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39. Engineering precursor supply for the high-level production of ergothioneine in Saccharomyces cerevisiae

Author

Hoek, Steven A.van der, Rusnák, Matej, Wang, Guokun, Stanchev, Lyubomir Dimitrov, de Fátima Alves, Luana, Jessop-Fabre, Mathew M., Paramasivan, Kalaivani, Jacobsen, Irene Hjorth, Sonnenschein, Nikolaus, Martínez, José L., Darbani, Behrooz, Kell, Douglas B., Borodina, Irina, Hoek, Steven A.van der, Rusnák, Matej, Wang, Guokun, Stanchev, Lyubomir Dimitrov, de Fátima Alves, Luana, Jessop-Fabre, Mathew M., Paramasivan, Kalaivani, Jacobsen, Irene Hjorth, Sonnenschein, Nikolaus, Martínez, José L., Darbani, Behrooz, Kell, Douglas B., and Borodina, Irina

Abstract

Ergothioneine (ERG) is an unusual sulfur-containing amino acid. It is a potent antioxidant, which shows great potential for ameliorating neurodegenerative and cardiovascular diseases. L-ergothioneine is rare in nature, with mushrooms being the primary dietary source. The chemical synthesis process is complex and expensive. Alternatively, ERG can be produced by fermentation of recombinant microorganisms engineered for ERG overproduction. Here, we describe the engineering of S. cerevisiae for high-level ergothioneine production on minimal medium with glucose as the only carbon source. To this end, metabolic engineering targets in different layers of the amino acid metabolism were selected based on literature and tested. Out of 28 targets, nine were found to improve ERG production significantly by 10%–51%. These targets were then sequentially implemented to generate an ergothioneine-overproducing yeast strain capable of producing 106.2 ± 2.6 mg/L ERG in small-scale cultivations. Transporter engineering identified that the native Aqr1 transporter was capable of increasing the ERG production in a yeast strain with two copies of the ERG biosynthesis pathway, but not in the strain that was further engineered for improved precursor supply. Medium optimization indicated that additional supplementation of pantothenate improved the strain's productivity further and that no supplementation of amino acid precursors was necessary. Finally, the engineered strain produced 2.39 ± 0.08 g/L ERG in 160 h (productivity of 14.95 ± 0.49 mg/L/h) in a controlled fed-batch fermentation without supplementation of amino acids. This study paves the way for the low-cost fermentation-based production of ergothioneine.

Published
2022

40. An integrated yeast-based process for cis,cis-muconic acid production

Author

Wang, Guokun, Tavares, Aline, Schmitz, Simone, França, Lucas, Almeida, Hugo, Cavalheiro, João, Carolas, Ana, Øzmerih, Süleyman, Blank, Lars M, Ferreira, Bruno S, Borodina, Irina, Wang, Guokun, Tavares, Aline, Schmitz, Simone, França, Lucas, Almeida, Hugo, Cavalheiro, João, Carolas, Ana, Øzmerih, Süleyman, Blank, Lars M, Ferreira, Bruno S, and Borodina, Irina

Abstract

Cis,cis-muconic acid (CCM) is a promising polymer building block. CCM can be made by whole-cell bioconversion of lignin hydrolysates or de novo biosynthesis from sugar feedstocks using engineered microorganisms. At present, however, there is no established process for large-scale CCM production. In this study, we developed an integrated process for manufacturing CCM from glucose by yeast fermentation. We systematically engineered the CCM-producing Saccharomyces cerevisiae strain by rewiring the shikimate pathway flux and enhancing phosphoenolpyruvate supply. The engineered strain ST10209 accumulated less biomass but produced 1.4 g/L CCM (70 mg CCM per g glucose) in microplate assay, 71% more than the previously engineered strain ST8943. The strain ST10209 produced 22.5 g/L CCM in a 2 L fermenter with a productivity of 0.19 g/L/h, compared to 0.14 g/L/h achieved by ST8943 in our previous report under the same fermentation conditions. The fermentation process was demonstrated at pilot scale in 10 L and 50 L steel tanks. In 10 L fermenter, ST10209 produced 20.8 g/L CCM with a CCM yield of 0.1 g/g glucose and a productivity of 0.21 g/L/h, representing the highest to-date CCM yield and productivity. We developed a CCM recovery and purification process by treating the fermentation broth with activated carbon at low pH and low temperature, achieving an overall CCM recovery yield of 66.3% and 95.4% purity. In summary, we report an integrated CCM production process employing engineered S. cerevisiae yeast. This article is protected by copyright. All rights reserved.

Published
2022

42. The Combination of Feature Tracking and Late Gadolinium Enhancement for Identification Between Hypertrophic Cardiomyopathy and Hypertensive Heart Disease

Author

Liu, Shengliang, primary, Li, Yunling, additional, Zhao, Yanming, additional, Wang, Xueying, additional, Wu, Zhiyuan, additional, Gu, Xia, additional, Xu, Bing, additional, Li, Ye, additional, Tian, Jinwei, additional, Cui, Jinjin, additional, Wang, Guokun, additional, and Yu, Bo, additional

Published
2022
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47. Molecular imaging of fibroblast activity in pressure overload heart failure using [68 Ga]Ga-FAPI-04 PET/CT.

Author

Wang, Guokun, Yang, Qinqin, Wu, Shengyong, Xu, Xudong, Li, Xiao, Liang, Siyu, Pan, Guixia, Zuo, Changjing, Zhao, Xianxian, Cheng, Chao, and Liu, Suxuan

Subjects
*FIBROBLASTS, *HEART failure patients, *MOLECULAR diagnosis, *POSITRON emission tomography, *HEART fibrosis
Abstract

Purpose: We aimed to evaluate whether [68 Ga]Ga-FAPI-04 PET/CT could characterize the early stages of cardiac fibrosis in pressure overload heart failure. Methods: Sprague–Dawley rats underwent abdominal aortic constriction (AAC) (n = 12) and sham surgery (n = 10). All rats were scanned with [68 Ga]Ga-FAPI-04 PET/CT at 2, 4, and 8 weeks after surgery. The expression of fibroblast activation protein (FAP) in the myocardium was detected by immunohistochemistry. [68 Ga]Ga-FAPI-04 PET signal and FAP expression were compared between two groups. Results: Compared with the sham group, the AAC group presented with decreased ejection fraction (EF) and fractional shortening (FS) and increased left ventricular internal dimensions in diastole (LVIDd) and systole (LVIDs) at 4 and 8 weeks (all p < 0.01). The AAC group showed higher [68 Ga]Ga-FAPI-04 accumulation in the heart than the sham group at 2, 4, and 8 weeks, and FAPI increased significantly from 2 to 8 weeks (all p < 0.001). Immunohistochemistry confirmed the higher density of the FAP+ area in the AAC group. The intensity of the [68 Ga]Ga-FAPI-04 correlated with the density of the FAP+ area (p < 0.001). The expression of the [68 Ga]Ga-FAPI-04 at 4 weeks correlated with the deterioration of cardiac function at 8 weeks (EF: R = − 0.87; FS: R = − 0.72; LVIDd: R = 0.77; LVIDs: R = 0.79; all p < 0.001). The AAC group also showed an increased [68 Ga]Ga-FAPI-04 signal in the liver, peaking at 4 weeks and then declining. Cardiac and liver PET signals correlated at 4 weeks in the AAC group (R = 0.69, p = 0.0010), suggesting an early fibrotic link between organs. A combination of the [68 Ga]Ga-FAPI-04 intensity in the heart and liver at 4 weeks better predicted the deterioration of cardiac function at 8 weeks. Conclusions: The activated fibroblasts in the heart and liver after pressure overload can be monitored by [68 Ga]Ga-FAPI-04 PET/CT, which reveals an early fibrotic link in cardio-liver interactions and could better predict nonischemic heart failure prognosis. [ABSTRACT FROM AUTHOR]

Published
2023
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