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Methylenesuccinic acid (Itaconic acid), also known as Itaconic acid, is a naturally occurring organic compound with the chemical formula C5H6O4.
Methylenesuccinic acid (Itaconic acid) is a dicarboxylic acid, which means it has two carboxylic acid functional groups (-COOH) in its molecular structure.
Methylenesuccinic acid (Itaconic acid) is a dicarboxylic acid and an olefinic compound.
CAS Number: 97-65-4
Molecular Formula: C5H6O4
Molecular Weight: 130.1
EINECS Number: 202-599-6
Methylenesuccinic acid (Itaconic acid) of the fermentationof the flamentous fungusAspergillus niger.
Methylenesuccinic acid (Itaconic acid) is used commercially in the production ofadhesives and paints.
Methylenesuccinic acid (Itaconic acid), is an organic compound.
This dicarboxylic acid is a white solid that is soluble in water, ethanol, and acetone.
Historically, Methylenesuccinic acid (Itaconic acid) was obtained by the distillation of citric acid, but currently it is produced by fermentation.
The name Methylenesuccinic acid (Itaconic acid) was devised as an anagram of aconitic acid, another derivative of citric acid.
Methylenesuccinic acid (Itaconic acid) is notable for its unsaturated nature, containing a carbon-carbon double bond (C=C) in its structure.
Methylenesuccinic acid (Itaconic acid) is produced by certain microorganisms, such as the bacterium Aspergillus terreus, through a fermentation process using carbohydrates as a carbon source.
Methylenesuccinic acid (Itaconic acid) can also be synthesized chemically.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic acid) is a dicarboxylic acid that is methacrylic acid in which one of the methyl hydrogens is substituted by a carboxylic acid group.
Methylenesuccinic acid (Itaconic acid) has a role as a fungal metabolite and a human metabolite.
Methylenesuccinic acid (Itaconic acid) derives from a succinic acid.
Methylenesuccinic acid (Itaconic acid) is a conjugate acid of an itaconate(2-).
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic acid) is a very hydrophobic molecule, practically insoluble in water, and relatively neutral.
Since the 1960s, it 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).
Methylenesuccinic acid (Itaconic acid) is also produced in cells of macrophage lineage.
Methylenesuccinic acid (Itaconic 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).
Methylenesuccinic acid (Itaconic acid) is also sythesized in the laboratory, where dry distillation of citric acid affords itaconic anhydride, which undergoes hydrolysis to Methylenesuccinic acid (Itaconic acid).
Methylenesuccinic acid (Itaconic acid) (methylenesuccinic acid, C5H6O4) is a white colorless crystalline, hygroscopic powder soluble in water, ethanol, and acetone.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid) was isolated from another natural source (Artemisia argyi).
The biosynthetic pathway of Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid).
Methylenesuccinic acid (Itaconic acid) is a dicarboxylic acid, which is used in industry as a precursor of polymers used in plastics, adhesives, and coatings.
New uses of Methylenesuccinic acid (Itaconic acid)-derived polymers are under active investigation.
The production of Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid) produced is by fermentation by specific strains of A. terreus.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic acid), a precursor of polymers, chemicals, and fuels, can be synthesized by many fungi.
Methylenesuccinic acid (Itaconic acid) also is a macrophage-specific metabolite.
Methylenesuccinic acid (Itaconic acid) mediates crosstalk between macrophage metabolism and peritoneal tumors.
Methylenesuccinic acid (Itaconic acid) is mainly used in the plastic and paint industry.
Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid) are used as plastics, adhesives elastomers, and coatings.
Styrene butadiene copolymers containing Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid) possess anti-inflammatory or analgesic activities, and a special new market has opened for the use of Methylenesuccinic acid (Itaconic acid) pharmaceutical fields.
A small quantity of Methylenesuccinic acid (Itaconic acid) is used as acidulant.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic acid) is a white, crystalline solid at room temperature.
Methylenesuccinic acid (Itaconic acid) readily dissolves in water and organic solvents.
Methylenesuccinic acid (Itaconic acid)s unsaturated double bond makes it a valuable compound for various chemical reactions, including polymerization.
Methylenesuccinic acid (Itaconic acid) (2-methylenesuccinic 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 (Kuenz et al., 2012).
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, Methylenesuccinic acid (Itaconic acid) applications have penetrated the dental, ophthalmic and drug delivery fields (Hajian and Yusoff, 2015).
Methylenesuccinic acid (Itaconic acid) polymers could even replace the petroleum-based polyacrylic acid, which has a multi-billion dollar market (Saha et al., 2019).
Not surprisingly, the US Department of Energy assigned Methylenesuccinic acid (Itaconic acid) as one of the top 12 most promising building block chemicals for bio-based economy in 2004 (Werpy and Petersen, 2004).
Little is known about the reasons why fungi produce itaconate.
Like the other organic acids, as outlined above, also Methylenesuccinic acid (Itaconic acid) might serve as acidifier of the environment and thus provide selective advantage for the acid-tolerant A. terreus over other micro-organisms.
However, Methylenesuccinic acid (Itaconic 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 (Itaconic 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 (McFadden et al., 1971), 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 (Sasikaran et al., 2014). Methylenesuccinic acid (Itaconic acid) also induces a transcription factor which is essential for protection against oxidative and xenobiotic stresses, and to attenuate inflammation (Kobayashi et al., 2013; Bambouskova et al., 2018).
Whether a similar function of itaconate exists in the fungi producing it has not yet been studied.
The biosynthetic pathway of Methylenesuccinic acid (Itaconic 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 (Bonnarme et al., 1995).
To this end, cis-aconitate is transported out of the mitochondria by a specific antiporter in exchange for oxaloacetate (Li et al., 2011a,b).
Methylenesuccinic acid (Itaconic 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 “Methylenesuccinic acid (Itaconic 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 its low pH-stable relative Ustilago cynodontis (Hosseinpour Tehrani et al., 2019b) – seems to be the only one with a reasonable chance to become another industrial platform organism (Hosseinpour Tehrani et al., 2019a).
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.
Methylenesuccinic acid (Itaconic acid) or methylenesuccinic 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 (Choi et al., 2015).
Methylenesuccinic acid (Itaconic acid) has broad applications manufacture of absorbents, phosphate-free detergents, cleaners, and bioactive compounds.
Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid) (IA) are used widely in adhesive and paints/coating industries.
Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid).
Methylenesuccinic acid (Itaconic acid) is an important building block in the chemical industry.
Methylenesuccinic acid (Itaconic acid) is a white crystalline powder and readily biodegrades in soil.
Hence, it 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 Methylenesuccinic acid (Itaconic acid) is high in the manufacturing of superabsorbent polymers, mainly used in diapers, adult incontinence, and feminine hygiene products.
Methylenesuccinic acid (Itaconic acid) is used as a cross-linking agent due to its ability to efficiently take part in addition polymerization.
Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid).
High price of Methylenesuccinic acid (Itaconic acid) is the major factor hampering the growth of Methylenesuccinic acid (Itaconic acid) market.
Methylenesuccinic acid (Itaconic acid) has the potential to replace sodium tripolyphosphate in detergents.
Methylenesuccinic acid (Itaconic 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, it 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 Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic acid) is used commercially as a comonomer in some synthetic rubbers (styrenebutadiene and nitrilic) and as a plasticizer in the formulation of other polymers.
Its 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 Methylenesuccinic acid (Itaconic acid) is renewed.
Methylenesuccinic acid (Itaconic acid), is an organic compound.
This Methylenesuccinic acid (Itaconic acid) is a white solid that is soluble in water, ethanol, and acetone.
Historically, Methylenesuccinic acid (Itaconic acid) was obtained by the distillation of citric acid, but currently it is produced by fermentation. The name itaconic
acid was devised as an anagram of aconitic acid, another derivative of citric acid.
Methylenesuccinic acid (Itaconic 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 (Kuenz et al., 2012).
Regarding the media composition, it was found that copper ions positively influence the Methylenesuccinic acid (Itaconic acid) production in a genetically engineered A. niger strain (Li et al., 2012).
However, it is not understood which biochemical reactions are responsible or involved in such an effect.
As already mentioned above, the biochemical reactions and effects of Methylenesuccinic acid (Itaconic acid) in the production hosts are not fully described.
The catabolization pathway of Methylenesuccinic acid (Itaconic acid) requires further investigations in order to engineer a production host with a disabled degradation pathway.
The effect of Methylenesuccinic acid (Itaconic 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, it can be an interesting target for medical research because in mammalian cells it was detected in a metastatic tumor cell line (Strelko et al., 2011).
Further knowledge about its role as an enzyme inhibitor can help to develop lessresistant enzyme varieties like in the case of the phosphofructokinase 2.
Another target for further engineering is the CadA enzyme, which is described as an unstable protein.
Prolonging its in vivo stability can help to increase the efficiency of existing production hosts.
Also the genetic regulation of the Methylenesuccinic acid (Itaconic acid) pathway in A. terreus requires a profound analysis.
The investigations on the molecular principles of Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid).
Methylenesuccinic acid (Itaconic acid) is an unsaturated dicarbonic acid which has a high potential as a biochemical building block, because it 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 Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid).
Methylenesuccinic acid (Itaconic acid) is well known as a precursor for polymer synthesis and has been involved in industrial processes for decades.
In a recent surprising discovery, Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid) production through an enzymatic function of this protein was only recently revealed.
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℃
Upon heating, itaconic anhydride isomerizes to citraconic acid anhydride, which can be hydrolyzed to citraconic acid (2-methylmaleic acid).
Partial hydrogenation of Methylenesuccinic acid (Itaconic acid) over Raney nickel affords 2-methylsuccinic acid.
Methylenesuccinic acid (Itaconic 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
Methylenesuccinic acid (Itaconic acid) or methylene succinic acid is a high-value platform chemical that finds application in polymer industry, wastewater treatment, and ion-exchange chromatography sector (Willke and Vorlop, 2001).
Methylenesuccinic acid (Itaconic acid) can be converted to 3-methyltetrahydrofuran that has superior emission and combustion properties when compared to gasoline.
Industrial production of Methylenesuccinic acid (Itaconic acid) is carried out with A. terreus using glucose as the sole carbon source.
Methylenesuccinic acid (Itaconic acid) production by metabolically engineered Neurospora crassa using lignocellulosic biomass was evaluated by Zhao et al. (2018).
Cis-aconitic acid decarboxylase gene was heterologously expressed in N. crassa to synthesize Methylenesuccinic acid (Itaconic acid).
The engineered strain was capable of producing Methylenesuccinic acid (Itaconic acid) (20.41 mg/L) directly from lignocellulosic biomass.
Methylenesuccinic acid (Itaconic acid) production from biomass hydrolyzate using Aspergillus strains was reported by Jiménez-Quero et al. (2016).
Acid and enzymatic hydrolyzates were evaluated for the production of Methylenesuccinic acid (Itaconic acid).
Maximum Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid).
Much is known about the biosynthesis of Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid) is scarce.
In mammalian cells (guinea pig and rat liver) it was found that itaconate is converted to itaconyl-CoA and is further processed via citramalyl-CoA to pyruvate and acetyl-CoA.
Hereby, it was found that malonate has an inhibitory effect and an addition prevents the degradation of Methylenesuccinic acid (Itaconic acid) (Adler et al., 1957).
The first step of this degradation pathway can be catalyzed by the ubiquitous succinyl-CoA synthetase (Adler et al., 1957; Nagai, 1963; Schürmann et al., 2011).
The third step of the pathway is catalyzed by a citramalyl-CoA lyase, where genes from Chloroflexus aurantiacus (Friedmann et al., 2007) and Pseudomonas putida (Jain, 1996) 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 (Cooper and Kornberg, 1964).
Metabolic Engineering of the Methylenesuccinic acid (Itaconic acid) Pathway in A. terreus and A. niger The levels of Methylenesuccinic acid (Itaconic acid) which were reached with A. terreus are currently limited to about 85 g/L.
Although this is already a substantial amount it cannot be compared with the production of citric acid where titers over 200 g/L are steadily obtained in industrial processes.
Transferred to the Methylenesuccinic acid (Itaconic acid) production a maximal theoretical titer of about 240 g/L should be achievable (Li et al., 2011).
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 Methylenesuccinic acid (Itaconic 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 (Capuder et al., 2009).
This truncated pfkA version had also a positive impact on the Methylenesuccinic acid (Itaconic acid) accumulation when expressed in A. terreus (Tevz et al., 2010).
Another engineering approach deals with the intracellular oxygen supply.
The production of Methylenesuccinic acid (Itaconic acid) requires continuous aeration and already a short interruption of oxygen decreases the Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid) production.
Furthermore, the strains exhibited a better recovery after the aeration was interrupted (Lin et al., 2004).
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 Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid).
When the cadA gene (Kanamasa et al., 2008) was characterized in A. terreus genetic engineering of the pathway into another organism became possible.
Li et al. (2011) 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 Methylenesuccinic acid (Itaconic 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 (Jore et al., 2011; van der Straat et al., 2012).
Production Of Methylenesuccinic acid (Itaconic acid):
Since the 1960s, Methylenesuccinic acid (Itaconic 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).
Methylenesuccinic acid (Itaconic acid) is also produced in cells of macrophage lineage.
Methylenesuccinic acid (Itaconic 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.
Uses Of Methylenesuccinic acid (Itaconic acid):
Methylenesuccinic acid (Itaconic acid) is used in the preparation of acrylonitrile-butadiene-styrene and acrylate latexes.
Methylenesuccinic acid (Itaconic acid) is also used to prepare poly-Methylenesuccinic acid (Itaconic acid), resins biofuel components and ionomer cements.
Methylenesuccinic acid (Itaconic acid) finds application in the textile, chemical and pharmaceutical industries.
Methylenesuccinic acid (Itaconic 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, it 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, it acts as a binder and sizing agent in non-weaving fibers.
Methylenesuccinic acid (Itaconic acid) is used in the following products: polymers.
Methylenesuccinic acid (Itaconic acid) is used for the manufacture of: chemicals, rubber products and plastic products.
Release to the environment of Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic acid) is used to produce various polymers and copolymers.
When polymerized, it forms polyMethylenesuccinic acid (Itaconic acid), which can be used in the production of synthetic resins and biodegradable plastics.
Methylenesuccinic acid (Itaconic acid) is employed as a co-monomer in the synthesis of copolymers, enhancing the properties of the resulting materials.
For example, Methylenesuccinic acid (Itaconic 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, Methylenesuccinic acid (Itaconic acid) is used in the formulation of adhesives, coatings, and sealants.
These materials find applications in various industries, including construction, automotive, and packaging.
Methylenesuccinic acid (Itaconic acid) is used as a chelating agent in water treatment processes.
Methylenesuccinic acid (Itaconic acid) can bind to metal ions, helping to remove impurities from water, prevent scale formation, and improve water quality in industrial settings.
Methylenesuccinic acid (Itaconic acid) derivatives have been investigated for potential use in pharmaceuticals and drug delivery systems due to their biocompatibility and controlled-release properties.
Methylenesuccinic acid (Itaconic acid) can be used in the extraction of certain metals from ores or waste materials.
Its ability to chelate metal ions helps in the separation and recovery of valuable metals from complex mixtures.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic acid) continues to be a subject of research for its potential applications in various fields, including materials science, biotechnology, and sustainable chemistry.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic acid) is used in the production of synthetic polymers, including polyMethylenesuccinic acid (Itaconic acid) and various copolymers.
These polymers find applications in adhesives, coatings, and superabsorbent materials.
Methylenesuccinic acid (Itaconic acid)-based polymers can be used to create biodegradable plastics, which are increasingly important in reducing plastic waste and environmental impact.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic acid) is used in the formulation of adhesives, coatings, and sealants due to its adhesive properties and the ability to form stable polymer matrices.
Methylenesuccinic acid (Itaconic acid) derivatives have been studied for their potential use in pharmaceuticals and drug delivery systems.
Methylenesuccinic acid (Itaconic acid) is an organic acid that is used as a precursor in the polymer industry.
Methylenesuccinic acid (Itaconic acid) has been used in production of a surfactant that can increase skin permeation of topical treatments.
Methylenesuccinic acid (Itaconic acid) has also been used in creation of controlled-release hydrogel antibiotics.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic acid) and its derivatives are used in the oil and gas industry as additives in drilling fluids and cementing formulations.
Methylenesuccinic acid (Itaconic acid) has gained attention in biotechnology for its potential as a platform chemical for the production of bio-based chemicals and fuels.
Methylenesuccinic acid (Itaconic acid) is also studied in the context of metabolic engineering to enhance microbial production of Methylenesuccinic acid (Itaconic acid) for various applications.
Methylenesuccinic acid (Itaconic acid) is used as a reagent and research chemical in various scientific experiments and chemical processes.
Methylenesuccinic acid (Itaconic acid)s versatile chemical structure makes it useful in organic synthesis and as a starting material for the preparation of other compounds.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic 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.
Methylenesuccinic acid (Itaconic 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, Methylenesuccinic acid (Itaconic acid) can be used to improve the performance of water-based formulations, including increasing the adhesion of coatings to surfaces.
Safety Profile Of Methylenesuccinic acid (Itaconic acid):
Methylenesuccinic acid (Itaconic 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.
It is essential to wear appropriate personal protective equipment (PPE), such as gloves and safety goggles, when working with it.
Inhalation of Methylenesuccinic acid (Itaconic 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 Methylenesuccinic acid (Itaconic acid) in dusty or aerosol-generating situations.
Ingesting Methylenesuccinic acid (Itaconic acid) is generally not a common hazard in industrial or laboratory settings.
However, Methylenesuccinic acid (Itaconic 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, Methylenesuccinic acid (Itaconic acid) may decompose and release potentially hazardous byproducts, such as carbon monoxide, carbon dioxide, and other toxic gases.
Synonyms Of Methylenesuccinic acid (Itaconic acid):
Methylenesuccinic acid (Itaconic 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
Methylenesuccinic acid (Itaconic acid), >=99%
bmse000137
Probes1_000076
Probes2_000247
EC 202-599-6
2-Methylenesuccinic acid #
Methylenesuccinic acid (Itaconic acid) [MI]
NCIStruc1_001783
NCIStruc2_000502
2-methylene-butanedioic acid
NCIOpen2_004822
SCHEMBL21523
Methylenesuccinic acid (Itaconic acid) [INCI]
2-Propene-1,2-dicarboxylate
Methylenesuccinic acid (Itaconic 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 (Methylenesuccinic acid (Itaconic 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
