Appl Microbiol Biotechnol (2001) 56:289–295

DOI 10.1007/s002530100685

MINI-REVIEW

Th. Willke · K.-D. Vorlop

Biotechnological production of itaconic acid

Received: 5 January 2001 / Received revision: 4 April 2001 / Accepted: 6 April 2001 / Published online: 27 June 2001
© Springer-Verlag 2001

Abstract Itaconic acid (IA) is an unsaturated dicarbonic Due to the two carboxylic groups, rather low comono-
organic acid. It can easily be incorporated into polymers mer contents lead to copolymers with effective acidity
and may serve as a substitute for petrochemical-based and thus better adhesion and increased latex stability.
acrylic or methacrylic acid. It is used at 1–5% as a co- A special new market has opened for the use of IA in
monomer in resins and also in the manufacture of syn- artificial glass (Kin et al. 1998) and in bioactive com-
thetic fibres, in coatings, adhesives, thickeners and bind- pounds in agriculture, pharmacy and medicine (Bagavant
ers. The favoured production process is fermentation of et al. 1993). Additionally, as a versatile starting material,
carbohydrates by fungi, with a current market volume of IA opens the way for many selective enzymatic transfor-
about 15,000 t/a. Due to the high price of about mations to form useful polyfunctional building-blocks
US$4/kg, the use of IA is restricted. At present, the pro- (Ferraboschi et al. 1994).
duction rates do not exceed 1 g l–1 h–1, accompanied by
product concentrations of about 80 g l–1. New biotech-
nology approaches, such as immobilisation techniques,
screening programmes and genetic engineering, could
lead to higher productivity. Also, the use of alternative
substrates may reduce costs and thus open the market for
new and increased applications.

Introduction
With a new interest in sustainable development, the
chemical industry is making many attempts to replace
petrochemical-based monomers with natural ones. Ita- Fig. 1 Formula and some properties of itaconic acid
conic acid (IA, OECD name: methylene butanedioic
acid; common synonyms: methylene succinic acid, 3-
carboxy-3-butanoic acid, propylenedicarboxylic acid) is
one of the promising substances within the group of or-
ganic acids. It is a white crystalline unsaturated dicar-
bonic acid with one carboxyl group conjugated to the
methylene group (Fig. 1).
An overview of the properties and possible reactions
of IA was given by Tate (1970). IA can be regarded as
an α-substituted acrylic or methacrylic acid (Fig. 2) and
is isomeric with citraconic and mesaconic acid. It is
stable at acidic, neutral and middle basic conditions at
moderate temperatures (Tate 1981).
Th. Willke (✉) · K.-D. Vorlop
Federal Agricultural Research Centre, Institute of Technology
and Biosystems Engineering, Bundesallee 50,
38116 Braunschweig, Germany
e-mail: thomas.willke@fal.de Fig. 2 Structure of itaconic acid and related compounds
290
Historical background
Itaconic acid was discovered by Baup (1837) as a ther-
mal decomposition product of citric acid. The biosynthe-
sis by fungi from carbohydrates was first reported by
Kinoshita (1932), who isolated IA from the growth me-
dium of an osmophilic fungi, Aspergillus itaconicus.
Later, other fungal strains, mainly of the species Asper-
gillus terreus, were found to be more suitable. At the
Northern Regional Research Laboratory (NRRL) of the
U.S. Department of Agriculture in Peoria, Illinois, a
screening programme of more than 300 strains identified
the most published strain, A. terreus NRRL 1960 (Lock-
wood and Reeves 1945). At the same institute, prelimi-
nary attempts were also made to develop a biotechnical
process for IA production (Nelson et al. 1952; Pfeifer et
al. 1952). Later, optimised industrial processes were
established providing the limited market with IA. The
main developments in IA production (batch fermenta-
tion, free suspended biomass) took place before about
1966. Over the next 15 years, the interest in IA produc-
tion declined, as indicated by the few publications during
this time. Since the early 1980s, there has been increas-
ing concern regarding sustainability, environmental con-
servation, renewable resources and rising energy costs.
Therefore, the development of new fermentation tech-
nologies and more sophisticated bioprocess control has
led to renewed interest in improving IA production, and
novel fed-batch strategies and continuous processes
using immobilised cells have now been developed and
investigated.
Chemical synthesis
The first method of producing IA was by pyrolysing cit-
ric acid and hydrolysing the anhydrides (Baup 1837).
Another early method, discovered by Crasso, was the de-
carboxylation of aconitic acid (see Luskin 1974). He also
named the product “itaconic acid” as an anagram of the
source.
Chemical synthesis is mainly performed by dry distil-
lation of citric acid and subsequent treatment of the an-
hydride with water (Blatt 1943), or using the method of
Montecatini (Italy), from propargyl chloride, carbon
monoxide, nickel carbonyl and water (Chiusoli 1962).
Alternative approaches are the oxidation of mesityl
oxide and subsequent isomerisation of the formed citric
acid (Berg and Hetzel 1978), or the oxidation of isoprene
(Pichler et al. 1967). But none of these processes can
really compete with fermentation by fungi and therefore
none are practised commercially (Tate 1981).
Analysis
Published methods for IA analysis were summarised by
Tate (1970). Today, quantitative analysis of fermentation
broths is successfully achieved by separation on an ion-
exclusion column in the hydrogen form (e.g. Aminex
HPX87H, Biorad) and detection by UV spectroscopy at
210 nm (Kautola et al. 1985; Welter 2000).
Biotechnology
Microorganisms
Although A. terreus is now the mostly frequently used
commercial producer of IA, several attempts have been
made to find other microorganisms that are not as sensi-
tive to particular fermentation conditions (e.g. substrate
impurities) or which have a more favourable product
composition. Among the filamentous fungi, some usti-
laginales species also produce IA. While screening sev-
eral Ustilago strains for the production of ustilagic acid
and other metabolic products, Haskins et al. (1955)
found IA in the fermentation broth of an Ustilago zeae
strain. In a further screening of this species, one strain
was found to produce about 15 g IA/l. The Iwata Corp.
(Japan) tested different Ustilago species including U.
maydis, which produced 53 g IA/l within 5 days from
glucose (Tabuchi and Nakahara 1980; Tabuchi 1991).
Since growing filamentous fungi may cause particular
problems in bioreactors, yeasts were also tested for IA
production. Screening and a subsequent mutation yielded
a strain, identified as Candida sp., which produces IA
from glucose at about 35% yield (up to 35 g IA/l) in
5 days (Tabuchi 1981). A Candida mutant produced up
to 42 g IA/l after 5 days (Hashimoto et al. 1989), where-
as Rhodotorula species reached only 15 g IA/l from glu-
cose after 7 days (Kawamura et al. 1981). Another way
to find better IA producing strains is by mutagenesis. In
Japan, after mutation of A. terreus, one strain produced
82 g IA/l after 7 days (Yahiro et al. 1995).
Pathway
There have been many theories regarding the biosynthe-
sis of IA in fungi (Kinoshita 1932; Eimhjellen and
Larsen 1955; Shimi et al. 1962; Jakubowska 1977).
However, it seems most likely that, according to
Kinoshita (1932), the main route is via glycolysis and
the tricarboxylic acid cycle (Bently and Thiessen 1957;
Winskill 1983; Bonnarme et al. 1995). Thus, citric acid
and aconitic acid are intermediates, and IA is formed
from the latter by enzymatic decarboxylation (Fig. 3).
Fermentation
The IA fermentation process works optimally under
phosphate-limited growth conditions at sugar concentra-
tions between 100 and 150 g l–1. Once the fungal bio-
mass is established – preferably after inoculation from
spores – the phosphate level should be kept rather low to

Fig. 3 Biosynthesis of itaconic acid
prevent growth. For A. terreus NRRL1963, for example,
IA production started after phosphate depletion to a level
less than 1 mg l–1 (Welter 2000). During fermentation,
the pH decreases to about 2 and IA becomes the main
product. The temperature normally is kept at around
37 °C, but some investigators have tried to increase the
optimum temperature. After mutagenesis, for example,
at 40 °C, an A. terreus strain was able to produce five-
fold higher amounts of IA than the parent strain (Kariya
and Fujiwara 1994).
An adequate oxygen supply is essential because an-
aerobic conditions will irreversibly damage the biomass.
IA production is strongly affected by several medium
components including Fe, Mn, Mg, Cu, Zn, P and N.
Many studies have been conducted on the influence and
regulation of these substances during the production pro-
cess (Lockwood and Reeves 1945; Batti and Schweiger
1963; for a brief review, see Roehr and Kubicek 1996).
Currently, the most productive process that has been re-
ported is the one used by the Pfizer company (Nubel and
Ratajak 1964) and which involves a submerged fermen-
tation process using suspended A. terreus biomass, inoc-
ulated as spores on pretreated molasses. The initial pH of
about 5 drops to less than about 3 during the initial
growth phase. The second phase is characterised by
phosphate-limited growth and increased production of
IA, substantially free from other organic acids. In the
batch process by Pfizer, after raising the pH to 3.8 with
lime, about 150 g of sugar are converted to 71 g IA/l
291
within 4 days, corresponding to a productivity of 1 g l–1
h–1). Also, Batti and Schweiger (1963); von Fries (1966)
and Rhône-Poulenc (Jarry and Seraudie 1997) published
very high product concentrations of 75, 87, and 70 g l–1
under comparable conditions but only at significantly
lower productivities of 0.66, 0.66 and 0.44 g l–1 h–1, re-
spectively. Continuous processes using suspended bio-
mass allow only low yields of 12–16% (molar), accom-
panied by low product concentrations of 15 and 8 g l–1
and productivities of 0.48 and 0.32 g l–1/h–1, respectively
(Kobayashi and Nakamura 1966; Rychtera and Wase
1981).
Substrates
The best yields of IA are achieved with glucose or su-
crose as substrate, but other carbon sources like starch,
molasses, hydrolysates of corn syrup (Grislis et al. 1976)
or wood (Kobayashi 1978), and many combinations
thereof were also tested. As mentioned above, IA pro-
duction is very sensitive to several medium components,
including Fe, Mn, Cu, Zn, P, and N. This means that, in
order to get reproducible high productivities, the sub-
strate quality has to be controlled either by using refined
quality starting materials or by pretreatment of raw ma-
terials before or during fermentation. Which is the better
choice depends on the plant location, the market situa-
tion, energy costs and other factors. The most frequently
used substrates are beet or sugarcane molasses (Kane et
al. 1945; Nubel and Ratajak 1964), also pretreated by ion
exchange or ferro-cyanide (Batti and Schweiger 1963;
von Fries 1966); hydrolysed starch (Cros and Schneider
1993; Yahiro et al. 1997; Petruccioli et al. 1999); or sim-
ply sugars (sucrose, glucose). Glycerol, and mixtures of
sucrose and glycerol, were tested with good IA yields
and glycerol fully assimilated (Jarry and Seraudie 1997).
Attempts were also made using organic acids and gly-
cine as carbon sources (Petuchow et al. 1980). A very
new approach is the use of citric acid as precursor in a
membrane reactor. With the price of citric acid at about
one tenth of that of IA, this method should prove to be
economical (Bressler and Braun 2000).
Immobilisation
Only a few investigators have tried to use immobilised
biomass to improve biomass handling and IA produc-
tion. Adsorption of A. terreus was established using a
porous disk reactor system (Ju and Wang 1986), silica
based material (Kautola et al. 1985) or cubes of polyure-
thane foam (Kautola et al. 1991). Iwata (Japan) used a
polyacrylamide gel for cell entrapment resulting in a
maximum IA productivity of 83.4 mg h–1 and 30 g gel
after 10 days, which means a specific IA production rate
of 2.8 mg g–1 h–1. This is the highest rate reported so far
with immobilised biomass; however, only 21 g IA l–1
were achieved (Horitsu et al. 1983; Horitsu and Kawai
292

1984). Alginate as immobilisation matrix was also used Economic aspects

for entrapment by Kautola et al. (1985), but with poor
results. A new and most promising immobilisation meth-
od is the entrapment of spores or cells in polyvinyl alco-
hol formed as small beads (Pruesse et al. 1998) or lens-
shaped particles (Jekel et al. 1998). The advantages over
the above-mentioned materials are the very good long-
term stability and ease of handling combined with a low
price. The specific IA production rate of these biocata-
lysts of 100 mg g–1h–1 exceeds the results of Horitsu et
al. (1985) by more than 30-fold (Welter 2000).
Large-scale production
Published data regarding IA production and sales vol-
umes are very scarce. Until 1979, the only producer in
the United States was the Charles Pfizer Co., owing the
patent of Nubel and Ratajak (1964). Later, manufacturers
in Europe, Russia (probably surface method), Japan and
China followed. Due to the lack of published data,
Table 1 can give only an impression.

Product Recovery Use

The ordinary product separation was described by Lock-
wood (1975): Mycelium and solids are removed by fil-
tration. After evaporation at sufficiently acidic condi-
tions, cooling and crystallisation, an industrial grade IA
(e.g. for esterification) is obtained. For higher grade IA,
the hot evaporate is treated with activated carbon and fil-
tered. Mother liquor from crystallisation may then be
solvent-extracted or treated by anion exchange. Other
recovery methods have been reviewed by Milsom and
Meers (1985). Recrystallisation from water gives a pure
product when the substrates are glucose or sucrose. Pre-
cipitation of insoluble IA salts is also possible. IA is then
redissolved with the addition of alkali salts like ammonia
(Kobayashi 1971). To lower the costs, new technologies
such as ultrafiltration, reverse osmosis (Kobayashi et al.
1973), ion exchange (Kobayashi et al. 1980), or electro-
dialysis have been evaluated. In the case of purified sub-
strates, e.g. sugars or high-test molasses, the use of elec-
trodialysis could lower the plant investment costs by
about 40% (Kobayashi et al. 1972). Furuya et al. (1968)
proposed the addition of methanol prior to clarifying the
fermentation broth with a filter press. Evaporation of the
filtrate should give 90.5% recovery.
The Canadian import of IA amounted to between 1,200
and 12,000 t in 1986, whereas Finland used 300–500 t/a
and Sweden 33–300 t/a at the same time (WHO/UNEP
2000). The total market size is regarded as about
10,000 t/a (Bressler and Braun 2000) to 15.000 t/a
(WHO/UNEP 2000)
Price Trends
Price calculations have been made on the basis of pub-
lished details from a pilot plant of a submerged-culture
batch process (Pfeifer et al. 1952). Providing a capacity
of 1,500 t/a, production costs were computed to be
US$0.69/kg. IA produced by fermentation was offered
commercially in 1955 at a price of US$1.3/kg. In 1971,
Pfizer supplied two grades of IA for US$0.76 and
US$0.84/kg respectively (Luskin 1974), whereas in 1974
refined IA was sold for US$1.84/kg and the industrial
grade product for US$0.49/kg (Lockwood 1975). In
1979, the US price was US$1.92–$2.04/kg (Tate 1981).
The most recent price information is between US$4/kg
(Cargill 2000) and US$4.3/kg (Bressler and Braun
2000).

Table 1 Manufacturers of itaconic acid

Company Location Since Capacity (t/a) Reference

Pfizer Food Science New York, USA; 1945 5,000–7,000 (Kane 1945; Miall 1978;
Sandwich, UK (1989) Bennett 1992)
Cargill/Cultor Food Science Eddyville, USA 1996 (Cargill 1996; CCCL 2000)
unknown Riga, Latvia (Karklins et al. 1969)
Iwata Chemicals Kogyo, Japan 1970 3,500 (Anonymous 1970b)
Rhodia (formerly Melle, France 1995 1,000–5,000 (WHO/UNEP 2000)
Rhône-Poulenc)
Tianli Biological Yunnan, China 1993 2,000 (SWB 1992)
Fermentation Factory
Leizhou Yueli Itaconic Acid Guangdong, China 1,000 (Yueli 2000)
Shandong Zhongshun Shandong, China 1,000 (Zhongshun 2000)
Jiangshan Guoguang Zhejiang, China 1996 2,000 (4,000) (Gouguang 1998)
Biochemistry
Qingdao Langyatai (Group) Qingdao, China 1,500 (Langyatai 2000)

Applications
Resins, lattices, fibres
The polymerised methyl, ethyl or vinyl esters of IA are
used as plastics, adhesives elastomers and coatings. Co-
polymers of IA yield rubber-like resins of excellent
strength and flexibility and water-proofing coatings with
good electrical insulation (Smith et al. 1974). Styrene-
butadiene lattices (1–5% IA) exhibit superior adhesion
and are preferably used in carpet backings and paper
coatings. IA is also used in emulsion paints where it im-
proves adhesion of the polymer. Acrylic lattices supple-
mented with IA are used as nonwoven fabric binders.
Small amounts (< 2%) of IA added to vinylidene chlo-
ride coatings lead to improved adhesion to paper, cello-
phane and poly(ethylene therephthalate) films, particu-
larly in packaging and photography. When, for example,
a cellophane film is coated with the polymer containing
IA, the heat-seal strength is about 3.5 times than that of
films coated with a copolymer not containing IA (Pitzl
1951).
Polyacrylonitrile copolymers incorporating low levels
of IA exhibit improved dye receptivity, which results in
more efficient dying and deeper shades (Tate 1981), a
process which is used in the textile industry. Pigmented
dispersion resins containing 0.1–1.5% IA possess im-
proved wet abrasion resistance (Zhao et al. 1999). IA
may also be used as an hardening agent in organosilox-
anes for use in contact lenses (Novicky 1981; Ellis et al.
1994). New fields of research include artificial gems and
synthetic glasses with special nonlinear characteristics
(Kin et al. 1998).
Detergents, cleaners and other products
Alkali salts of the homopolymer poly(itaconic acid) have
been recommended for use in detergents (Lancashire
1969) and sequestrants (Carter and Irani 1968). Copoly-
mers of acrylic acid and IA (5–95%) applied at concen-
trations up to 100 ppm may be used as a scale inhibitor
in boilers (Walinsky 1984).
An important reaction of IA with amines results in N-
substituted pyrrolidones, which can be used as thickeners
in lubricating grease (Gordon and Coupland 1980) and in
detergents, shampoos, pharmaceuticals and herbicides.
An imidazoline derivative has also been claimed as an
active component in shampoos (Christiansen 1980). In
the detergent industry, IA competes with fumaric or
malic acid (Smith et al. 1974). The sulfonated poly(ita-
conic) acid is probably also used as an industrial cleaner
(Citrex) (Anonymous 1970a). It may remove unsaturated
polyester resins, cleans gel coat lines, paint-guns and
lines, chopper guns, uncured polyurethane foam, most
paints, graffiti and inks (InTech 1996). Terpolymers con-
taining up to 10% IA can be used as drilling fluids. IA
monoester compounds with excellent hardness, compres-
sion strength and durability are useful for dental adhe-
sives or dental fillers (Saitoh et al. 1993).
293
Bioactive components
Several mono- and diesters of partly substituted IA pos-
sess significant anti-inflammatory or analgesic activities
(Bagavant et al. 1994). IA is also used as a precursor for
some potential nootropic agents (Valenta et al. 1994).
Some monoesters of IA have several plant-growth re-
lated properties. In the 1980s, much work was done, es-
pecially in Eastern Europe and Japan, on the influences
of IA-methylester and hexylester of IA on plant physiol-
ogy (Karanov et al. 1989; Isogai et al. 1987; Suzuki et al.
1986).
Trends and Prospects
The potential for substitution of acrylic or methacrylic
acid in polymers is high. Therefore the market for IA is
still growing. In addition, the outstanding properties in
polymer chemistry, pharmacy and agriculture open up
new applications. The reactions of IA and its derivatives
to polymers have by far not been exhausted (Rüdiger
2000). Further research in this area to find new or modi-
fied polymers is of great interest and most promising. A
major area of application is the building industry, with
its strong demand for sealing materials, adhesives and
elastic fillers. In 1995, the German market for adhesives
for use in buildings was about 470 million DM. The sub-
stitution of these products with natural ones, based on
renewable resources, creates the possibility for an in-
creasing market for IA.
Nonetheless, it is clear that expansion of the IA mar-
ket is only possible by further reduction of production
costs. Since possible low-cost substrates for IA produc-
tion are well-known, process costs can only be lowered,
for example, by the introduction of new technologies.
One promising means is immobilisation of the biocata-
lyst in biocompatible polymers, which permits nonsterile
process conditions with repeated use of the biocatalysts,
and at the same time better protection of the cells against
inhibitory effects or process disturbance. Immobilisation
also may ease process handling and facilitate down-
stream processing. All of this reduces personnel needs
and may reduce process and energy costs.
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