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2-methylidenebutanedioic acid is a versatile organic compound produced primarily by fermentation using microorganisms like Aspergillus terreus and is used commercially in the production of polymers, resins, and coatings.
Historically derived from the distillation of citric acid, 2-methylidenebutanedioic acid is now primarily synthesized through fermentation processes, which are more sustainable and environmentally friendly compared to chemical synthesis.
2-methylidenebutanedioic acid's unique unsaturated structure allows it to be incorporated into various polymers and materials, making it a valuable substitute for petroleum-based chemicals in industries such as plastics, paints, and adhesives.
CAS Number: 97-65-4
EC Number: 202-599-6
Molecular Formula: C5H6O4
Molecular Weight: 130.1
Synonyms: 2-methylidenebutanedioic acid, 97-65-4, 2-Methylenesuccinic acid, METHYLENESUCCINIC ACID, 2-methylidenebutanedioic acid, Methylenebutanedioic acid, Propylenedicarboxylic acid, Butanedioic acid, methylene-, itaconate, 2-Propene-1,2-dicarboxylic acid, Succinic acid, methylene-, 2-methylenebutanedioic acid, MFCD00004260, 25119-64-6, AI3-16901, 2-Methylene-Succinic Acid, CHEMBL359159, butanedioic acid, 2-methylene-, DTXSID2026608, CHEBI:30838, NSC3357, NSC-3357, Q4516562YH, DTXCID006608, CAS-97-65-4, HSDB 5308, methylene-butanedioicaci, NSC 3357, EINECS 202-599-6, Methylenesuccinate, UNII-Q4516562YH, ITN, Methylenebutanedioate, 2-Methylenesuccinate, Propylenedicarboxylate, 2-methylenebutanedioate, 2-methylidenebutanedioic acid, >=99%, bmse000137, Probes1_000076, Probes2_000247, EC 202-599-6, 2-Methylenesuccinic acid #, 2-methylidenebutanedioic acid [MI], NCIStruc1_001783, NCIStruc2_000502, 2-methylene-butanedioic acid, NCIOpen2_004822, SCHEMBL21523, 2-methylidenebutanedioic acid [INCI], 2-Propene-1,2-dicarboxylate, 2-methylidenebutanedioic acid, analytical standard, Succinic acid, methylene- (8CI), HY-Y0520, Tox21_201299, Tox21_303071, BBL011584, BDBM50036216, LMFA01170063, s3095, STL163322, AKOS000118895, 2-Hydroxy-3-Naphthoyl-2-Naphthylamine, SB67306, Butanedioic acid,ethylidene-,(E)-(9ci), NCGC00249019-01, NCGC00257141-01, NCGC00258851-01, AS-11816, CS-0015302, FT-0627543, M0223, EN300-18045, C00490, E80791, Q903311, Z57127539, F2191-0234, 2-METHYLENE,1,4-BUTANEDIOIC ACID (2-methylidenebutanedioic acid), 53EEC7A3-4846-4588-BBC9-CB8846377B96, InChI=1/C5H6O4/c1-3(5(8)9)2-4(6)7/h1-2H2,(H,6,7)(H,8,9)
2-methylidenebutanedioic acid is a naturally occurring organic compound with the chemical formula C5H6O4.
2-methylidenebutanedioic acid is a dicarboxylic acid, which means it has two carboxylic acid functional groups (-COOH) in its molecular structure.
2-methylidenebutanedioic acid is a dicarboxylic acid and an olefinic compound.
2-methylidenebutanedioic acid of the fermentationof the flamentous fungusAspergillus niger.
2-methylidenebutanedioic acid is used commercially in the production ofadhesives and paints.
2-methylidenebutanedioic acid, is an organic compound.
2-methylidenebutanedioic acid is a white solid that is soluble in water, ethanol, and acetone.
Historically, 2-methylidenebutanedioic acid was obtained by the distillation of citric acid, but currently it is produced by fermentation.
2-methylidenebutanedioic acid was devised as an anagram of aconitic acid, another derivative of citric acid.
2-methylidenebutanedioic acid is notable for its unsaturated nature, containing a carbon-carbon double bond (C=C) in its structure.
2-methylidenebutanedioic acid is produced by certain microorganisms, such as the bacterium Aspergillus terreus, through a fermentation process using carbohydrates as a carbon source.
2-methylidenebutanedioic acid can also be synthesized chemically.
2-methylidenebutanedioic acid is used in various industrial applications, including the production of plastics, synthetic resins, and as a chemical intermediate in the synthesis of various other compounds.
2-methylidenebutanedioic acid is a dicarboxylic acid that is methacrylic acid in which one of the methyl hydrogens is substituted by a carboxylic acid group.
2-methylidenebutanedioic acid has a role as a fungal metabolite and a human metabolite.
2-methylidenebutanedioic acid derives from a succinic acid.
2-methylidenebutanedioic acid is a conjugate acid of an itaconate(2-).
2-methylidenebutanedioic acid, also known as itaconate, belongs to the class of organic compounds known as branched fatty acids.
These are fatty acids containing a branched chain.
2-methylidenebutanedioic acid is a very hydrophobic molecule, practically insoluble in water, and relatively neutral.
Since the 1960s, 2-methylidenebutanedioic acid is produced industrially by the fermentation of carbohydrates such as glucose or molasses using fungi such as Aspergillus itaconicus or Aspergillus terreus.
For A. terreus the itaconate pathway is mostly elucidated.
The generally accepted route for itaconate is via glycolysis, tricarboxylic acid cycle, and a decarboxylation of cis-aconitate to itaconate via cis-aconitate-decarboxylase.
The smut fungus Ustilago maydis uses an alternative route.
Cis-aconitate is converted to the thermodynamically favoured trans-aconitate via aconitate-Δ-isomerase (Adi1).
Trans-Aconitate is further decarboxylated to itaconate by trans-aconitate-decarboxylase (Tad1).
2-methylidenebutanedioic acid is also produced in cells of macrophage lineage.
2-methylidenebutanedioic acid was shown that itaconate is a covalent inhibitor of the enzyme isocitrate lyase in vitro.
As such, itaconate may possess antibacterial activities against bacteria expressing isocitrate lyase (such as Salmonella enterica and Mycobacterium tuberculosis).
2-methylidenebutanedioic acid is also sythesized in the laboratory, where dry distillation of citric acid affords itaconic anhydride, which undergoes hydrolysis to 2-methylidenebutanedioic acid.
2-methylidenebutanedioic acid (2-methylidenebutanedioic acid, C5H6O4) is a white colorless crystalline, hygroscopic powder soluble in water, ethanol, and acetone.
2-methylidenebutanedioic acid is an unsaturated diprotic acid, which derives its unique chemical properties from the conjugation of one of its two carboxylic acid groups with its methylene group.
2-methylidenebutanedioic acid was discovered by Baup in 1837 as a product of pyrolytic distillation of citric acid.
The name itaconic was devised as an anagram of aconitic.
2-methylidenebutanedioic acid is formed in fermentation of some sugars.
In 1929, Kinoshita first showed the acid to be a metabolic product of Aspergillus itaconicus.
A derivative of 2-methylidenebutanedioic acid was isolated from another natural source (Artemisia argyi).
The biosynthetic pathway of 2-methylidenebutanedioic acid from glucose is similar to that of citric acid, which occurs via the glycolytic pathway and anaplerotic formation of oxaloacetate by CO2 fixation and via the TCA cycle.
2-methylidenebutanedioic acid is formed by the cytosolic enzyme aconitate decarboxylase from cis-aconitic acid.
Another biosynthetic pathway from pyruvate through citramalic acid, citraconic acid, and itartaric acid also results in 2-methylidenebutanedioic acid.
2-methylidenebutanedioic acid is a dicarboxylic acid, which is used in industry as a precursor of polymers used in plastics, adhesives, and coatings.
New uses of 2-methylidenebutanedioic acid-derived polymers are under active investigation.
The production of 2-methylidenebutanedioic acid for 2001 was quoted as 15 000 tons.
There is a renewed interest in this chemical as industry searches for substitutes of petroleum-derived chemicals.
Virtually all 2-methylidenebutanedioic acid produced is by fermentation by specific strains of A. terreus.
2-methylidenebutanedioic acid production is a further perversion of the Krebs cycle, citrate is converted as normally into cis-aconitate, which for reasons unknown is, in some organisms, decarboxylated into itaconitate, which has no known metabolic role in the cell.
The fact that different strains of Aspergillus and more generally of fungi can divert metabolic pathways to the overproduction and secretion of useful chemicals, coupled with the fact that these organisms can grow on residues of processes such as sugar and ethanol production, open the possibility of engineering pathways to produce high value chemicals through ‘green’, low polluting, waste-eliminating procedures.
2-methylidenebutanedioic acid, a precursor of polymers, chemicals, and fuels, can be synthesized by many fungi.
2-methylidenebutanedioic acid also is a macrophage-specific metabolite.
2-methylidenebutanedioic acid mediates crosstalk between macrophage metabolism and peritoneal tumors.
2-methylidenebutanedioic acid is mainly used in the plastic and paint industry.
2-methylidenebutanedioic acid is an unsaturated dicarbonic acid, and can readily be incorporated into polymers and used at a concentration of 1–5% (w/w) as a comonomer in polymers.
The polymerized methyl, ethyl, or vinyl esters of 2-methylidenebutanedioic acid are used as plastics, adhesives elastomers, and coatings.
Styrene butadiene copolymers containing 2-methylidenebutanedioic acid yield rubber-like resins of excellent strength and flexibility and water-proofing coatings with good electrical insulation.
Other fields for use are synthetic fibers, lattices, detergents, and cleaners.
On the other hand, several mono- and diesters of partially substituted 2-methylidenebutanedioic acid possess anti-inflammatory or analgesic activities, and a special new market has opened for the use of 2-methylidenebutanedioic acid pharmaceutical fields.
A small quantity of 2-methylidenebutanedioic acid is used as acidulant.
2-methylidenebutanedioic acid can be produced through the fermentation of various carbohydrates by microorganisms, most notably by the fungus Aspergillus terreus.
This biological process is a more sustainable and environmentally friendly method compared to chemical synthesis.
2-methylidenebutanedioic acid is a white, crystalline solid at room temperature.
2-methylidenebutanedioic acid readily dissolves in water and organic solvents.
2-methylidenebutanedioic acids unsaturated double bond makes it a valuable compound for various chemical reactions, including polymerization.
2-methylidenebutanedioic acid (2-2-methylidenebutanedioic acid, 1-propene-2–3-dicarboxylic acid) is an unsaturated, weak dicarboxylic acid (pKa =3.83 and 5.41), discovered in 1837 as a thermal decomposition product of citric acid.
The presence of the conjugated double bond of the methylene group allows polymerization both by addition and condensation.
Esterification of the two carboxylic groups with different co-monomers is also possible.
These diverse properties have led to a variety of applications in the pharmaceutical, architectural, paper, paint, and medical industries such as plastics, resins, paints, synthetic fibers, plasticizers, and detergents.
Recently, 2-methylidenebutanedioic acid applications have penetrated the dental, ophthalmic and drug delivery fields.
2-methylidenebutanedioic acid polymers could even replace the petroleum-based polyacrylic acid, which has a multi-billion dollar market.
Not surprisingly, the US Department of Energy assigned 2-methylidenebutanedioic acid as one of the top 12 most promising building block chemicals for bio-based economy in 2004.
Little is known about the reasons why fungi produce itaconate.
Like the other organic acids, as outlined above, also 2-methylidenebutanedioic acid might serve as acidifier of the environment and thus provide selective advantage for the acid-tolerant A. terreus over other micro-organisms.
However, 2-methylidenebutanedioic acid also has clear inhibitory properties: in macrophages of mammals, bacterial infection prompts the induction of a gene encoding a cisaconitate decarboxylase, resulting in ethylenesuccinic acid formation that inhibits bacterial metabolism as part of the immune response.
The effect has been attributed to the inhibition of succinate dehydrogenase and isocitrate lyase, the latter being a key enzyme of the glyoxylate cycle, required for the survival of pathogens inside a host.
In turn, a few strains of these bacteria have evolved to be capable of degrading itaconate.
2-methylidenebutanedioic acid also induces a transcription factor which is essential for protection against oxidative and xenobiotic stresses, and to attenuate inflammation.
Whether a similar function of itaconate exists in the fungi producing 2-methylidenebutanedioic acid has not yet been studied.
The biosynthetic pathway of 2-methylidenebutanedioic acid resembles that of citric acid, the latter acid being a direct precursor of the former.
The only difference is that citric acid in A. terreus is further metabolized via cis-aconitate to itaconate by cis-aconitate decarboxylase.
To this end, cis-aconitate is transported out of the mitochondria by a specific antiporter in exchange for oxaloacetate.
2-methylidenebutanedioic acid formed upon cis-aconitate decarboxylation is finally secreted out of mycelia by a specific cell membrane transporter.
Genes encoding these three enzymes, and a fourth one encoding a transcription factor, constitute the “2-methylidenebutanedioic acid gene cluster” in the A. terreus genome, while the cluster is notably absent in A. niger.
Although several itaconate producers have been tested, the plant pathogenic Basidiomycete Ustilago maydis (the corn smut fungus) and particularly 2-methylidenebutanedioic acid's low pH-stable relative Ustilago cynodontis seems to be the only one with a reasonable chance to become another industrial platform organism.
Ustilago has developed an alternative biochemical pathway to synthetize itaconate inasmuch as cis-aconitate is converted to the thermodynamically favored transaconitate by aconitate-delta-isomerase.
Trans-aconitate is then decarboxylated to itaconate by trans-aconitate-decarboxylase.
2-methylidenebutanedioic acid or 2-methylidenebutanedioic acid is a five-carbon unsaturated dicarboxylic acid with one carboxyl group conjugated to the methylene group.
According to the annual forecast, market is predicted to exceed 410,000 t by 2020.
2-methylidenebutanedioic acid has broad applications manufacture of absorbents, phosphate-free detergents, cleaners, and bioactive compounds.
2-methylidenebutanedioic acid is sought as a compound for replacement of petroleum-based chemicals such as acrylic acid or methyl acrylic acids which are used presently in the polymer industry.
The polymerized esters of 2-methylidenebutanedioic acid (IA) are used widely in adhesive and paints/coating industries.
2-methylidenebutanedioic acid is also used in the polymer industry and is also used in the synthesis of 3-methyltetrahydrofuran.
A company called Itaconix is working on the use of wood biomass as a feedstock for fermenting 2-methylidenebutanedioic acid.
2-methylidenebutanedioic acid is an important building block in the chemical industry.
2-methylidenebutanedioic acid is a white crystalline powder and readily biodegrades in soil.
Hence, 2-methylidenebutanedioic acid is an optimum substitute for petro-derived chemicals such as acrylic acid, maleic anhydride, or acetone cyanohydrin in various end-user industries.
The demand for 2-methylidenebutanedioic acid is high in the manufacturing of superabsorbent polymers, mainly used in diapers, adult incontinence, and feminine hygiene products.
2-methylidenebutanedioic acid is used as a cross-linking agent due to its ability to efficiently take part in addition polymerization.
2-methylidenebutanedioic acid also finds large application in seed coating, root dipping, ornamental gardens, food packaging, and artificial snow.
Moreover, increasing demand for unsaturated polyester resins in pipes, artificial stones, electrical cabinets, and laminating resins is expected to increase the demand for 2-methylidenebutanedioic acid.
High price of 2-methylidenebutanedioic acid is the major factor hampering the growth of 2-methylidenebutanedioic acid market.
2-methylidenebutanedioic acid has the potential to replace sodium tripolyphosphate in detergents.
2-methylidenebutanedioic acid is produced solely by batch submerged fungal fermentation.
Aspergillus terreus has been used from the 1940s in the fermentation process, which is similar to that of citric acid (see ‘Citric acid’), that is, 2-methylidenebutanedioic acid requires an excess of readily metabolizable sugar (glucose syrup, crude starch hydrolysates, and decationized molasses – up to 200 g l−1 sugar), continuous aeration, a low initial pH (between 3 and 5), sufficient nitrogen, high magnesium sulfate concentration (0.5%), low phosphate to limit biomass production, and a limitation in metal ions (zinc, copper, and iron).
However, there exists one significant difference in that the sensitivity of this fungus to the formed acid, in contrast to A. niger, necessitates maintaining of the pH at 2.8–3.1 throughout the fermentation, in order to obtain high amounts of the acid.
At present, the published production yield of 2-methylidenebutanedioic acid is about 85% of theoretical, accompanied by product concentrations of about 80 g l−1 during a cultivation at 39–42 °C for 8–10 days.
Recovery of 2-methylidenebutanedioic acid is accomplished by first separating the fungal biomass by filtration followed by evaporation, treatment with active carbon, and crystallization and recrystallization.
Actual markets for 2-methylidenebutanedioic acid are currently limited because the fungal fermentation is carried out at a relatively high cost.
New biotechnological approaches, such as published immobilization techniques, screening programs for other producing organisms (such as yeast), and genetic engineering of A. terreus (the annotated genome sequence of A terreus strain NIH 2624 has been publicly released), or of A. niger, could lead to higher production of 2-methylidenebutanedioic acid.
Also, the use of alternative substrates may reduce costs and thus open the market for new and expanded applications of this acid.
This valuable acid can be produced by several organisms, such as Candida sp., Pseudozyma antarctica, and several species of Aspergillus, but the two most common microorganisms used are Aspergillus terreus, used in industrial processes, and Ustilago maydis, which is currently being actively investigated as a possible industrial product.
2-methylidenebutanedioic acid is used commercially as a comonomer in some synthetic rubbers (styrenebutadiene and nitrilic) and as a plasticizer in the formulation of other polymers.
2-methylidenebutanedioic acid's production is traditionally done using sugars as raw materials, in a technology that was developed in the first half of the 20th century, but that was not developed due to the low competitivity of the acid with the petrochemical acrylic acid.
With the development of integrated and sustainable processes, the interest in the bioproduction of 2-methylidenebutanedioic acid is renewed.
2-methylidenebutanedioic acid, is an organic compound.
2-methylidenebutanedioic acid is a white solid that is soluble in water, ethanol, and acetone.
Historically, 2-methylidenebutanedioic acid was obtained by the distillation of citric acid, but currently it is produced by fermentation.
The name 2-methylidenebutanedioic acid was devised as an anagram of aconitic acid, another derivative of citric acid.
2-methylidenebutanedioic acid as a renewable organic acid is of growing interest for the chemical industry, because of its potential to replace crude oil based products like acrylic acid.
Up to now, the microorganism based processes were improved by classical strain breeding and optimizations of the fermentation strategies and conditions.
Especially the knowledge about the biotechnological process including oxygen supply, media compositions, and different bioreactor systems was significantly expanded.
Regarding the media composition, 2-methylidenebutanedioic acid was found that copper ions positively influence the 2-methylidenebutanedioic acid production in a genetically engineered A. niger strain.
However, 2-methylidenebutanedioic acid is not understood which biochemical reactions are responsible or involved in such an effect.
As already mentioned above, the biochemical reactions and effects of 2-methylidenebutanedioic acid in the production hosts are not fully described.
The catabolization pathway of 2-methylidenebutanedioic acid requires further investigations in order to engineer a production host with a disabled degradation pathway.
The effect of 2-methylidenebutanedioic acid on other metabolic pathways is also of interest because the understanding of its physiological role can prevent undesired side effects (toxicity, health risk, pathway inhibition) and increase the safety of its use.
Furthermore, 2-methylidenebutanedioic acid can be an interesting target for medical research because in mammalian cells it was detected in a metastatic tumor cell line.
Further knowledge about 2-methylidenebutanedioic acid's role as an enzyme inhibitor can help to develop lessresistant enzyme varieties like in the case of the phosphofructokinase.
Another target for further engineering is the CadA enzyme, which is described as an unstable protein.
Prolonging 2-methylidenebutanedioic acid's in vivo stability can help to increase the efficiency of existing production hosts.
Also the genetic regulation of the 2-methylidenebutanedioic acid pathway in A. terreus requires a profound analysis.
The investigations on the molecular principles of 2-methylidenebutanedioic acid synthesis revealed that cis-aconitic acid decarboxylase is the dedicated step in its biosynthesis in A. terreus.
Genetic engineering of this enzymatic step also renders other microbial hosts like A. niger to producers of 2-methylidenebutanedioic acid.
2-methylidenebutanedioic acid is an unsaturated dicarbonic acid which has a high potential as a biochemical building block, because 2-methylidenebutanedioic acid can be used as a monomer for the production of a plethora of products including resins, plastics, paints, and synthetic fibers.
Some Aspergillus species, like A. itaconicus and A. terreus, show the ability to synthesize this organic acid and A. terreus can secrete significant amounts to the media (>80 g/L).
However, compared with the citric acid production process (titers >200 g/L) the achieved titers are still low and the overall process is expensive because purified substrates are required for optimal productivity.
Itaconate is formed by the enzymatic activity of a cis-aconitate decarboxylase (CadA) encoded by the cadA gene in A. terreus.
Cloning of the cadA gene into the citric acid producing fungus A. niger showed that it is possible to produce 2-methylidenebutanedioic acid also in a different host organism.
This review will describe the current status and recent advances in the understanding of the molecular processes leading to the biotechnological production of 2-methylidenebutanedioic acid.
2-methylidenebutanedioic acid is well known as a precursor for polymer synthesis and has been involved in industrial processes for decades.
In a recent surprising discovery, 2-methylidenebutanedioic acid was found to play a role as an immune-supportive metabolite in mammalian immune cells, where it is synthesized as an antimicrobial compound from the citric acid cycle intermediate cis-aconitic acid.
Although the immune-responsive gene 1 protein (IRG1) has been associated to immune response without a mechanistic function, the critical link to 2-methylidenebutanedioic acid production through an enzymatic function of this protein was only recently revealed.
Upon heating, itaconic anhydride isomerizes to citraconic acid anhydride, which can be hydrolyzed to citraconic acid (2-methylmaleic acid).
Partial hydrogenation of 2-methylidenebutanedioic acid over Raney nickel affords 2-methylsuccinic acid.
2-methylidenebutanedioic acid is primarily used as a co-monomer in the production of acrylonitrile butadiene styrene and acrylate latexes with applications in the paper and architectural
2-methylidenebutanedioic acid or methylene succinic acid is a high-value platform chemical that finds application in polymer industry, wastewater treatment, and ion-exchange chromatography sector.
2-methylidenebutanedioic acid can be converted to 3-methyltetrahydrofuran that has superior emission and combustion properties when compared to gasoline.
Industrial production of 2-methylidenebutanedioic acid is carried out with A. terreus using glucose as the sole carbon source.
2-methylidenebutanedioic acid production by metabolically engineered Neurospora crassa using lignocellulosic biomass was evaluated by Zhao et al.
Cis-aconitic acid decarboxylase gene was heterologously expressed in N. crassa to synthesize 2-methylidenebutanedioic acid.
The engineered strain was capable of producing 2-methylidenebutanedioic acid (20.41 mg/L) directly from lignocellulosic biomass.
2-methylidenebutanedioic acid production from biomass hydrolyzate using Aspergillus strains was reported by Jiménez-Quero et al.
Acid and enzymatic hydrolyzates were evaluated for the production of 2-methylidenebutanedioic acid.
Maximum 2-methylidenebutanedioic acid production (0.14%) was observed when submerged fermentation was carried out with corncob hydrolyzate by A. oryzae.
The study reveals the possibility of SSF of biomass for the production of 2-methylidenebutanedioic acid.
Much is known about the biosynthesis of 2-methylidenebutanedioic acid and the underlying enzymatic mechanisms, but for a complete biochemical picture of a certain metabolite, also the knowledge about its degradation is necessary.
Unfortunately, the information about the degradation pathway of 2-methylidenebutanedioic acid is scarce.
In mammalian cells (guinea pig and rat liver) 2-methylidenebutanedioic acid was found that itaconate is converted to itaconyl-CoA and is further processed via citramalyl-CoA to pyruvate and acetyl-CoA.
Hereby, 2-methylidenebutanedioic acid was found that malonate has an inhibitory effect and an addition prevents the degradation of 2-methylidenebutanedioic acid.
The first step of this degradation pathway can be catalyzed by the ubiquitous succinyl-CoA synthetase.
The third step of the pathway is catalyzed by a citramalyl-CoA lyase, where genes from Chloroflexus aurantiacus and Pseudomonas putida have been cloned.
However, no protein and gene sequence was identified so far, which can catalyze the second step of the degradation pathway, which is an itaconyl-CoA hydratase.
Metabolic Engineering of the 2-methylidenebutanedioic acid Pathway in A. terreus and A. niger The levels of 2-methylidenebutanedioic acid which were reached with A. terreus are currently limited to about 85 g/L.
Although this is already a substantial amount 2-methylidenebutanedioic acid cannot be compared with the production of citric acid where titers over 200 g/L are steadily obtained in industrial processes.
Transferred to the 2-methylidenebutanedioic acid production a maximal theoretical titer of about 240 g/L should be achievable.
This goal could be reached by further breeding of currently existing strains or targeted genetic engineering.
In A. terreus, a gene was shown to influence the performance of 2-methylidenebutanedioic acid production, which is a key enzyme of glycolysis.
However, a truncated version of the A. niger pfkA gene was shown to exhibit a higher citric acid yield due to a reduced inhibition by citrate and ATP.
This truncated pfkA version had also a positive impact on the 2-methylidenebutanedioic acid accumulation when expressed in A. terreus.
Another engineering approach deals with the intracellular oxygen supply.
The production of 2-methylidenebutanedioic acid requires continuous aeration and already a short interruption of oxygen decreases the 2-methylidenebutanedioic acid yield.
In order to reduce the sensitivity to oxygen a hemoglobin gene from Vitreoscilla was expressed in A. terreus.
Indeed, the expression of this gene leads to an increased 2-methylidenebutanedioic acid production.
Furthermore, the strains exhibited a better recovery after the aeration was interrupted.
There is the possibility that the genetic make-up of A. terreus is not efficient enough to support the production of higher titers of organic acids.
Therefore, a strategy is to genetically engineer the 2-methylidenebutanedioic acid biosynthesis pathway into another host organism, which is already known to support the production of high titers of organic acids.
As already mentioned, A. niger is such a candidate.
The unique and crucial step in the biosynthesis pathway is the decarboxylation of cis-aconitic acid toward 2-methylidenebutanedioic acid.
When the cadA gene was characterized in A. terreus genetic engineering of the pathway into another organism became possible.
Li et al. expressed the A. terreus cadA gene in A. niger strain AB 1.13.
For this purpose, the cadA gene was placed under the control of the A. niger gpdA promoter, which enables a strong and constitutive expression.
An A. niger strain which expresses the cadA gene alone has the ability to produce about 0.7 g/L 2-methylidenebutanedioic acid.
This level is not comparable with current production strains of A. terreus, but is a promising starting point for further engineering steps.
Further attempts to rise the yield are to express genes like the above mentioned mitochondrial carrier protein together with the cadA gene.
Uses of 2-Methylidenebutanedioic Acid:
2-methylidenebutanedioic acid is used in the preparation of acrylonitrile-butadiene-styrene and acrylate latexes.
2-methylidenebutanedioic acid is also used to prepare poly-2-methylidenebutanedioic acid, resins biofuel components and ionomer cements.
2-methylidenebutanedioic acid finds application in the textile, chemical and pharmaceutical industries.
2-methylidenebutanedioic acid is also used as an additive in fibers and ion exchange resins to increase abrasion, waterproofing, physical resistance, dying affinity and better duration.
Further, 2-methylidenebutanedioic acid acts as a co-monomer used in the preparation of acrylic fibers and rubbers, reinforced glass fiber, artificial diamonds and lens.
In addition to this, 2-methylidenebutanedioic acid acts as a binder and sizing agent in non-weaving fibers.
2-methylidenebutanedioic acid is used in the following products: polymers.
2-methylidenebutanedioic acid is used for the manufacture of: chemicals, rubber products and plastic products.
Release to the environment of 2-methylidenebutanedioic acid can occur from industrial use: as an intermediate step in further manufacturing of another substance (use of intermediates), as processing aid, for thermoplastic manufacture and as processing aid.
2-methylidenebutanedioic acid is used to produce various polymers and copolymers.
When polymerized, 2-methylidenebutanedioic acid forms poly2-methylidenebutanedioic acid, which can be used in the production of synthetic resins and biodegradable plastics.
2-methylidenebutanedioic acid is employed as a co-monomer in the synthesis of copolymers, enhancing the properties of the resulting materials.
For example, 2-methylidenebutanedioic acid can be copolymerized with acrylic acid to create superabsorbent polymers used in diapers and sanitary products.
Due to its adhesive properties and ability to form stable polymer matrices, 2-methylidenebutanedioic acid is used in the formulation of adhesives, coatings, and sealants.
These materials find applications in various industries, including construction, automotive, and packaging.
2-methylidenebutanedioic acid is used as a chelating agent in water treatment processes.
2-methylidenebutanedioic acid can bind to metal ions, helping to remove impurities from water, prevent scale formation, and improve water quality in industrial settings.
2-methylidenebutanedioic acid derivatives have been investigated for potential use in pharmaceuticals and drug delivery systems due to their biocompatibility and controlled-release properties.
2-methylidenebutanedioic acid can be used in the extraction of certain metals from ores or waste materials.
2-methylidenebutanedioic acid's ability to chelate metal ions helps in the separation and recovery of valuable metals from complex mixtures.
2-methylidenebutanedioic acid and its salts are used as food additives, primarily as acidity regulators and preservatives in the food industry.
They help control the pH of food products and extend their shelf life.
2-methylidenebutanedioic acid continues to be a subject of research for its potential applications in various fields, including materials science, biotechnology, and sustainable chemistry.
2-methylidenebutanedioic acid's production from renewable resources and its potential to replace petroleum-based chemicals in certain applications align with the goals of sustainable chemistry and environmentally friendly technologies.
2-methylidenebutanedioic acid is used in the production of synthetic polymers, including poly2-methylidenebutanedioic acid and various copolymers.
These polymers find applications in adhesives, coatings, and superabsorbent materials.
2-methylidenebutanedioic acid-based polymers can be used to create biodegradable plastics, which are increasingly important in reducing plastic waste and environmental impact.
2-methylidenebutanedioic acid can be used as a chelating agent, which means it can bind to metal ions.
This property is valuable in various industrial processes, such as water treatment and metal extraction.
2-methylidenebutanedioic acid is used in the formulation of adhesives, coatings, and sealants due to its adhesive properties and the ability to form stable polymer matrices.
2-methylidenebutanedioic acid derivatives have been studied for their potential use in pharmaceuticals and drug delivery systems.
2-methylidenebutanedioic acid is an organic acid that is used as a precursor in the polymer industry.
2-methylidenebutanedioic acid has been used in production of a surfactant that can increase skin permeation of topical treatments.
2-methylidenebutanedioic acid has also been used in creation of controlled-release hydrogel antibiotics.
2-methylidenebutanedioic acid is often used in the production of superabsorbent polymers (SAPs), which have the ability to absorb and retain large amounts of liquid relative to their own mass.
SAPs are commonly found in products like diapers, adult incontinence products, and feminine hygiene products.
2-methylidenebutanedioic acid-based polymers can be used in the textile industry for various purposes, including as a finishing agent to improve the wrinkle resistance and crease recovery of fabrics.
2-methylidenebutanedioic acid derivatives, such as sodium itaconate, are used as detergent builders.
They help improve the cleaning efficiency of detergents by sequestering calcium and magnesium ions in hard water, preventing the formation of soap scum and improving the detergents' overall effectiveness.
2-methylidenebutanedioic acid and its derivatives are used in the oil and gas industry as additives in drilling fluids and cementing formulations.
2-methylidenebutanedioic acid has gained attention in biotechnology for its potential as a platform chemical for the production of bio-based chemicals and fuels.
2-methylidenebutanedioic acid is also studied in the context of metabolic engineering to enhance microbial production of 2-methylidenebutanedioic acid for various applications.
2-methylidenebutanedioic acid is used as a reagent and research chemical in various scientific experiments and chemical processes.
2-methylidenebutanedioic acids versatile chemical structure makes it useful in organic synthesis and as a starting material for the preparation of other compounds.
2-methylidenebutanedioic acid and its derivatives can be used in metalworking fluids, which are employed in machining and metal cutting operations to improve cooling, lubrication, and corrosion protection.
2-methylidenebutanedioic acid-based polymers can be used as retention aids and dry strength additives in the paper and pulp industry, helping improve the quality and strength of paper products.
2-methylidenebutanedioic acid derivatives are sometimes used in personal care products, such as shampoos and conditioners, to enhance their performance and texture.
In the paint and coatings industry, 2-methylidenebutanedioic acid can be used to improve the performance of water-based formulations, including increasing the adhesion of coatings to surfaces.
Production of 2-Methylidenebutanedioic Acid:
Since the 1960s, 2-methylidenebutanedioic acid is produced industrially by the fermentation of carbohydrates such as glucose or molasses using fungi such as Aspergillus itaconicus or Aspergillus terreus.
For A. terreus the 2-methylidenebutanedioic acid pathway is mostly elucidated.
The generally accepted route for 2-methylidenebutanedioic acid is via glycolysis, tricarboxylic acid cycle, and a decarboxylation of cis-aconitate to itaconate via cis-aconitate-decarboxylase.
The smut fungus Ustilago maydis uses an alternative route.
Cis-aconitate is converted to the thermodynamically favoured trans-aconitate via aconitate-Δ-isomerase (Adi1).
Trans-Aconitate is further decarboxylated to itaconate by trans-aconitate-decarboxylase.
2-methylidenebutanedioic acid is also produced in cells of macrophage lineage.
2-methylidenebutanedioic acid was shown that itaconate is a covalent inhibitor of the enzyme isocitrate lyase in vitro.
As such, itaconate may possess antibacterial activities against bacteria expressing isocitrate lyase (such as Salmonella enterica and Mycobacterium tuberculosis).
However, cells of macrophage lineage have to "pay the price" for making itaconate, and they lose the ability to perform mitochondrial substrate-level phosphorylation.
Biological Significance of 2-Methylidenebutanedioic Acid:
Metabolic Pathway:
2-methylidenebutanedioic acid is a key intermediate in the citric acid cycle (Krebs cycle), a crucial metabolic pathway for energy production in cells.
Health Benefits:
In addition to its pharmaceutical uses, 2-methylidenebutanedioic acid has been studied for its potential benefits in various health conditions, including its role in antioxidant defense.
Reactions of 2-Methylidenebutanedioic Acid:
Upon heating, itaconic anhydride isomerizes to citraconic acid anhydride, which can be hydrolyzed to citraconic acid (2-methylmaleic acid).
Steps in conversion of citric acid to citraconic acid via itaconic and aconitic acids.
Partial hydrogenation of 2-methylidenebutanedioic acid over Raney nickel affords 2-methylsuccinic acid.
2-methylidenebutanedioic acid is primarily used as a co-monomer in the production of acrylonitrile butadiene styrene and acrylate latexes with applications in the paper and architectural coating industry.
Handling and Storage of 2-Methylidenebutanedioic Acid:
Handling:
Precautions:
Handle with care to avoid dust formation.
Use appropriate personal protective equipment (PPE) such as gloves and safety goggles.
Avoid:
Avoid inhaling dust and avoid contact with eyes, skin, or clothing.
Use in a well-ventilated area.
Storage:
Conditions:
Store in a cool, dry place in a tightly closed container.
Keep away from heat, moisture, and incompatible substances.
Containers:
Use containers made of materials compatible with the chemical to prevent contamination or degradation.
Reactivity and Stability of 2-Methylidenebutanedioic Acid:
Reactivity:
Conditions to Avoid:
Avoid exposure to excessive heat and moisture.
Avoid contact with strong oxidizers and bases.
Stability:
Stable under recommended storage conditions.
Decomposition:
Decomposes at high temperatures, releasing carbon dioxide, carbon monoxide, and other potentially hazardous gases.
Safety Profile of 2-Methylidenebutanedioic Acid:
2-methylidenebutanedioic acid can be irritating to the skin and eyes upon direct contact.
Prolonged or repeated exposure may lead to skin or eye irritation, including redness, itching, and discomfort.
2-methylidenebutanedioic acid is essential to wear appropriate personal protective equipment (PPE), such as gloves and safety goggles, when working with it.
Inhalation of 2-methylidenebutanedioic acid dust or aerosols should be avoided, as it may irritate the respiratory tract.
Ensure adequate ventilation and, if necessary, use respiratory protection when handling 2-methylidenebutanedioic acid in dusty or aerosol-generating situations.
Ingesting 2-methylidenebutanedioic acid is generally not a common hazard in industrial or laboratory settings.
However, 2-methylidenebutanedioic acid and its derivatives should not be consumed, and measures should be in place to prevent accidental ingestion.
When exposed to high temperatures or certain chemicals, 2-methylidenebutanedioic acid may decompose and release potentially hazardous byproducts, such as carbon monoxide, carbon dioxide, and other toxic gases.
First Aid Measures of 2-Methylidenebutanedioic Acid:
Inhalation:
Move the affected person to fresh air.
If symptoms persist or are severe, seek medical attention.
Skin Contact:
Wash the affected area with soap and water.
Remove contaminated clothing.
If irritation persists, seek medical attention.
Eye Contact:
Rinse immediately with plenty of water for at least 15 minutes.
Seek medical attention if irritation persists.
Ingestion:
Rinse the mouth with water.
Do not induce vomiting unless directed by medical personnel.
Seek medical attention immediately.
Fire Fighting Measures of 2-Methylidenebutanedioic Acid:
Suitable:
Use water spray, foam, dry chemical, or carbon dioxide.
Special Fire Fighting Procedures:
Precautions:
Wear self-contained breathing apparatus (SCBA) and protective clothing.
Use water to cool containers exposed to fire.
Hazardous Combustion Products:
Decomposition Products:
May include carbon monoxide, carbon dioxide, and other toxic fumes.
Accidental Release Measures of 2-Methylidenebutanedioic Acid:
Personal Precautions:
Protection:
Wear appropriate PPE, including gloves, safety goggles, and a dust mask.
Avoid inhalation and contact with skin and eyes.
Environmental Precautions:
Containment:
Prevent the chemical from entering waterways, sewers, or soil.
Cleanup Procedures:
Methods:
Collect the material using an appropriate method (e.g., vacuum or damp cloth).
Dispose of waste according to local regulations.
Exposure Controls/Personal Protection of 2-Methylidenebutanedioic Acid:
Exposure Limits:
Threshold Limit Value (TLV):
Ensure exposure levels are below recommended TLVs or occupational exposure limits set by regulatory agencies.
Engineering Controls:
Ventilation:
Use local exhaust ventilation or other engineering controls to minimize dust and exposure.
Personal Protective Equipment (PPE):
Respiratory Protection:
Use a dust mask or respirator if necessary.
Hand Protection:
Wear gloves resistant to the chemical.
Eye Protection:
Use safety goggles or face shields to protect eyes from dust.
Skin Protection:
Wear protective clothing to prevent skin contact.
Identifiers of 2-Methylidenebutanedioic Acid:
IUPAC Name: 2-Methylidenebutanedioic acid
Common Name: Fumaric Acid
CAS Registry Number: 110-17-8
UNII Code: T6F4H8DH9T
PubChem CID: 704
SMILES (Simplified Molecular Input Line Entry System): C=C(C(=O)O)C(=O)O
InChI (International Chemical Identifier): InChI=1S/C4H4O4/c1-2(5)3(6)4(7)8/h1H2,(H,5,6)(H,7,8)
CAS: 97-65-4
MF: C5H6O4
MW: 130.1
EINECS: 202-599-6
Properties of 2-Methylidenebutanedioic Acid:
Melting point: 165-168 °C (lit.)
Boiling point: 268°C
Density: 1.573 g/mL at 25 °C (lit.)
vapor pressure: 0.0000115 Pa (20 °C)
refractive index: 1.4980 (estimate)
Flash point: 268°C
storage temp.: Store below +30°C.
solubility: 77.49g/l
form: Crystalline Powder or Crystals
pka: 3.85(at 25℃)
Specific Gravity: 1.573
color: White to light beige
PH: 3.5(1 mM solution);2.95(10 mM solution);2.43(100 mM solution);
Odor: Characteristic Odor
Water Solubility: Soluble in water, acetone, methanol, hexane and ethanol. Slightly soluble in benzene, chloroform, carbon disulfide and petroleum ether.
Sensitive: Hygroscopic
Merck: 14,5242
BRN: 1759501
Stability: Light Sensitive
InChIKey: LVHBHZANLOWSRM-UHFFFAOYSA-N
LogP: -0.301 at 20℃
Melting point: 165-168 °C (lit.)
Boiling point: 268°C
Density: 1.573 g/mL at 25 °C (lit.)
Vapor pressure: 0.0000115 Pa (20 °C)
Refractive index: 1.4980 (estimate)
Fp: 268°C
Storage temp.: Store below +30°C.
Solubility: 77.49g/l
Form: Crystalline Powder or Crystals
pka: 3.85(at 25℃)
Specific Gravity: 1.573
Color: White to light beige
PH: 3.5(1 mM solution);2.95(10 mM solution);2.43(100 mM solution);
Water Solubility: Soluble in water, acetone, methanol, hexane and ethanol.
Slightly soluble in benzene, chloroform, carbon disulfide and petroleum ether.
Sensitive: Hygroscopic
Merck: 14,5242
BRN: 1759501
Stability: Light Sensitive
InChIKey: LVHBHZANLOWSRM-UHFFFAOYSA-N
LogP: -0.301 at 20℃
CAS DataBase Reference: 97-65-4(CAS DataBase Reference)
NIST Chemistry Reference: Itaconic acid (97-65-4)
EPA Substance Registry System: Itaconic acid (97-65-4)
