressing strain produced maximum GA-T, GA-S, GA-Mk, and GA-Me contents of 90.4 ± 7.5, 35.9 ± 5.4, 6.2 ± 0.5, and 61.8 ± 5.8 μg/100 mg dry weight, respectively. These values were 5.9, 4.5, 2.4, and 5.8 times higher than those produced by the WT strain. This is the first example of the successful manipulation of multiple biosynthetic genes to improve GA content in G. lingzhi.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Overexpression of the Squalene Epoxidase Gene Alone and in Combination with the 3-Hydroxy-3-methylglutaryl Coenzyme A Gene Increases Ganoderic Acid Production in Ganoderma lingzhi

Zhang

Lei

et al. 2017

J. Agric. Food Chem.

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“…Since genome data makes discovering and analyzing the biosynthesis of bioactive metabolites easier in higher fungi, chances for conducting research and developing their metabolic products can be provided by advancements in genome sequencing [ 129 ]. Up until now, genomic information of some edible/medicinal mushrooms including, A. bisporus [ 130 ], V. volvacea [ 23 ], Schizophyllum commune [ 131 ], F. velutipes [ 132 ], H. erinaceus [ 133 ] , G. lucidum [ 134 ], C. militaris [ 138 ] , Lignosus rhinocerotis [ 135 ] , Ganoderma sinense [ 139 ] , and Sanghuangporus sanghuang [ 140 ] has become available and resulted in gaining new insights into various aspects.…”

Section: Genomics Studies On Different Medicinal Mushroomsmentioning

confidence: 99%

Increasing the production of the bioactive compounds in medicinal mushrooms: an omics perspective

2023

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Macroscopic fungi, mainly higher basidiomycetes and some ascomycetes, are considered medicinal mushrooms and have long been used in different areas due to their pharmaceutically/nutritionally valuable bioactive compounds. However, the low production of these bioactive metabolites considerably limits the utilization of medicinal mushrooms both in commerce and clinical trials. As a result, many attempts, ranging from conventional methods to novel approaches, have been made to improve their production. The novel strategies include conducting omics investigations, constructing genome-scale metabolic models, and metabolic engineering. So far, genomics and the combined use of different omics studies are the most utilized omics analyses in medicinal mushroom research (both with 31% contribution), while metabolomics (with 4% contribution) is the least. This article is the first attempt for reviewing omics investigations in medicinal mushrooms with the ultimate aim of bioactive compound overproduction. In this regard, the role of these studies and systems biology in elucidating biosynthetic pathways of bioactive compounds and their contribution to metabolic engineering will be highlighted. Also, limitations of omics investigations and strategies for overcoming them will be provided in order to facilitate the overproduction of valuable bioactive metabolites in these valuable organisms.

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“…Higher fungi have versatile life-cycles and complex metabolisms that enable adaption to many environmental conditions and thus they are important sources of interesting secondary metabolites such as polyketides, non-ribosomal peptides, terpenes and others [ 1 , 2 ]. They are valuable producers of enzymes, organic acids, nutraceuticals, agrochemicals, and pharmaceuticals such as lefamulin, a pleuromutilin derivative recently launched for the treatment of community-acquired pneumonia [ 3 – 5 ].…”

Section: Introductionmentioning

confidence: 99%

Optimization of the production process for the anticancer lead compound illudin M: improving titers in shake-flasks

2022

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Background The fungal sesquiterpenes Illudin M and S are important base molecules for the development of new anticancer agents due to their strong activity against some resistant tumor cell lines. Due to nonspecific toxicity of the natural compounds, improvement of the pharmacophore is required. A semisynthetic derivative of illudin S (Irofulven) entered phase II clinical trials for the treatment of castration-resistant metastatic prostate cancer. Several semisynthetic illudin M derivatives showed increased in vitro selectivity and improved therapeutic index against certain tumor cell lines, encouraging further investigation. This requires a sustainable supply of the natural compound, which is produced by Basidiomycota of the genus Omphalotus. We aimed to develop a robust biotechnological process to deliver illudin M in quantities sufficient to support medicinal chemistry studies and future preclinical and clinical development. In this study, we report the initial steps towards this goal. Results After establishing analytical workflows, different culture media and commercially available Omphalotus strains were screened for the production of illudin M.Omphalotus nidiformis cultivated in a medium containing corn steep solids reached ~ 38 mg L−1 setting the starting point for optimization. Improved seed preparation in combination with a simplified medium (glucose 13.5 g L−1; corn steep solids 7.0 g L− 1; Dox broth modified 35 mL), reduced cultivation time and enhanced titers significantly (~ 400 mg L−1). Based on a reproducible cultivation method, a feeding strategy was developed considering potential biosynthetic bottlenecks. Acetate and glucose were fed at 96 h (8.0 g L−1) and 120 h (6.0 g L−1) respectively, which resulted in final illudin M titer of ~ 940 mg L−1 after eight days. This is a 25 fold increase compared to the initial titer. Conclusion After strict standardization of seed-preparation and cultivation parameters, a combination of experimental design, empirical trials and additional supply of limiting biosynthetic precursors, led to a highly reproducible process in shake flasks with high titers of illudin M. These findings are the base for further work towards a scalable biotechnological process for a stable illudin M supply.

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Cell Factories of Higher Fungi for Useful Metabolite Production

Cited by 7 publications

References 186 publications

Overexpression of the Squalene Epoxidase Gene Alone and in Combination with the 3-Hydroxy-3-methylglutaryl Coenzyme A Gene Increases Ganoderic Acid Production in Ganoderma lingzhi

Overexpression of the Squalene Epoxidase Gene Alone and in Combination with the 3-Hydroxy-3-methylglutaryl Coenzyme A Gene Increases Ganoderic Acid Production in Ganoderma lingzhi

Increasing the production of the bioactive compounds in medicinal mushrooms: an omics perspective

Optimization of the production process for the anticancer lead compound illudin M: improving titers in shake-flasks

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