REVIEW Enzymatic synthesis of kojic acid esters and ...

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Chen, C. S., Liu, K. J., Lou, Y. H., & Shieh, C. J. (2002). Optimisation of kojic acid .... Li, X. F., Jeong, J. H., Lee, K. T., Rho, J. R., Choi, H. D.,. Kang, J. S., & Son ...
Chemical Papers 67 (6) 573–585 (2013) DOI: 10.2478/s11696-013-0336-6

REVIEW

Enzymatic synthesis of kojic acid esters and their potential industrial applications Ahmad Firdaus B. Lajis, c,d Mahiran Basri, a,d Rosfarizan Mohamad, Muhajir Hamid, a Siti Efliza Ashari, a Nurazwa Ishak, a Azulia Zookiflie, a,d Arbakariya B. Ariff*

a Department

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a

b,d

of Bioprocess Technology, b Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, of Chemistry, Faculty of Science, d Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

c Department

Received 16 July 2012; Revised 5 October 2012; Accepted 18 November 2012

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In this paper, enzymatic methods for the synthesis of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4one (kojic acid) esters are reviewed. Important process parameters related to the synthesis of kojic acid esters such as the type of immobilized lipase, solvent, temperature, initial water activity, water content, pH, metal salts, enzyme loading, substrates mole ratio, and acyl donors are highlighted and discussed. The properties of kojic acid esters related to their solubility, stability, cytotoxicity, depigmenting activity, tyrosinase inhibitory, metal-chelating, anti-oxidant, and other biological activities are also highlighted. At present, kojic acid and its esters are widely used in cosmetic and skin health industries as skin whitening agents. The advantages and disadvantages of various kojic acid esters are compared and possible industrial applications of these derivatives are also discussed. c 2013 Institute of Chemistry, Slovak Academy of Sciences 

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Keywords: kojic acid, kojic acid esters, esterification, depigmenting, tyrosinase, immobilized lipase

Introduction

Large scale production of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (kojic acid, KA), a fungal secondary metabolite and a naturally occurring organic acid, has been studied intensively by several researchers (Ariff et al., 1997; Wan et al., 2005; ElAasar, 2006; Mohamad & Ariff, 2007; Terabayashi et al., 2010). KA is an iron and copper chelator capable to prevent oxidation, photodamage, hyperpigmentation, and skin wrinkling (Mitani et al., 2001; Briganti et al., 2003). As natural organic acid, KA is biodegradable. This organic acid also possesses some other valuable and potent biological activities such as the ability to reduce mustard toxicity (Smith & Lindsay, 2001), potential to be used in therapeutic drugs (Sudhir et al., 2005), as an inducer of microphage activation (Rodrigues et al., 2011), and metal chelating agent (Stenson & Cioffi, 2007). Potential industrial *Corresponding author, e-mail: [email protected]

applications of KA have been reviewed by Mohamad et al. (2010). KA and KA derivatives are widely used as skin whiteners in cosmetic creams. Antimicrobial activities of KA and KA derivatives against bacteria and fungi have been reported (Dowd, 1990). KA and KA derivatives possess also other biological activities such as antioxidant, anti-inflammatory, and metal-chelating ones (Kobayashi et al., 2001; Rho et al., 2007). However, prominent commercial applications of kojic acid and its esters are in the cosmetic and skin health industries. The hydrophilicity of KA has restricted its application in cosmetic, oily food, and pharmaceutical products. Moreover, there are concerns about its toxicity (Burdock et al., 2001), irritancy (Nakagawa et al., 1995), carcinogenicity, mutagenicity (Wei et al., 1991), hepatocarcinogenicity (Chusiri et al., 2011; Moto et al., 2006), genotoxicity, and tumor-initiating activity (Nohynek et al., 2004; Nawarak et al., 2008; Tamura

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Fig. 1. Basic molecular structure of kojic acid esters; esterification at position 7 (C-7) (a), esterification at position 5 (C-5) (b).

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et al., 2006). In order to improve the chemical and biological activities of KA, its derivatives with new and improved chemical properties and biological activities have been developed. Most of KA derivatives were chemically synthesized and less effort has been made to consider enzymatic synthesis of KA derivatives. Initial attempts were made to synthesize KA glucoside via an enzymatic process using sucrose phosphorylase from Leucostoc mesenteroides, α-amylase from Bacillus subtilis, immobilized β-galactosidase from Bacillus circulans, cultured cells of Eucalyptus perriniana, and mutated Xanthomonas campestris (Hassan et al., 1995; Yamamoto et al., 1997; Nishimura et al., 1994; Hsieh et al., 2007; Nakajima et al., 2001). Unfortunately, KA glucoside is highly water soluble due to its hydrophilicity, which can restrict its application in oil based products (Nishimura et al., 1994). Several attempts on enzymatic esterification of KA and fatty acid to KA esters were made (Ashari et al., 2009) aimed at the improvement of their hydrophobicity in order to widen their application possibilities in other areas such as cosmetic industry. KA esters such as KA dipalmitate have been commercialized for cosmetic and skin health applications (Al-Edresi & Baie, 2010). However, the development of KA esters via enzymatic processes and their possible industrial and commercial applications have not been reviewed and discussed thoroughly.

Synthesis of KA esters Chemical and enzymatic esterification Basic molecular structure of KA esters is shown in Fig. 1. KA has two functional groups: a hydroxyl group (OH) at C-5 and a carboxylic group (COOH) at C-7. During the esterification process, the OH group is removed and the fatty acid (R) is attached to KA to form KA monoesters such as 5-O-KA monoester and 7-O-KA monoester. Several KA esters have been chemically and enzymatically synthesized at the position C-5 and C-7 of KA with fatty acids. In chemical processes, esterification of KA oleate has been catalyzed by N,N  -dicyclohexylcarbodiimide

(DCC)/4-dimethylaminopyridine (DMAP) in dichloromethane. The yield of up to 80 % was achieved via this process with the reaction time from 24 h to 48 h (Manosroi et al., 2005). However, this process employs chemicals such as dichloromethane and other hazardous chemicals which are not environmentally friendly and extra safety precautions are necessary to be employed during the process. Other chemical esterification processes require multiple steps and use various chemicals, which add cost to the KA esters production (Rho et al., 2010a, 2010b; Streffer et al., 1998; Kang et al., 2009; Kim et al., 2003; Yoon et al., 2010). In enzymatic processes, esterification of KA is prepared and catalyzed by lipases and proteases in organic or solvent-free systems (Liu & Shaw, 1998; Ashari et al., 2009; Chaibakhsh et al., 2009; Raku & Tokiwa, 2003). This process utilizes fewer chemicals, which is more cost-effective and environmentally friendly. Most of the enzyme, if used in its immobilized form can be reused repeatedly with consistent specific enzyme activity and yield for the KA esters synthesis (Kawashima et al., 2001; Liu & Shaw, 1998; Yee et al., 1997). The yield of enzymatically synthesized KA monoesters was affected by the type of the catalytic enzyme, acyl donors, reaction temperature, organic solvents, KA to fatty acid ratio, metal ions, water content, and pH. Screening of enzymes for esterification

Various enzymes have been screened for enzymatic synthesis of KA esters and most of them were derived from fungi and bacteria (Table 1). For instance, esterification of KA and fatty acids was catalyzed by lipases from Candida rugosa, Candida antarctica, Rhizomucor miehei, Pseudomonas cepacia, Penicillium camembertii, Mucor sp., and the protease from Bacillus subtilis. Screening of various lipases showed that the specific enzyme activity of Pseudomonas cepacia lipase, Rhizomucor miehei lipase, Candida antarctica lipase, and Candida rugosa lipase is of about 3.738 × 10−6 mmol of ester per min per mg of protein, 1.678 × 10−6 mmol of ester per min per mg of

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Table 1. Enzymatic synthesis of kojic acid esters in organic solvent Substrate (KA/FA) Temperature Reaction time Trade name/ Source type of enzyme

KA esters

Yield References

mole ratio

◦C

h

%

PS amano

Pseudomonas cepacia

KAML KAMO

4:1 4 : 1–1 : 4

50 50

24–48 24–48

22.0–82.0 Liu and Shaw (1998), 26.0–45.0 Khamaruddin et al. (2008), Chen et al. (2002)

Novozyme 435

Candida antarctica

KAML KAMO

4:1 4:1

50 50

24–48 48

1.0–53.0 Liu and Shaw (1998), 0.6 Kobayashi et al. (2001), Khamaruddin et al. (2008)

RMIM

Rhizomucor miehei

KAMO KAML KAMP

2 : 1–4 : 1 1:5 1:5

50 50 50

24–48 15–42 12–42

Amano AP-6

Aspergillus niger

KAML KAMO KAML KAMO

Sigma

Candida cylindracea

KAML KAMO

Toyo Jozo

Chromobacterium viscosum (LP-101-S)

KAML KAMO

Novo IM

Mucor miehei

KAML KAMO KAMO

4:1 4:1

50 50

24–48 48

0.2 0

Liu and Shaw (1998), Khamaruddin et al. (2008)

4:1 4:1

50 50

48 48

0.3 0.1

Liu and Shaw (1998)

4:1 4:1

50 50

48 48

1.0 0.6

Liu and Shaw (1998)

4:1 4:1

50 50

48 48

9.5 12.0

Liu and Shaw (1998)

4:1 4:1

50 50

48 48

9.2 8.4

Liu and Shaw (1998)

4:1

50

24–48



4:1 4:1

50 50

48 48

13.0 36.5

30

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Lipase (Sigma) Candida rugosa

Khamaruddin et al. (2008), Ashari et al. (2009), Lajis et al. (2012)

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Amano N-conc. Rhizopus sp.

37.2 34.9 39.3

KAML KAMO

Khamaruddin et al. (2008)

Amano G

Penicillium camembertii

Protease

Bacillus subtilis

Lipase

Eupergit C-lipase

KAMO

4:1

50

24



Khamaruddin et al. (2008)

TLIM

Thermomyces lanuginosus

KAMO

2:1

50

24–32



Khamaruddin et al. (2008), Ashari et al. (2009)

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7-O-kojic 1 : 5–1 : 6 acid ester

Liu and Shaw (1998)

13.0–27.0 Raku and Tokiwa (2003)

FA – fatty acid, KAMP – kojic acid monopalmitate.

protein, 4.407 × 10−7 mmol of ester per min per mg of protein, and 2.597 × 10−7 mmol of ester per min per mg of protein, respectively (Khamaruddin et al., 2008). The yield ranging from 40–60 % was obtained for the enzymatic synthesis of C-5-KA monoester using lipases from Candida antarctica, Pseudomonas cepacia, and Rhizomucor miehei (Liu & Shaw, 1998; Kobayashi et al., 2001; Khamaruddin et al., 2008; Ashari et al., 2009). Very low yield (13–27 %) of regioselective synthesis of C-7-KA ester by Bacillus subtilis protease was reported (Raku & Tokiwa, 2003). Pseudomonas cepacia lipase can also be employed to synthesize a wide range of KA esters using different fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid for specific synthesis of KA laurate (25.4 %), KA myristate (2.3 %), KA palmitate (11.9 %), KA stearate (7.0 %), KA oleate (40.1 %), and KA linoleate (9.7 %) (Khamaruddin et al., 2008).

Other immobilized lipases such as Aspergillus niger lipase, Rhizopus sp. lipase, Candida cylindracea lipase, and Chromobacterium viscosum lipase were reported to have very low or no catalytic activity towards the esterification of fatty acids and kojic acid (Liu & Shaw, 1998).

Process parameters of kojic acid esters synthesis Organic solvent Organic solvents are more suitable than aqueous and inorganic solvents for specific synthesis, enzyme recovery, stability increase, and enzyme reusability, unwanted side reaction reduction and contamination risk lowering (Yee et al., 1997). It is important to identify the most suitable organic solvent for the synthesis of KA esters. The value of logP of an organic sol-

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in the esterification rate can occur at temperatures lower than the optimum temperature for lipase activity while protein denaturation and enzyme activity reduction can occur at temperatures higher than the optimum temperature. The optimum temperature for enzymatic synthesis of KA esters is depended on the source of lipase and also on the substrates used. The highest yield (40.1 %) of KAMO synthesis using lipase from Pseudomonas cepacia was obtained at 50 ◦C (Khamaruddin et al., 2008). On the other hand, the highest yield (82.0 %) of KAML synthesis using lipase from Pseudomonas cepacia was obtained at 44 ◦C (Chen et al., 2002). The reaction temperature also affects the stability and reusability of immobilized enzymes. For instance, the maximum activity of lipases from Pseudomonas cepacia and Penicillium camembertii can be maintained for ten days at low temperatures (40 ◦C), while Novozyme 435 lipase from Candida antarctica was capable to retain its enzymatic activity at temperatures of up to 70 ◦C for several cycles (Zheng, 2012; Mutschler et al., 2009; Tai & Brunner, 2009). However, lipase activity of Candida antarctica at temperatures higher than 80 ◦C was greatly reduced, to 90 %, after ten cycles (Zheng, 2012). Lipases from Candida sp. and Mucor miehei-20 (IM-20) were active even at 100 ◦C and 90 ◦C, respectively (Zhang & Xu, 1995; Knez et al., 1990; Chowdary et al., 2000). In solvent-free systems, the melting point of fatty acids can also affect the esterification process (Mutschler et al., 2009). The optimum temperature for enzymatic synthesis of KA esters also changed with the different substrates used. For example, oleic acid and lauric acid, with the melting points at 14.0 ◦C and 43.2 ◦C, respectively, can be employed in the esterification process at the reaction temperature of 50 ◦C in a solvent-free system (Mutschler et al., 2009). However, reaction temperatures above 50 ◦C were required for palmitic acid, stearic acid, and myristic acid with the melting points at 62.9 ◦C, 69.6 ◦C, and 54.4 ◦C, respectively (Mutschler et al., 2009). Therefore, a suitable enzyme which can maintain its catalytic activity at high temperatures should be chosen for the esterification to synthesize kojic acid esters.

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vent can significantly affect the esterification process (Laane et al., 1987). High ratio of KA and fatty acids esterification to KA esters was achieved with specific solvents such as acetonitrile, acetone, and chloroform, which have the logP values of –0.33, –0.21, and 2.00, respectively (Zong et al., 2008). This observation suggests that a suitable logP value and the hydrophobicity of the solvent are necessary conditions to achieve the required solubility of the substrates. Organic solvents such as methanol, ethyl acetate, toluene, hexane, cyclohexanol, dimethyl sulfoxide (DMSO), diethyl ether, t-butanol, and isooctane are not suitable for this esterification process due to the substrate insolubility and enzyme–solvent incompatibility (Liu & Shaw, 1998; Tai & Brunner, 2009). Incompatible solvent may strip off water present as the microaqueous layer around the enzyme, affecting thus its active conformation. Hydrophobic solvents can preserve the catalytic activity of immobilized lipase for several cycles (Krishna et al., 2001; Syamsul et al., 2010). A co-solvent mixture can also be used to improve the hydrophobicity of the reaction mixture to achieve higher efficiency of the esterification process (Zong et al., 2008). On the other hand, inappropriate solvent can significantly reduce the enzyme activity and stability. For instance, immobilized lipase B from Candida antarctica (Novozyme 435) was found stable at high temperatures (60 ◦C) in a mixture of toluene/water (ϕr = 10 : 1) for 48 h. However, it completely disappeared in the presence of 6–12 M hydrogen peroxide (T¨ ornvall et al., 2007). Immobilized lipase also showed excellent catalytic activity in solventfree systems (Li et al., 2011). However, the number of studies on the esterification of KA in solvent-free systems is low and the process is not widely discussed. Solvent-free systems have been identified as a potential alternative for KA esters production (Adnani et al., 2011). For possible irreversible conversion of KA and fatty acids to KA esters, water has to be removed in these systems using a vacuum pump or molecular sieves (Mutschler et al., 2009). Temperature Immobilized lipases are normally thermostable and have higher catalytic activity than free enzymes (Kumar et al., 2006). In general, optimal KA esters synthesis is related to optimum temperature of the immobilized enzymes used in the esterification. For example, lipases from Pseudomonas cepacia and Penicillin camembertii have the optimum temperature of 50 ◦C (Liu & Shaw, 1998). The yield of KA monolaurate (KAML) synthesized using lipase from Pseudomonas cepacia at 30 ◦C and 50 ◦C was 19.7 % and 26.0 %, respectively. Meanwhile, the yield of KA monooleate (KAMO) synthesized by lipase from Penicillin camembertii at 30 ◦C and 50 ◦C was 17.2 % and 36.5 %, respectively (Liu & Shaw, 1998). A decrease

Initial water activity (aw ), water content, pH, and metal salts Khamaruddin et al. (2008) demonstrated that the yield of KAMO decreases with the increasing initial water activity. Low water activity was needed for lipase active conformation during the esterification, increasing thus its activity (Chowdary & Prapulla, 2002; Radzi et al., 2011). The yield of KAMO obtained at the initial water activity of 0.11 and 0.90 was 30 % and 10 %, respectively. Reduced yield of KA esters can be caused by the enzyme inactivation and reverse hydrolysis (Zong et al., 2008), and also by the pro-

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Pb2+ , Mo2− , Fe3+ , NH4+ , K+ , and Zn2+ (Kumar & Kanwar, 2011; Kanwar et al., 2005) in the reaction mixture. Enzyme loading, substrate molar ratio, and acyl donor The KA esterification process is significantly influenced by the enzyme loading. The yield of KAML of up to 80 % was achieved at the enzyme to substrate mass ratio of 38 % in a 19 h reaction (Chen et al., 2002). In most cases, the enzyme to substrate mass ratio of 1 % to 10 % is sufficient to achieve optimum synthesis of KA esters (Kapucu et al., 2003; Liu & Shaw, 1998; Masyithah et al., 2011). In the scale-up, the enzyme loading was important for the KA esters synthesis as excessive enzyme loading can hinder the catalytic process of esterification (Syamsul et al., 2010). Theoretically, ideal mole ratio of KA and fatty acid is 1 : 1. However, the use of different KA to fatty acid ratios, either lower or higher than 1, to obtain optimum yield of KA esters has been reported (Khamaruddin et al., 2008; Liu & Shaw, 1998). The acyl donor also plays an important role in the synthesis of KA monoesters to obtain high yields and ensure a specific attachment site. Higher KAML yield was obtained in the esterification using lauric acid compared to those using lauric anhydride, ethyl laurate, and trilaurin (Liu & Shaw, 1998). On the other hand, higher KAMO yield was obtained in the esterification using oleic acid compared to those using oleic anhydride, ethyl oleate, and triolein (Liu & Shaw, 1998). Various acyl donors also exhibit different viscosities that may also affect the viscosity of the reaction mixture, which in turn, may affect the yield of KA esters.

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duction of water as a side product of the esterification process (Laane et al., 1987). It is important to remove water during the esterification process to achieve a high product yield. Several methods, such as membrane processes, vaporization, vacuum evaporation, air drying, reactive distillation, and molecular sieves can be used to eliminate water from the reaction mixture (Syamsul et al., 2010). During the esterification, active conformation of lipase is influenced by water activity, the rate of acyl migration decreased as the water activity increases (Salis et al., 2003). These researchers also claimed that the optimum water activity for esterification using Lipozyme RMIM and Novozyme 435 was 0.35 and 0.53, respectively. Water content also affects the enzymatic synthesis of kojic acid oleate, where high water content reverses the esterification process (Liu & Shaw, 1998). The optimum water content for the highest yield of KAML from the esterification of KA and lauric acid was 10 % (Chen et al., 2002). Optimum water activity is important to maintain its catalytic activity; complete removal of water form the reaction mixture can distort the enzymatic three-dimensional conformation (Yee et al., 1997). On the other hand, the presence of an excessive water content in the reaction mixture and during the enzyme recovery can also affect the stability and reusability of the immobilized lipase (Martins et al., 2011). For example, the activity of Candida antarctica lipase is significantly reduced in the presence of initial water activity of more than 0.1 (Chamouleau et al., 2001). Enzymatic synthesis of KA esters is also greatly influenced by the pH of the reaction mixture. The highest yield of KA esters for the esterification using lipase from Penicillium camembertii was obtained at pH 6 (Liu & Shaw, 1998). pH of the esterification mixture can be influenced by the catalytic pH of a particular enzyme. For other lipases, such as the lipase from Candida sp., optimum pH is in the range of 6 to 9 (Dahlan et al., 2005; Zhang & Xu, 1995). Catalytic pH of an immobilized enzyme relies on the pH of the solvent from which it was recovered (Yee et al., 1997). Immobilized lipase from Candida antarctica type B has the highest stability at pH 8 (Brígda et al., 2007) and pH 10 (Zoumpanioti et al., 2010). On the other hand, catalytic pH of the lipase from Rhizomucor miehei is 7.0 (Zoumpanioti et al., 2010) and 7.5 (Acosta et al., 2011). Catalytic pH for the lipase from Psedomonas cepacia, Penicillium simplictssimum, Rhizopus delemar, and Rhizopus arrhizux was observed ranging from 5 to 7 (Stamatis et al., 1993). Moreover, pH of the substrates has also to be optimized to enhance the esterification process (Yee et al., 1997). Enzymatic synthesis of KA esters was also enhanced by the presence of metal salts such as CaCl2 , CuCl2 , and MnCl2 , (Liu & Shaw, 1998) and metal ions such as Co2+ , Ba2+ ,

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Purification of kojic acid esters Chromatography can be used as a simple method of KA esters separation and purification. KA and fatty acids can be easily separated from KA esters using column chromatography with ethyl acetate and hexane as the mobile phase while a silica gel column was used as the stationary phase (Kobayashi et al., 2001; Ashari et al., 2009). In this method, silica gel was kept in hexane for 24 h before it was packed in the column. The efficiency and time required for total separation depends on the column length and the amount of mixture to be separated. The mobile phase, e.g. acetonitrile, was removed from the KA esters solution by a rotary vacuum evaporator at temperatures ranging from 70 ◦C to 80 ◦C. The solvent and the mobile phase can be collected from the vacuum evaporator and reused in the subsequence purification process. KA esters are stable at higher temperatures than KA (Raku & Tokiwa, 2003).

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Table 2. Large scale esterification process for the synthesis of various products Solvent

Immobilized lipase Candida sp. 99-125. Organic Thermomyces Solventlanuginosus free (Lipozyme TLIM).

Batch

0.5 1 2 50

Oleyl oleate Wax esters Adipate ester Oleyl alcohol Sterol esters

Semicontinuous

3

7-O-lauroyl kojic acid

Novozyme 435

Batch

60

Glycerol distearate

Novozyme 435

2-ethylhexyl palmitate

Candida sp. 99–125 immobilized Organic on surfactant modified cotton membrane

Batch

2

Continuous

Fluidized bed reContiactor nuous (FBR)

Disadvantages



Celite, the fabric membrane is a better immobilization support A large surface area Reused for at least 21 batches



16

Diacylglycerol (DAG) sterol esters citronellyl butyrate farnesyl laurate

Candida rugosa Lipozyme RM SolventIM Thermomyces free lanuginosus (Lipozyme TLIM)



Amyl caprylate

Candida rugosa

Easy to control Less shear effect Easy enzyme recycle

Large scale kojic acid esters production The synthesis of KA esters has been successfully optimized using central composite rotatable design

References

Specific reactions Not using homogeneous chemical catalysts Reaction at low temperatures Shorter time period

High efficiency Low cost and ease of construction, operation and maintenance Shorter reaction times Reuse of the enzyme without separation Able to handle substrates of low solubility – Consistent product quality Improved enzyme stability Suitable for long-term and large production More cost effective than the batch operation

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Packed bed reactor (PBR)

Advantages

Radzi et al. (2006), Sengupta et al. The lipase (2010), Specific reactions activity deLi et al. Not using homogecreased in (2011), neous chemical catastirred tank Keng et Organic lysts reactors may al. (2008), Reaction at low be due to the Chaibakhsh temperatures higher shear et al. (2009), force Kobayashi et Extremely low vapour al. (2001), pressure Csanádi et al. Thermal stability (2010) Ionic liquid Tuneable property regard to polarity, hydrophobicity and solvent miscibility

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Stirred tank reactor

Immobilized lipase

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Stirred tank reactor

Mode of Volume Product of operation /L esterification

ho

Type of reactor

Organic



Tan et al. (2006)

Cheong et al. (2007), Sengupta et al. (2010), Dahlan et al. (2005), Rahman et al. (2011)

Saponji´c et al. (2010)

and response surface methodology (Chen et al., 2002; Ashari et al., 2009). Research on enzymatic esterification of KA is mostly carried out at the laboratory scale using a screw-capped test tube and a shake flask,

A. F. B. Lajis et al./Chemical Papers 67 (6) 573–585 (2013)

STR: immobilized enzymes can be reused without prior separation, consistent quality of the product, no shear effect and it is easy to control and suitable for long-term industrial production (Rahman et al., 2011; Dahlan et al., 2005). Higher synthesis yield of sterolester with lower migration of acyl groups was achieved using the PBR compared to STR (Sengupta et al., 2010). Lower substrate to enzyme ratio is required for efficient esterification process in a PBR than in an STR as the reaction times are significantly reduced (Rahman et al., 2011; Dahlan et al., 2005). However, the use of a PBR for the production of KA derivatives by enzymatic esterification has not been reported in literature. FBR is a combination of a CSTR and a PBR, which consists of settling and stirring compartments. The substrate is passed upwards through the immobilized enzyme bed at high velocity to lift the particles from the fixed bed state. A conventional FBR does not encounter problems with plugging and thus problems related to significant pressure drop can be avoided (Saponji´c et al., 2010). However, a pump with high power prevents extensive utilization of FBR (Kosugi et al., 1990). Direct utilization of crude palm oil in large scale production of KA esters reduced the production cost, but the yield was very low and the reaction was not specific. It was shown that direct esterification of crude palm oil and KA gave only a 8.9 %, 1.1 %, and 7.6 % yield of KA palmitate, KA linoleate, and KA oleate, respectively (Khamaruddin et al., 2008). Therefore, specific substrates have to be used for high performance KA esters production. In most cases, commercial immobilized enzymes were used for the synthesis of KA and the use of laboratory prepared immobilized enzymes has not yet been reported. For instance, the supports method normally applies commercial immobilized lipase immobilized on acrylic resin, on anionic resin (Duolite A568), and on a macroporous anionic resin for Novozyme 435, IM-20, and RMIM, respectively (Laszlo et al., 2011; Soledad de Castro et al., 2000; Kuo et al., 2012; Radzi et al., 2011). Others reported support methods for Novozyme 435 use Lewatit E (Soledad de Castro et al., 2000).

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where mixing and mass transfer limit the reactions. In order to industrially commercialize this technology, it is essential to run the KA esters production in reactors enabling scale-up of the process. Various types of reactors, such as stirred tank reactor (STR), membrane reactor (MR), fluidized bed reactor (FBR), and packed bed reactor (PBR), have been used for large scale esterification to obtain various products (Table 2). The use of a reactor also enables the process to be conducted in various modes of operation: batch, continuous, and semi-continuous. A reactor with the volume of up to 60 L has been used for large scale esterification process using organic solvents, solvent-free conditions, and ionic liquid. The use of STR for the esterification with free and immobilized lipase has been reported (Keng et al., 2008; Jin et al., 2012; Chaibakhsh et al., 2009, 2010). Mixing conditions for the improvement of the mass transfer in the STR were achieved using a suitable design of the impeller and agitation speed (Radzi et al., 2006; Keng et al., 2008). The improvement of the mass transfer increasing the frequency of the contact between the enzyme and substrates increased the reaction rate and product yield. In an STR system, optimum agitation speed was necessary to achieve optimum esterification process performance and enzyme sustainability, especially for systems employing immobilized lipase (Keng et al., 2008). For example, optimum agitation speed in a reactor with rushton turbine impellers gave the highest reaction yield compared to AL-hydrofoil and 2-bladed elephant ear impellers for the production of oleyl alcohol (Keng et al., 2008). In the study of Keng et al. (2008), high stability of Lipozyme RMIM was observed confirmed by its ability to be repeatedly used to provide palm esters in a high yield even after 15 reaction cycles at optimum agitation speed. The shear effect of excessive agitation speed reduced the performance and stability of the enzyme after several cycles (Keng et al., 2008). Moreover, scale-up of the process using an STR system was not complicated and it required simple modification for consistent and maximum KA esters production. The use of a continuous stirred tank reactor (CSTR) for the production of 7-O-lauroyl KA was reported by Kobayashi et al. (2001); the KA esters yield of 53 % was achieved after four runs using immobilized lipase from Candida antarctica in acetonitrile. In a stirred MR, the enzyme was immobilized on a fabric membrane which provided large surface area for the reaction (Tan et al., 2006). Since direct interaction between the impeller and the enzyme did not occur in the MR, the shear effect can be avoided. Esterification in an MR could be repeated up to 21 batches with consistent esterification degree of up to 95 % for 2-ethylhexyl palmitate. PBR is another option of industrial production through the enzymatic esterification process. PBR is known to have some advantages over the CSTR and

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Future development in enzymatic synthesis of kojic acid esters Synthesis of KA esters using immobilized lipases in solvent systems has been used and widely reported. Recently, a method of KA esters synthesis using immobilized lipases in solvent-free systems has been proposed (Chaibakhsh et al., 2009; Adachi & Kobayashi, 2005). In solvent-free systems, fatty acids can be liquefied by altering the reaction temperature according to their respective melting points (Mutschler et al., 2009). For a high performance esterification process, lipases stable at high temperatures are required.

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Table 3. Chemical properties and biological activities of kojic acid esters Chemical properties Kojic acid esters

Method of synthesis

Polarity

Kojic acid monooeleate Enzymatic Hydrophobic

C-5

Unknown

Depigmenting agent



Unknown

Depigmenting agent Depigmenting agent Depigmenting agent

Unknown

Kojic acid monopalmitate Kojic acid monolaurate

Enzymatic Hydrophobic

C-5

Unknown

Enzymatic Hydrophobic

C-5

Unknown

Lauroyl kojic acid

Hydrophobic

Liu and Shaw (1998), Khamaruddin et al. (2008), Ashari et al. (2009) Al-Edresi and Baie (2010) Lajis et al. (2012) Liu and Shaw (1998), Chen et al. (2002), Lajis et al. (2012)



Unknown

Depigmenting agent

Kaatz et al. (1999)

C-5

Unknown

Kobayashi et al. (2001)

C-7

Unknown



Unknown

Depigmenting and metal chelating agent Depigmenting agent Unknown

C-7

Improved

C-7

Improved

Enzymatic Hydrophobic

7-O-kojic acid oleate

Chemical

Hydrophobic

O-vinylated and Cvinylated kojic acid 7-O-vinyl adipoyl kojic acid 7-O-hexanoyl kojic acid 7-O-octanoyl kojic acid, 5-O-octanoyl kojic acid, 2 -O-octanoyl kojic acid, and 2 ,5-Ooctanoyl kojic acid 7-O-deconoyl kojic acid Dimers of (4-oxo-4Hpyran-2-yl)acrylic acid 3,4-methylenedioxy cinnamic acid ester of kojic acid

Chemical

Hydrophobic

Enzymatic Hydrophobic Enzymatic Hydrophobic

C-7 and C-5

Improved

Enzymatic Hydrophobic

C-7

Improved

ut

Enzymatic Hydrophobic

Chemical

Hydrophobic



Unknown

Chemical

Hydrophobic



Unknown

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Kojic acid dipalmitate

Kojic acid octanoates

Hydrophobic

Biological Esterification at Biodegradability activities

Manosroi et al. (2005) Asghari et al. (2010)

Depigmenting agent Depigmenting agent Depigmenting agent

Raku and Tokiwa (2003) Raku and Tokiwa (2003) Raku and Tokiwa (2003), Streffer et al. (1998)

Depigmenting agent Depigmenting agent Depigmenting agent and antioxidant

Raku and Tokiwa (2003) Yoon et al. (2010) Rho et al. (2007)

4-oxo-4H-pyran-2yl) acrylic acid ester derivatives Kojic acid esters

Chemical

Hydrophobic



Unknown

Depigmenting agent

Kang et al. (2009)

Chemical

Hydrophobic



Unknown

Depigmenting and antiinflammatory agent

Rho et al. (2011)

Kojic acid cinnamate

Chemical

Hydrophobic



Unknown

Depigmenting agent

Cho et al. (2012)

The synthesis of KA monoesters using a single lipase is another focus in research related to enzymatic esterification of KA (Ashari et al., 2009). A specific lipase can be used to esterify kojic acid with a fatty acid at a specific position, such as at the C-5 and C-7 (Kobayashi et al., 2001; Ashari et al., 2009). Therefore, it is possible to synthesize another type of KA derivatives using two or more lipases. KA dipalmitate is commercially used in many cosmetic and skin beauty products (Al-Edresi & Baie,

2010). Some esters of carboxylic acid create a sweet odor or flavor for food industry (Rajendran et al., 2009; Jin et al., 2012). Many other types of carboxylic acids, such as amino acid, keto acids, aromatic carboxylic acid, dicarboxylic acid, tricarboxylic acid, and α-hydroxyl carboxylic acid can also be used in the development of KA derivatives via enzymatic processes. However, there is a lack of reports on the use of carboxylic acid for enzymatic synthesis of KA derivatives.

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Chemical and physical properties of kojic acid esters

Conclusions

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Chemical properties of KA esters are summarized in Table 3. At least 14 hydrophobic KA esters with improved biodegradability have been reported so far. KAMO (C24 H38 O5 ), an example of generally studied KA ester, is a semisolid compound with the molecular mass of 407 g mol−1 , melting point at 34.6 ◦C, insoluble in water and other polar solvents (Manosroi et al., 2005). The melting point of KAMO is between the melting points of KA (153.5 ◦C) and oleic acid (14 ◦C). This means that the melting point of KA esters is strongly affected by the fatty acid used. Specific melting point of KA esters is necessary for their specific formulation and utilization in food and cosmetic products. Other lipasecatalyzed KA esters are KAML (C18 H28 O5 ), KA palmitate (C24 H36 O5 ), KA myristate (C24 H38 O5 ), KA sterate (C24 H40 O5 ), KA linoleate (C24 H36 O5 ), 7-O-vinyl adipoyl KA (C14 H16 O7 ), 7-O-hexanoyl KA (C12 H16 O5 ), 7-O-octanoyl KA (C14 H20 O5 ), and 7-O-deconoyl KA (C16 H24 O5 ) (Raku & Tokiwa, 2003; Khamaruddin et al., 2008). Most acylations of KA esters improved their solubility in hexane, soybean oil, chloroform, DMSO, and other non-polar solvents (Kobayashi et al., 2001). Some KA esters were proven to have higher biodegradability and can be considered as environmentally friendly compounds, which are safe to be used in food, cosmetic, and pharmaceutical products (Raku & Tokiwa, 2003; Rajendran et al., 2009).

2010). KA esters are potential anti-oxidants. For example, the ability of 3,4-methylenedioxy cinnamic acid ester of KA to inhibit lipid peroxidation of HaCaT keratinocytes is by about 47 % higher compared to that of tertbutylhydroperoxide, which was used as the control (Rho et al., 2007). KA esters also have radical scavenging activity that prevents wrinkles and the aging process (Kobayashi et al., 2001; Raku & Tokiwa, 2003). Dowd (1990) also claimed that KA esters are effective synergists for pyrethroid and carbamate insecticides on Helicoverpa zea and Spodoptera frugiperda.

Biological activities and potential industrial application of kojic acid esters

A

Table 3 also summarized the biological activities of KA esters. Structural modification of KA esters has broaden their application range in cosmetic, food, agricultural, medicine, and pharmaceutical industries due to their enhanced biological activities as depigmenting, anti-oxidant, anti-inflammatory, and antiscavenging agents. It also improved their entrapment in the vesicles with higher entrapment efficiency and also their permeability for topical skin whitening applications through skin and drug carriers into the blood circulation system (Kobayashi et al., 2001; Kang et al., 2009; Raku & Tokiwa, 2003; Streffer et al., 1998). The depigmenting effect of KA esters on pigmented cell lines such as B16F10, B16F1, melan-A, melan-AB, and human melanocytes has been reported (Kang et al., 2009; Rho et al., 2007, 2010b; Kim et al., 2003; Lajis et al., 2012). KA esters inhibit tyrosinase activities and melanin production in the pigmented B16F10 cell line by about 2–10 times better than KA (Yoon et al., 2010; Kang et al., 2009; Cho et al., 2012). The depigmenting activity of KA dipalmitate has also been tested in vivo using mouse (Al-Edresi & Baie,

In conclusion, enzymatic processes can be efficiently used for the production of KA esters. These processes require fewer chemicals and hazardous compounds compared to other KA esters production methods. Efficient production of KA esters by enzymatic esterification can be easily scaled-up to enable mass production at industrial scale. Several parameters such as the type of the enzyme, solvent, temperature, water activity, water content, pH, metal salts, enzyme loading, substrate molar ratio, and acyl donor should be considered in the optimization of the esterification process to achieve improved KA esters production. It is also interesting to note that the chemical and biological activities of KA esters, synthesized by the esterification process, have significantly improved compared to that of KA. KA esters are not only less toxic and have higher depigmenting activity than KA, they are also hydrophobic which makes them readily incorporated in oil based cosmetic and skin care products. The depigmenting activity of KA esters has been tested on hyper-pigmented cells in vitro. It is known that KA esters such as KA monoesters and KA diesters have been commercially produced and are widely used in cosmetics and other commercial products (Balaguer et al., 2008; Al-Edresi & Baie, 2010; Whittemore & Neis, 1998; Nagai & Izumi, 1981; Tokiwa et al., 2003; Clendennen et al., 2012). The development of KA derivatives has enhanced their chemical properties, improved their biological activities, and broadened their application range in new industrial areas. Therefore, kojic acid derivatives are considered to be promising compounds for the applications in various biotechnology and health industries. References

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