Applied Microbiology and Biotechnology

, Volume 84, Issue 4, pp 597–606 | Cite as

Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus

  • Mitsuyasu Okabe
  • Dwiarti Lies
  • Shin Kanamasa
  • Enoch Y. Park


More than 80,000 tons of itaconic acid (IA) is produced worldwide each year and is sold at a price of around US$ 2/kg. The IA production yield from sugar is higher than 80 g/l. The widespread use of IA in synthetic resins, synthetic fibers, plastics, rubbers, surfactants, and oil additives has resulted in an increased demand for this product. However, at present, the IA production capacity exceeds the demand because this product has a restricted range of applications. Studies have been actively conducted in different biomedical fields—dental, ophthalmic, and drug delivery—to extend the range of applications of IA. Recently, many researchers have attempted to replace the carbon source used for microbial production of IA with cheaper alternative substrates. However, there is still a need for new biotechnology innovations that would help to reduce the production costs, such as innovative process development and strain improvement to allow the use of a low-quality carbon source. In this short review, we discuss the following aspects of IA production: strain improvement, process development, identification of the key enzyme cis-aconitic acid decarboxylase (CAD) in the IA metabolic pathway, metabolic importance of CAD, and new applications of IA.


Itaconic acid Aspergillus terreus cis-Aconitic decarboxylase Biorefinery 


  1. Abraham M, Sawant SB (1990) Hydrodynamics and mass transfer characteristics of packed bubble columns. Chem Eng J 43:95–105CrossRefGoogle Scholar
  2. Batti M, Schweiger LB (1963) Process for the production of itaconic acid. US Patent 3,078,217 (to Miles Laboratories)Google Scholar
  3. Bentley R, Thiessen CP (1957a) Biosynthesis of itaconic acid in Aspergillus terreus. I. Tracer studies with 14C-labeled substrates. J Biol Chem 226:673–687Google Scholar
  4. Bentley R, Thiessen CP (1957b) Biosynthesis of itaconic acid in Aspergillus terreus. II. Early stages in glucose dissimilation and the role citrate. J Biol Chem 226:689–701Google Scholar
  5. Bentley R, Thiessen CP (1957c) Biosynthesis of itaconic acid in Aspergillus terreus. III. The properties and reaction mechanism of cis-aconitic acid decarboxylase. J Biol Chem 226:703–720Google Scholar
  6. Blanco MD, Bernardo MV, Teijón C, Sastre RL, Teijón JM (2003) Transdermal application of bupivacaine-loaded poly(acrylamide(A)-co-monomethyl itaconate) hydrogels. Int J Pharm 255:99–107CrossRefGoogle Scholar
  7. Bonnarme P, Gillet B, Sepulchre AM, Role C, Beloeil JC, Ducrocq C (1995) Itaconate biosynthesis in Aspergillus terreus. J Bacteriol 177:3573–3578Google Scholar
  8. Bresser E, Braun S (2000) Conversion of citric acid to itaconic acid in a novel liquid membrane bioreactor. J Chem Technol Biotechnol 75:66–72CrossRefGoogle Scholar
  9. Christiansen A (1980) Surface active amide and amideazolines. GB Patent 1,574,916 (to Miranol Chemical)Google Scholar
  10. Crisp S, Wilson AD (1980) Cements. US Patent 4,222,920 (to Mat’l Res Dev Co. England)Google Scholar
  11. Culbertson BM (2006) New polymeric materials for use in glass-ionomer cements. J Dent 34:556–565CrossRefGoogle Scholar
  12. De TK, Bergey EJ, Chung SJ, Rodman DJ, Bharali DJ, Prasad PN (2004) Polycarboxylic acid nanoparticles for ophthalmic drug delivery: an ex vivo evaluation with human cornea. J Microencapsul 21:841–855CrossRefGoogle Scholar
  13. Dwiarti L (2006) Study of biorefinery of sago starch for itaconic acid production. PhD thesis, United Graduate School of Agricultural Science, Gifu University (Shizuoka University)Google Scholar
  14. Dwiarti L, Yamane K, Yamatani H, Kahar P, Okabe M (2002) Purification and characterization of cis-aconitic acid decarboxylase from Aspergillus terreus TN484-M1. J Biosci Bioeng 94:29–33CrossRefGoogle Scholar
  15. Dwiarti L, Otsuka M, Miura S, Yaguchi M, Okabe M (2007) Itaconic acid production using sago starch hydrolysate by Aspergillus terreus TN484-M1. Bioresour Technol 98(17):3329–37CrossRefGoogle Scholar
  16. Eimhjellen KE, Larsen H (1955) The mechanism of itaconic acid formation by Aspergillus terreus. 2. The effect of substrates and inhibitors. Biochem 60:139–147Google Scholar
  17. Ellis EJ, Olson AP, Bonafini JR (1994) Improved itaconic acid copolymeric compositions for contact lenses. WO Patent 9,423,314 (to Polymer Technology Corp., MA)Google Scholar
  18. Ferraboschi P, Casati S, Grisenti P, Santaniello E (1994) Selective enzymatic transformations of itaconic acid derivates: An access to potentially useful building blocks. Tetrahedron 50:3251–3258CrossRefGoogle Scholar
  19. Goda H, Nagase T, Tanoue S, Sugiyama J, Steidl S, Tuncher A, Kobayashi T, Tsukagoshi N, Brakhage AA, Kato M (2005) Nuclear translocation of the heterotrimeric CCAAT binding factor of Aspergillus oryzae is dependent on two redundant localising signals in a single subunit. Arch Microbiol 184:93–100CrossRefGoogle Scholar
  20. Gong B, Wang Y (2002) ICP-AES determination of traces of noble metal ions pre-concentrated and separated on a new polyacrylacrylaminothiourea chelating fiber. Anal Bioanal Chem 372:597–600CrossRefGoogle Scholar
  21. Gordon AA, Coupland K (1980) Mehrzweckschmiermittel. DE Patent 3,001,000 (to Exxon Research and Engineering)Google Scholar
  22. Hashimoto K, Shray Y, Tanigaki M (1989) Culture method for microorganism and plant cell. JP Patent 01,296,977 (to Kao Co., Japan)Google Scholar
  23. Helle U, Onken U (1988) Continuous microbial leaching of a pyritic concentrate by Leptospirillum-like bacteria. Appl Microbiol Biotechnol 28:553–558CrossRefGoogle Scholar
  24. Horitsu H, Takahashi Y, Tsuda J, Kawai K, Kawano Y (1983) Production of itaconic acid by Aspergillus terreus immobilized in polyacrylamide gels. Eur J Appl Microbiol Biotechnol 18:358–360CrossRefGoogle Scholar
  25. Horton P, Park K, Obayashi T, Nakai K (2006) Protein Subcellular Localization Prediction with WoLF PSORT. Proceedings of the 4th Annual Asia Pacific Bioinformatics Conference APBC06, Taipei, Taiwan. pp. 39–48Google Scholar
  26. Kanamasa S, Dwiarti L, Okabe M, Park EY (2008) Cloning and functional characterization of the cis-aconitic acid decarboxylase (CAD) gene from Aspergillus terreus. Appl Microbiol Biotechnol 80:223–229CrossRefGoogle Scholar
  27. Kato M, Aoyama A, Naruse F, Tateyama Y, Hayashi K, Miyazaki M, Papagiannopoulos P, Davis MA, Hynes MJ, Kobayashi T, Tsukagoshi N (1998) The Aspergillus nidulans CCAAT-binding factor AnCP/AnCF is a heteromeric protein analogous to the HAP complex of Saccharomyces cerevisiae. Mol Gen Genet 257:404–411CrossRefGoogle Scholar
  28. Kautola H, Vahvaselka M, Linko YY, Linko P (1985) Itaconic acid production by immobilized Aspergillus terreus from xylose and glucose. Biotechnol Lett 7:167–172CrossRefGoogle Scholar
  29. Kautola H, Vassilev N, Linko YY (1990) Continuous itaconic acid production by immobilized biocatalysts. J Biotechnol 13:315–323CrossRefGoogle Scholar
  30. Kautola H, Rymowicz W, Linko YY, Linko P (1991) Itaconic acid production by immobilized Aspergillus terreus with varied metal additions. Appl Microbiol Biotechnol 35:154–158Google Scholar
  31. Kawamura D, Furuhashi M, Saito O, Matsui H (1981) Production of itaconic acid by fermentation. JP Patent 56,137,893 (to Iwata)Google Scholar
  32. Kiese S, Ebner HG, Onken U (1980) A simple laboratory air-lift fermentor. Biotechnol Lett 2:345–350CrossRefGoogle Scholar
  33. Kin R, Sai T, So S (1998) Itaconate copolymer with quadratic nonlinear optical characteristic. JP Patent 10,293,331Google Scholar
  34. Kinoshita K (1932) Über die Produktion von Itaconsäure und Mannit durch einen neuen Schimmelpilz Aspergillus itaconicus. Acta Phytochim 5:271–287Google Scholar
  35. Kobayashi T (1967) Itaconic acid fermentation. Process Biochem 2:61–65Google Scholar
  36. Kobayashi T, Nakamura I (1964) Dynamics in mycelia concentration of A. terreus K26 in steady state of continuous culture. J Ferment Technol 44:264–274Google Scholar
  37. König B, Schügerl K, Seewald C (1982) Strategies for penicillin fermentation in tower-loop reactors. Biotechnol Bioeng 24:259–280CrossRefGoogle Scholar
  38. Kurian JV (2005) A new polymer platform for the future—Sorona from corn derived 1, 3-propanediol. J Pol Env 13:159–167CrossRefGoogle Scholar
  39. Lancashire E (1969) Soap compositions having improved curd-dispersing properties. US Patent 3,454,500 (to Procter and Gamble)Google Scholar
  40. Lockwood LB, Reeves MD (1945) Some factors affecting the production of itaconic acid by Aspergillus terreus. Arch Biochem 6:455–469Google Scholar
  41. Matsushima H, Maeda K, Fukaya H, Kasahara K, Mase Y (1972) Scale-up of fermentors (I). Power requirement. J. Ferment Technol 50:100–104Google Scholar
  42. Moshaverinia A, Roohpour N, Darr JA, Rehman IU (2009) Synthesis and characterization of a novel N-vinylcarrolactam-containing acrylic acid terpolymer for application in glass-ionomer dental cements. Acta Biomater 5:2101–2108CrossRefGoogle Scholar
  43. Moser A (1991) Tubular bioreactor: case study of bioreactor performance for industrial production and scientific research. Biotechnol Bioeng 37:1054–1065CrossRefGoogle Scholar
  44. Nagaraja UP, Kishore G (2005) Glass ionomer cement—the difference generation. Trends Biomater Artif Organs 18:158–165Google Scholar
  45. Naihu J, Wang SS (1986) Continuous itaconic acid production by Aspergillus terreus immobilized in a porous disk bioreactor. Appl Microbiol Biotechnol 23:311–314Google Scholar
  46. Nubel RC, Ratajak ED (1964) Process for producing itaconic acid. US Patent 3,044,941 (to Pfizer)Google Scholar
  47. Okabe M, Ohta N, Park Y (1993) Itaconic acid production in an air-lift bioreactor using a modified draft tube. J Ferment Bioeng 76:117–122CrossRefGoogle Scholar
  48. Onken U, Jostmann Th (1984) Influence of pressure on growth of pseudomonas fluorescens. Biotechnol Lett 6:413–418CrossRefGoogle Scholar
  49. Park Y, Ohta M, Okabe M (1993) Effect of dissolved oxygen concentration and agitation rate on itaconic acid production by Aspergillus terreus. Biotechnol Lett 15:583–586CrossRefGoogle Scholar
  50. Park Y, Itida M, Ohta N, Okabe M (1994) Itaconic acid production using an air-lift bioreactor in repeated batch culture of Aspergillus terreus. J Ferment Bioeng 77:329–331CrossRefGoogle Scholar
  51. Pfeifer VF, Vojnovich C, Heger EN (1952) Itaconic acid by fermentation with Aspergillus terreus. Ind Eng Chem 44:2975–2980CrossRefGoogle Scholar
  52. Pitzl G (1951) US Patent 2,570,478 (to Du Pont)Google Scholar
  53. Reddy CS, Singh RP (2002) Enhanced production of itaconic acid from corn starch and market refuse fruits by genetically manipulated Aspergillus terreus SKR10. Bioresour Technol 85:69–71CrossRefGoogle Scholar
  54. Rober M, Kubicek C (1996) Production of primary metabolism. In: Rehm HJ, Reed G (eds) Biotechnology. VCHmbH, Weinhelm, pp 364–379Google Scholar
  55. Saitoh Y, Kanda K, Fukuda K (1993) Dental adhesive comprising an itaconic acid monoester compound. US Patent 5,234,972 (to Ube Ind. Ltd. Japan)Google Scholar
  56. Sakai A, Kusumoto A, Kiso Y, Furuya E (2004) Itaconate reduces visceral fat by inhibiting fructose 2, 6-bisphosphate synthesis in rat liver. Nutrition 20:997–1002CrossRefGoogle Scholar
  57. Sen M, Yakar A (2001) Controlled release oof antifungal drug terbinafine hydrocholode from poly(N-vinyl 2-pyrrolidone/itaconic acid) hydrogels. Int J Pharm 228:33–41CrossRefGoogle Scholar
  58. Siegel MH, Merchuk JC, Schugerl K (1986) Air-lift reactor analysis: Interrelationships between riser, downcomer, and gas–liquid separator behavior, including gas recirculation effects. AIChE J 32:1585–1596CrossRefGoogle Scholar
  59. Shimi IR, Nour EL, Dein MS (1962) Biosynthesis of itaconic acid by Aspergillus terreus. Arch Mikrobiol 44:181–188CrossRefGoogle Scholar
  60. Smith JE, Nowakowska-Waszczuk A, Anderson JG (1974) Organic acid production by mycelial fungi. In: Spencer B (ed) Industrial aspects of biochemistry. Elsevier, Amsterdam, pp 297–317Google Scholar
  61. Stanojević M, Krušić MK, Filipović J, Parojći J, Stupar M (2006) An investigation into the influence of hydrogel composition on swelling behavior and drug release from poly(acrylamide-co-itaconic acid) hydrogels in various media. Informa Pharm Sci 13:1–7Google Scholar
  62. Tabuchi T (1981) Itaconic acid production by a yeast belonging to the group Candida. Agric Biol Chem 45:475–479Google Scholar
  63. Tabuchi T, Nakahara T (1980) Preparation of itaconic acid. JP Patent 55 034 017 (to Mitsubishi)Google Scholar
  64. Tasdelen B, Kayaman-Apohan N, Güven O, Baysal BM (2004) Preparation of poly(N-isopropylacrylamide/itaconic acid) copolymeric hydrogels and their drug release behavior. Int J Pharm 278:343–351CrossRefGoogle Scholar
  65. Tate BE (1981) Itaconic acid and derivatives. In: Grayson M, Eckroth E (eds) Kirk–Othmer encyclopedia of chemical technology, vol 3. Wiley, New York, pp 865–873Google Scholar
  66. Träger M, Qazi GN, Onken U, Chopra CL (1989) Comparison of airlift and stirred reactors for fermentation with Aspergillus niger. J Ferment Bioeng 68:112–116CrossRefGoogle Scholar
  67. Träger M, Qazi GN, Buse R, Onken U (1992) Comparison of direct glucose oxidation by Gluconobacter oxydans subsp. suboxydans and Aspergillus niger in a pilot scale airlift reactor. J Ferment Bioeng 74:274–281CrossRefGoogle Scholar
  68. Tsao GT, Cao NJ, Du J, Gong CS (1999) Production of multifunctional organic acids from renewable resources. Adv Biochem Eng Biotechnol 65:243–280Google Scholar
  69. Walinsky SW (1984) (Meth) acrylic acid/itaconic acid copolymers their preparation and use as antiscalants. US Patent 4,485,223 (to Pfizer)Google Scholar
  70. Willke T, Vorlop KD (2001) Biotechnological production of itaconic acid. Appl Microbiol Biotechnol 56(3–4):289–295CrossRefGoogle Scholar
  71. Wu JY, Wu WT (1991) Fed-batch culture of Saccharomyces cerevisiae in an airlift reactor with net draft tube. Biotechnol Prog 7:230–233CrossRefGoogle Scholar
  72. Xing Y, Fikes JD, Guarente L (1993) Mutations in yeast HAP2/HAP3 define a hybrid CCAAT box binding domain. EMBO J 12:4647–4655Google Scholar
  73. Yahiro K, Takahama T, Park Y, Okabe M (1995) Breeding of Aspergillus terreus Mutant TN-484 for an itaconic acid production with high yield. J Ferm Bioeng 79:506–508CrossRefGoogle Scholar
  74. Yahiro K, Takahama T, Jia S, Park Y, Okabe M (1997a) Comparison of air-lift and stirred tank reactors for itaconic acid production by Aspergillus terreus. Biotechnol Lett 19:619–621CrossRefGoogle Scholar
  75. Yahiro K, Takahama T, Park Y, Okabe M (1997b) Efficient itaconic acid production from raw corn starch. J Ferm Bioeng 84:375–377CrossRefGoogle Scholar
  76. Yoshida F (1988) Bubble column research in Japan. Chem Eng Technol 11:205–212CrossRefGoogle Scholar
  77. Zhao CL, Roser J, Dersch R, Baunstark R (1999) Dispersion resins containing itaconic acid for improving wet abrasion resistance. WO Patent 9 947 611 (to BASF)Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Mitsuyasu Okabe
    • 1
  • Dwiarti Lies
    • 3
  • Shin Kanamasa
    • 2
  • Enoch Y. Park
    • 4
  1. 1.Musashino Chemical Laboratory, Ltd.TokyoJapan
  2. 2.Department of Environmental Biology, College of Bioscience and BiotechnologyChubu UniversityKasugaiJapan
  3. 3.Faculty of AgricultureShizuoka UniversityShizuokaJapan
  4. 4.Integrated Bioscience Section, Graduate School of Science and TechnologyShizuoka UniversityShizuokaJapan

Personalised recommendations