fumarates and itaconic-acid

Cellular metabolism is a means of generating ATP to provide energy for key cellular functions. However, recent research shows that citric acid cycle intermediates target vital cellular functions of the innate immune system. Succinate, itaconate, citrate, and fumarate have been shown to mediate or regulate important myeloid cell functions during infection and inflammation. This review covers the regulatory functions of citric acid cycle intermediates in myeloid cells and discusses potential translational applications, key mechanistic questions, and future research directions.

Topics: Animals; Citric Acid; Citric Acid Cycle; Fumarates; Humans; Leukocytes; Reactive Oxygen Species; Succinates; Succinic Acid

Various economic and environmental sustainability concerns as well as consumer preference for bio-based products from natural sources have paved the way for the development and expansion of biorefining technologies. These involve the conversion of renewable biomass feedstock to fuels and chemicals using biological systems as alternatives to petroleum-based products. Filamentous fungi possess an expansive portfolio of products including the multifunctional organic acids itaconic, fumaric, and malic acids that have wide-ranging current applications and potentially addressable markets as platform chemicals. However, current bioprocessing technologies for the production of these compounds are mostly based on submerged fermentation, which necessitates physicochemical pretreatment and hydrolysis of lignocellulose biomass to soluble fermentable sugars in liquid media. This review will focus on current research work on fungal production of itaconic, fumaric, and malic acids and perspectives on the potential application of solid-state fungal cultivation techniques for the consolidated hydrolysis and organic acid fermentation of lignocellulosic biomass.

Topics: Biomass; Carbohydrate Metabolism; Fermentation; Fumarates; Fungi; Hydrolysis; Lignin; Malates; Succinates

Recently, the microbial production of multifunctional organic acid has received interest due to their increased use in the food industry and their potential as raw materials for the manufacture of biodegradable polymers. Certain species of microorganisms produce significant quantities of organic acids in high yields under specific cultivation conditions from biomass-derived carbohydrates. The accumulation of some acids, such as fumaric, malic and succinic acid, are believed to involve CO2-fixation which gives high yields of products. The application of special fermentation techniques and the methods for downstream processing of products are described. Techniques such as simultaneous fermentation and product recovery and downstream processing are likely to occupy an important role in the reduction of production costs. Finally, some aspects of process design and current industrial production processes are discussed.

Topics: Aspartic Acid; Carboxylic Acids; Citric Acid; Conservation of Natural Resources; Fermentation; Fumarates; Lactic Acid; Malates; Succinates

Filamentous fungi are well known for their potential to accumulate organic acids in the medium when supplied with large amounts of sugar. Commercial applications of this are the production of citric and itaconic acids. The present review attempts to present the current state of knowledge on the biochemical basis of organic acid accumulation by filamentous fungi (citric, itaconic, fumaric and oxalic acids), particularly with respect to the role of citric acid cycle reactions. The explanations offered are based on recent advances in understanding the compartmentation of the fungal cell, and regulation of some key enzymes. The general conclusion is that fungi accumulate organic acids by mechanisms which avoid the channeling of substrates into the citric acid cycle under conditions of strongly active glycolysis.

Topics: Carboxylic Acids; Citric Acid Cycle; Fumarates; Fungi; Oxalates; Oxalic Acid; Succinates

The NLRP3 inflammasome is a multiprotein complex that regulates caspase-1 activation and subsequent interleukin (IL)-1β and IL-18 release from innate immune cells in response to infection or injury. Derivatives of the metabolites itaconate and fumarate, dimethyl itaconate (DMI), 4-octyl itaconate (4OI) and dimethyl fumarate (DMF) limit both expression and release of IL-1β following NLRP3 inflammasome activation. However, the direct effects of these metabolite derivatives on NLRP3 inflammasome responses require further investigation. Using murine bone marrow-derived macrophages, mixed glia and organotypic hippocampal slice cultures (OHSCs), we demonstrate that DMI, 4OI and DMF pretreatments inhibit pro-inflammatory cytokine production in response to lipopolysaccharide (LPS), as well as inhibit subsequent NLRP3 inflammasome activation induced by nigericin. DMI, 4OI, DMF and monomethyl fumarate (MMF), another fumarate derivative, also directly inhibited biochemical markers of NLRP3 activation in LPS-primed macrophages, mixed glia, OHSCs and human macrophages in response to nigericin and imiquimod, including ASC speck formation, caspase-1 activation, gasdermin D cleavage and IL-1β release. DMF, an approved treatment of multiple sclerosis, as well as DMI, 4OI and MMF, inhibited NLRP3 activation in macrophages in response to lysophosphatidylcholine, which is used to induce demyelination, suggesting a possible mechanism for DMF in multiple sclerosis through NLRP3 inhibition. The derivatives also reduced pro-IL-1α cleavage in response to the calcium ionophore ionomycin. Together, these findings reveal the immunometabolic regulation of both the priming and activation steps of NLRP3 activation in macrophages. Furthermore, we highlight itaconate and fumarate derivatives as potential therapeutic options in NLRP3- and IL-1α-driven diseases, including in the brain.

Topics: Animals; Caspase 1; Caspases; Fumarates; Humans; Inflammasomes; Interleukin-1beta; Lipopolysaccharides; Macrophages; Mice; Multiple Sclerosis; Nigericin; NLR Family, Pyrin Domain-Containing 3 Protein; Succinates

Oxidative stress plays a key role in the development of metabolic complications associated with obesity, including insulin resistance and the most common chronic liver disease worldwide, nonalcoholic fatty liver disease. We have recently discovered that the microRNA miR-144 regulates protein levels of the master mediator of the antioxidant response, nuclear factor erythroid 2-related factor 2 (NRF2). On miR-144 silencing, the expression of NRF2 target genes was significantly upregulated, suggesting that miR-144 controls NRF2 at the level of both protein expression and activity. Here we explored a mechanism whereby hepatic miR-144 inhibited NRF2 activity upon obesity via the regulation of the tricarboxylic acid (TCA) metabolite, fumarate, a potent activator of NRF2.. We performed transcriptomic analysis in liver macrophages (LMs) of obese mice and identified the immuno-responsive gene 1 (Irg1) as a target of miR-144. IRG1 catalyzes the production of a TCA derivative, itaconate, an inhibitor of succinate dehydrogenase (SDH). TCA enzyme activities and kinetics were analyzed after miR-144 silencing in obese mice and human liver organoids using single-cell activity assays in situ and molecular dynamic simulations.. Increased levels of miR-144 in obesity were associated with reduced expression of Irg1, which was restored on miR-144 silencing in vitro and in vivo. Furthermore, miR-144 overexpression reduces Irg1 expression and the production of itaconate in vitro. In alignment with the reduction in IRG1 levels and itaconate production, we observed an upregulation of SDH activity during obesity. Surprisingly, however, fumarate hydratase (FH) activity was also upregulated in obese livers, leading to the depletion of its substrate fumarate. miR-144 silencing selectively reduced the activities of both SDH and FH resulting in the accumulation of their related substrates succinate and fumarate. Moreover, molecular dynamics analyses revealed the potential role of itaconate as a competitive inhibitor of not only SDH but also FH. Combined, these results demonstrate that silencing of miR-144 inhibits the activity of NRF2 through decreased fumarate production in obesity.. Herein we unravel a novel mechanism whereby miR-144 inhibits NRF2 activity through the consumption of fumarate by activation of FH. Our study demonstrates that hepatic miR-144 triggers a hyperactive FH in the TCA cycle leading to an impaired antioxidant response in obesity.

Topics: Animals; Carboxy-Lyases; Citric Acid Cycle; Disease Models, Animal; Fatty Liver; Fumarate Hydratase; Fumarates; Humans; Hydro-Lyases; Insulin Resistance; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; MicroRNAs; NF-E2-Related Factor 2; Obesity; Oxidative Stress; RAW 264.7 Cells; Reactive Oxygen Species; Signal Transduction; Succinates

The bioproduction of high-value chemicals such as itaconic and fumaric acids (IA and FA, respectively) from renewable resources via solid-state fermentation (SSF) represents an alternative to the current bioprocesses of submerged fermentation using refined sugars. Both acids are excellent platform chemicals with a wide range of applications in different market, such as plastics, coating, or cosmetics. The use of lignocellulosic biomass instead of food resources (starch or grains) in the frame of a sustainable development for IA and FA bioproduction is of prime importance. Filamentous fungi, especially belonging to the

Topics: Aspergillus oryzae; Biomass; Bioreactors; Biotechnology; Fermentation; Fumarates; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Lignin; Succinates

Itaconic acid (IA) is a dicarboxylic acid included in the US Department of Energy's (DOE) 2004 list of the most promising chemical platforms derived from sugars. IA is produced industrially using liquid-state fermentation (LSF) by Aspergillus terreus with glucose as the carbon source. To utilize IA production in renewable resource-based biorefinery, the present study investigated the use of lignocellulosic biomass as a carbon source for LSF. We also investigated the production of fumaric acid (FA), which is also on the DOE's list. FA is a primary metabolite, whereas IA is a secondary metabolite and requires the enzyme cis-aconitate decarboxylase for its production. Two lignocellulosic biomasses (wheat bran and corn cobs) were tested for fungal fermentation. Liquid hydrolysates obtained after acid or enzymatic treatment were used in LSF. We show that each treatment resulted in different concentrations of sugars, metals, or inhibitors. Furthermore, different acid yields (IA and FA) were obtained depending on which of the four Aspergillus strains tested were employed. The maximum FA yield was obtained when A. terreus was used for LSF of corn cob hydrolysate (1.9% total glucose); whereas an IA yield of 0.14% was obtained by LSF of corn cob hydrolysates by A. oryzae.

Topics: Aspergillus niger; Biofuels; Biomass; Fermentation; Fumarates; Lignin; Succinates

Pseudomonas aeruginosa, Yersinia pestis, and many other bacteria are able to utilize the C5-dicarboxylic acid itaconate (methylenesuccinate). Itaconate degradation starts with its activation to itaconyl coenzyme A (itaconyl-CoA), which is further hydrated to (S)-citramalyl-CoA, and citramalyl-CoA is finally cleaved into acetyl-CoA and pyruvate. The xenobiotic-degrading betaproteobacterium Burkholderia xenovorans possesses a P. aeruginosa-like itaconate degradation gene cluster and is able to grow on itaconate and its isomer mesaconate (methylfumarate). Although itaconate degradation proceeds in B. xenovorans in the same way as in P. aeruginosa, the pathway of mesaconate utilization is not known. Here, we show that mesaconate is metabolized through its hydration to (S)-citramalate. The latter compound is then metabolized to acetyl-CoA and pyruvate with the participation of two enzymes of the itaconate degradation pathway, a promiscuous itaconate-CoA transferase able to activate (S)-citramalate in addition to itaconate and (S)-citramalyl-CoA lyase. The first reaction of the pathway, the mesaconate hydratase (mesaconase) reaction, is catalyzed by a class I fumarase. As this enzyme (Bxe_A3136) has similar efficiencies (kcat/Km) for both fumarate and mesaconate hydration, we conclude that B. xenovorans class I fumarase is in fact a promiscuous fumarase/mesaconase. This promiscuity is physiologically relevant, as it allows the growth of this bacterium on mesaconate as a sole carbon and energy source.

Topics: Acetyl Coenzyme A; Burkholderia; Fumarate Hydratase; Fumarates; Hydro-Lyases; Kinetics; Malates; Maleates; Metabolic Networks and Pathways; Pyruvic Acid; Substrate Specificity; Succinates

Deuterium-labelled compounds were prepared by (transfer) deuterogenation of unsaturated compounds using H(2) or HCO(2)H in acidic D(2)O as deuterium source with almost quantitative yields and high deuterium contents under mild reaction conditions via heterolytic cleavage of H(2) (or decomposition of HCO(2)H) and rapid H(+)/D(+) exchange using iridium catalysts with 4,4'-dihydroxy-2,2'-bipyridine.

Topics: 2,2'-Dipyridyl; Catalysis; Deuterium; Deuterium Oxide; Formates; Fumarates; Hydrogen; Iridium; Maleates; Succinates

Polycarboxylate-type green surfactants with either sulfide- (S-) or imino- (N-) linkages were prepared in high yields by a single addition reaction of fatty mercaptan or fatty amine with unsaturated polycarboxylic acids such as fumaric, maleic, itaconic and aconitic acids. They exhibited surfactant properties and excellent biodegradabilities. Also, green surfactants with S-linkages showed better calcium ion sequestration abilities compared to the corresponding surfactant having an N-linkage. Among these surfactants, aconitic acid-derived polycarboxylate with an S-linkage exhibited calcium ion sequestration capacities similar to that of disodium 3-oxapentanedioate (ODA), a conventional calcium ion sequestrant on a molar basis of the surfactant.

Topics: Aconitic Acid; Biodegradation, Environmental; Calcium; Carboxylic Acids; Cations; Fumarates; Imines; Maleates; Propofol; Succinates; Sulfhydryl Compounds; Sulfides; Surface Properties; Surface-Active Agents

Topics: Aluminum Oxide; Biomass; Catalysis; Dimethyl Fumarate; Fumarates; Green Chemistry Technology; Microwaves; Models, Chemical; Succinates