isocitric acid
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Fermentation ◽  
2021 ◽  
Vol 7 (4) ◽  
pp. 283
Author(s):  
Svetlana V. Kamzolova ◽  
Igor G. Morgunov

Isocitric acid (ICA) has found wide application in medicine as a promising compound with powerful antioxidant activity to combat oxidative stress. In the known microbiological processes of ICA production by non-conventional yeast Yarrowia lipolytica, the pure carbon sources are commonly used. ICA can be also synthetized by Y. lipolytica from ester-aldehyde fraction (EAF)-waste of the ethanol production process. A highly effective method of ICA production from EAF based on regulation of key enzymes (aconitate hydratase and isocitrate lyase) by metabolic regulators (iron and itaconic acid) and aeration was developed. It is recommended to cultivate Y. lipolytica VKM Y-2373 under nitrogen deficiency conditions, a high aeration (60% of air saturation), an addition of 15 mM itaconic acid, and 2.4 mg/L iron. Under optimal conditions, Y. lipolytica VKM Y-2373 produced 83 g/L ICA with isocitrate to citrate ratio of 4.1:1 and mass yield of 1.1 g/g. The putative mechanism of ICA overproduction from EAF by Y. lipolytica was suggested.


2021 ◽  
Author(s):  
Moongi Ji ◽  
Yunju Jo ◽  
Seung Joon Choi ◽  
Seong Min Kim ◽  
Kyoung Kon Kim ◽  
...  

Rationale: We performed targeted metabolomics with machine learning (ML)-based interpretation to identify metabolites that distinguish the progression of nonalcoholic fatty liver disease (NAFLD) in a cohort. Methods: We conducted plasma metabolomics analysis in healthy control subjects (n=25) and patients with NAFL (n=42) and nonalcoholic steatohepatitis (NASH, n=19) by gas chromatography-tandem mass spectrometry (MS/MS) and liquid chromatography-MS/MS as well as RNA sequencing (RNA-seq) analyses on liver tissues from patients with varying stages of NAFLD (n=12). The resulting metabolomic data were subjected to routine statistical and ML-based analyses and multiomics interpretation with RNA-seq data. Results: We found six metabolites that were significantly altered in NAFLD among 79 detected metabolites. Random-forest and multinomial logistic regression analyses showed that eight metabolites (glutamic acid, cis-aconitic acid, aspartic acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, myristoleic acid, and tyrosine) could distinguish the three groups. Then, the recursive partitioning and regression tree algorithm selected three metabolites (glutamic acid, isocitric acid, and aspartic acid) from these eight metabolites. With these three metabolites, we formulated an equation, the MetaNASH score that distinguished NASH with excellent performance. Finally, metabolic map construction and correlation assays integrating metabolomics data into the transcriptome datasets of the liver showed correlations between the concentration of plasma metabolites and the expression of enzymes governing metabolism and specific alterations of these correlations in NASH. Conclusions: We found several metabolites that distinguish NASH from non-NASH via metabolomics analysis and ML approaches, developed the MetaNASH score, and suggested the pathophysiologic implications of metabolite profiles in relation to NAFLD progression.


Fermentation ◽  
2021 ◽  
Vol 7 (3) ◽  
pp. 146
Author(s):  
Svetlana V. Kamzolova ◽  
Vladimir A. Samoilenko ◽  
Julia N. Lunina ◽  
Igor G. Morgunov

There is ever increasing evidence that isocitric acid can be used as a promising compound with powerful antioxidant activity to combat oxidative stress. This work demonstrates the possibility of using waste product from the alcohol industry (so-called ester-aldehyde fraction) for production of isocitric acid by yeasts. The potential producer of isocitric acid from this fraction, Yarrowia lipolytica VKM Y-2373, was selected by screening of various yeast cultures. The selected strain showed sufficient growth and good acid formation in media with growth-limiting concentrations of nitrogen, sulfur, phosphorus, and magnesium. A shortage of Fe2+ and Ca2+ ions suppressed both Y. lipolytica growth and formation of isocitric acid. The preferential synthesis of isocitric acid can be regulated by changing the nature and concentration of nitrogen source, pH of cultivation medium, and concentration of ester-aldehyde fraction. Experiments in this direction allowed us to obtain 65 g/L isocitric acid with a product yield (YICA) of 0.65 g/g in four days of cultivation.


Fermentation ◽  
2020 ◽  
Vol 6 (4) ◽  
pp. 112
Author(s):  
Svetlana V. Kamzolova ◽  
Vladimir A. Samoilenko ◽  
Julia N. Lunina ◽  
Igor G. Morgunov

The microbiological production of isocitric acid (ICA) is more preferable for its application in medicine and food, because the resulting product contains only the natural isomer—threo-DS. The aim of the present work was to study ICA production by yeast using sunflower oil as carbon source. 30 taxonomically different yeast strains were assessed for their capability for ICA production, and Y. lipolytica VKM Y-2373 was selected as a promising producer. It was found that ICA production required: the limitation of Y. lipolytica growth by nitrogen, phosphorus, sulfur or magnesium, and an addition of iron, activating aconitate hydratase, a key enzyme of isocitrate synthesis. Another regulatory approach capable to shift acid formation to a predominant ICA synthesis is the use of inhibitors (itaconic and oxalic acids), which blocks the conversion of isocitrate at the level of isocitrate lyase. It is recommended to cultivate Y. lipolytica VKM Y-2373 under nitrogen deficiency conditions with addition of 1.5 mg/L iron and 30 mM itaconic acid. Such optimized nutrition medium provides 70.6 g/L ICA with a ratio between ICA and citric acid (CA) equal 4:1, a mass yield (YICA) of 1.25 g/g and volume productivity (QICA) of 1.19 g/L·h.


Author(s):  
Evgeniya Y. Yuzbasheva ◽  
Pasquale Scarcia ◽  
Tigran V. Yuzbashev ◽  
Eugenia Messina ◽  
Iuliia M. Kosikhina ◽  
...  

2020 ◽  
Vol 12 (18) ◽  
pp. 7364 ◽  
Author(s):  
Piotr Hapeta ◽  
Magdalena Rakicka-Pustułka ◽  
Piotr Juszczyk ◽  
Małgorzata Robak ◽  
Waldemar Rymowicz ◽  
...  

Yarrowia lipolytica is a non-conventional yeast producing valuable compounds, such as citric acids, from renewable raw materials. This study investigated the impact of citrate synthase overexpression on the biosynthesis of citric and isocitric acid in Y. lipolytica. Two transformants of Y. lipolytica A101.1.31 strain (efficient citric acid producer), overexpressing CIT1 or CIT2 gene (encoding proteins with citrate synthase activity), were constructed. The results revealed that overexpression of either of these genes enhances citrate synthase activity. Additionally, the cit1 knockout strain was unable to use propionate as the sole carbon source, which proves that CIT1 gene encodes a dual activity protein–citrate and 2-methylcitrate synthase. In the overexpressing mutants, a significant increase in isocitric acid biosynthesis was observed. Both CIT1 and CIT2 overexpressing strains produced citric and isocitric acid from vegetable oil in a ratio close to 1 (CA/ICA ratio for wild-type strain was 4.12).


2020 ◽  
Vol 8 (4) ◽  
pp. 462 ◽  
Author(s):  
Igor G. Morgunov ◽  
Svetlana V. Kamzolova ◽  
Olga V. Karpukhina ◽  
Svetlana B. Bokieva ◽  
Julia N. Lunina ◽  
...  

Within this work, the microbial synthesis of (2R,3S)-isocitric acid (ICA), a metabolite of the nonconventional yeast Yarrowia lipolytica, from biodiesel waste, has been studied. The selected strain Y. lipolytica VKM Y-2373 synthesized ICA with citric acid (CA) as a byproduct. This process can be regulated by changing cultivation conditions. The maximal production of ICA with the minimal formation of the byproduct was provided by the use of a concentration of (NH4)2SO4 (6 g/L); the addition of biodiesel waste to cultivation medium in 20–60 g/L portions; maintaining the pH of the cultivation medium at 6, and degree of aeration between 25% and 60% of saturation. Itaconic acid at a concentration of 15 mM favorably influenced the production of ICA by the selected strain. The optimization of cultivation conditions allowed us to increase the concentration of ICA in the culture liquid from 58.32 to 90.2 g/L, the product yield (Y) by 40%, and the ICA/CA ratio from 1.1:1 to 3:1. Research on laboratory animals indicated that ICA counteracted the negative effect of ammonium molybdate (10−5 М) and lead diacetate (10−7 М) on the learning and spatial memory of rats, including those exposed to emotional stress.


Cephalalgia ◽  
2020 ◽  
Vol 40 (7) ◽  
pp. 735-747 ◽  
Author(s):  
Wei-Hsiang Hsu ◽  
Shuu-Jiun Wang ◽  
Yen-Ming Chao ◽  
Chao-Jung Chen ◽  
Yen-Feng Wang ◽  
...  

Background The pathophysiology of reversible cerebral vasoconstriction syndrome is unclear. An unbiased systems-based approach might help to illustrate the metabolite profiling and underlying pathophysiology. Methods Urine samples were collected from reversible cerebral vasoconstriction syndrome patients and matched controls recruited in Taipei Veterans General Hospital. 1H-Nuclear magnetic resonance was used to initially explore the metabolic profile, and liquid chromatography tandem mass spectrometry was then used to identify metabolic alterations in reversible cerebral vasoconstriction syndrome. Untargeted metabolite screening was randomly performed on 10 reversible cerebral vasoconstriction syndrome patients and 10 control subjects in the discovery phase. The selected untargeted metabolites were further validated on 47 reversible cerebral vasoconstriction syndrome patients during their ictal stage (with 40 of them having remission samples) and 47 controls in the replication phase. Results and conclusion Six metabolites-hippurate, citrate, 1,3,7-trimethyluric acid, ascorbic acid, D-glucurono-6,3-lactone, and D- threo-isocitric acid-with t-test derived p-value < 0.05 and VIP score >1, were identified as potential urine signatures that can well distinguish reversible cerebral vasoconstriction syndrome subjects at ictal stage from controls. Among them, citrate, hippurate, ascorbic acid, and D-glucurono-6,3-lactone were significantly lower, and 1,3,7-trimethyluric acid and D- threo-isocitric acid were higher in reversible cerebral vasoconstriction syndrome patients. Of these, four selected metabolites, citrate, D-glucurono-6,3-lactone, ascorbic acid, and 1,3,7-trimethyluric acid, returned to normal levels in remission. These metabolites are related to pathways associated with free radical scavenging, with the hub molecules being associated with endothelial dysfunction or sympathetic overactivity. Whether these metabolites and their implicated networks play a role in the pathogenesis of reversible cerebral vasoconstriction syndrome remains to be confirmed.


2019 ◽  
Vol 103 (23-24) ◽  
pp. 9321-9333 ◽  
Author(s):  
Svetlana V. Kamzolova ◽  
Igor G. Morgunov

Synlett ◽  
2019 ◽  
Vol 30 (12) ◽  
pp. 1401-1418 ◽  
Author(s):  
Athanassios Giannis ◽  
Farnoush Mousavizadeh

In this Account we present the total syntheses of artemisinin (an important antimalarial agent) and cyclopamine (the first natural inhibitor of the hedgehog signaling pathway). Furthermore, we describe the design and development of a γ-butyrolactone as an inhibitor of Gcn5 (a histone N-acetyltransferase), discuss the discovery of hyperforin and guttiferon G as the first natural products acting as inhibitors of sirtuins, and present the design of inhibitors of sialic acid biosynthesis. The biomedical background and importance are also discussed. Finally, we present the discovery and development of methods for transesterification, IBX-mediated oxidations, reduction of several functional groups with LiBH4/Me3SiCl, as well as a process enabling the synthesis of kilogram amounts of D-isocitric acid and its transformation to valuable chiral derivatives.1 Artemisinin and Malaria2 Cyclopamine and Cyclops3 Sunflowers, Krebs Cycle, and Isocitric acid4 Histones and N-Acetyltransferase Gcn55 St. John’s Wort, Hippocrates, and Sirtuins6 Sialic Acid and Inhibitors of Its Biosynthesis7 Transesterification8 IBX Reloaded9 And Finally: A Small Mistake with a Big Impact10 Epilogue


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