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Biotechnological routes based on lactic acid production from biomass


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Contents 1. 2. 3. Introduction . . . . . . . . . . . . . . . . . . . . Fermentative production of lactic acid . . . . . . . . Biotechnological production of lactic acid derivatives . 3.1. Esterication of lactic acid . . . . . . . . . . 3.2. Polymerization of lactic acid . . . . . . . . . 3.3. Hydrogenation of lactic acid . . . . . . . . . 3.4. Dehydrogenation of lactic acid . . . . . . . . 3.5. Dehydration of lactic acid . . . . . . . . . . 3.6. Comparison between the biotechnological and 4. Conclusions and prospects . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

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State Key Laboratory of Microbial Technology, Shandong University, Jinan 250100, People's Republic of China State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China

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Chao Gao a, b, Cuiqing Ma a,, Ping Xu b,

Keywords: Lactic acid Polylactic acid Pyruvic acid Acrylic acid 1,2-Propanediol Lactate ester

Article history: Received 24 January 2011 Received in revised form 25 July 2011 Accepted 26 July 2011 Available online xxxx

Lactic acid, the most important hydroxycarboxylic acid, is now commercially produced by the fermentation of sugars present in biomass. In addition to its use in the synthesis of biodegradable polymers, lactic acid can be regarded as a feedstock for the green chemistry of the future. Different potentially useful chemicals such as pyruvic acid, acrylic acid, 1,2-propanediol, and lactate ester can be produced from lactic acid via chemical and biotechnological routes. Here, we reviewed the current status of the production of potentially valuable chemicals from lactic acid via biotechnological routes. Although some of the reactions described in this review article are still not applicable at current stage, due to their greener properties, biotechnological processes for the production of lactic acid derivatives might replace the chemical routes in the future. 2011 Published by Elsevier Inc.

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1. Introduction

Currently, fossil resources are used to produce the vast majority of chemicals. However, the use of fossil resources causes serious environmental problems. Discovery of new environment-friendly sources of chemicals has captured the attention of researchers. Different

Corresponding author. Tel.: + 86 531 88364003; fax: + 86 531 88369463. Correspondence to: P. Xu, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China. Tel.: + 86 21 34206647; fax: + 86 21 34206723. E-mail addresses: macq@sdu.edu.cn (C. Ma), pingxu@sjtu.edu.cn (P. Xu). 0734-9750/$ see front matter 2011 Published by Elsevier Inc. doi:10.1016/j.biotechadv.2011.07.022

building-block intermediates have been produced from biomass via biotechnological routes (Corma et al., 2007). Lactic acid (2-hydroxypropionic acid, CH3\CHOHCOOH) is a naturally occurring organic acid (John et al., 2007). Owing to its versatile applications in food, pharmaceutical, textile, leather, and chemical industries, lactic acid is the most important hydroxycarboxylic acid (Datta and Henry, 2006). Because lactic acid has both carboxylic and hydroxyl groups, it can also be converted into different potentially useful chemicals such as pyruvic acid, acrylic acid, 1,2propanediol, and lactate ester (Fan et al., 2009) (Fig. 1). Chemical and biotechnological routes that can help transform lactic acid into valuable chemicals have been described in previous studies. For green production of those valuable chemicals, biotechnological

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Please cite this article as: Gao C, et al, Biotechnological routes based on lactic acid production from biomass, Biotechnol Adv (2011), doi:10.1016/j.biotechadv.2011.07.022

C. Gao et al. / Biotechnology Advances xxx (2011) xxxxxx


L-lactate

Fig. 1. Summary of the chemicals derived directly from lactic acid (Corma et al., 2007).

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routes are desirable. In this review, we focused our attention on biotechnological routes based on lactic acid from biomass. The drawbacks as well as improvements of the production of lactic acid derivatives via biotechnological routes were also discussed. 2. Fermentative production of lactic acid Lactic acid has 2 optical isomers: L-lactic acid and D-lactic acid. Lactic acid can be produced via either chemical synthesis or microbial fermentation. Chemical synthesis of lactic acid is mainly based on the hydrolysis of lactonitrile by strong acids, and this process yields a racemic mixture of the 2 isomers (Holten et al., 1971; John et al., 2007). Other chemical routes, such as base-catalyzed degradation of sugars; oxidation of propylene glycol; reaction of acetaldehyde, carbon monoxide, and water at high temperatures and pressures; hydrolysis of chloropropionic acid; and nitric acid oxidation of propylene, are not technically and economically feasible processes for lactic acid production (Datta et al., 1995). Compared to chemical synthesis, the biotechnological process for lactic acid production offers several advantages: low substrate costs, production temperature and energy consumption (Datta and Henry, 2006). Lactic acid-producing microorganisms use pyruvic acid as the precursor for lactic acid production. The conversion of pyruvic acid to lactic acid can be catalyzed by 2 types of enzymes: NAD-dependent

dehydrogenase and NAD-dependent D-lactate dehydrogenase (Garvie, 1980). The stereospecicity of lactic acid produced by microorganisms depends on the type of enzymes involved in the lactic acid production. Because the optical purity of lactic acid is a crucial factor in lactic acid-based industries, numerous studies have investigated the biotechnological production of optically pure lactic acid (John et al., 2007; Okano et al., 2010; Wee et al., 2006; Zhang et al., 2007; Zhao et al., 2010a, 2010b). There are 2 bottlenecks in the biotechnological production of optically pure lactic acid. One bottleneck is the high substrate cost because of the addition of sugars as carbon sources. This problem can be resolved through fermentative production of lactic acid from cheap materials. As shown in Table 1, many cheap, renewable raw materials such as molasses, starch, lignocellulose, and wastes from agricultural and agro-industrial residues have been used as substrates for lactic acid fermentation. However, most starchy and lignocellulose materials must be pretreated by physicochemical and enzymatic methods because lactic acid-fermenting microorganisms cannot directly use those materials (Okano et al., 2010). Improvement of the efcacy of these microorganisms through gene modication is an essential and interesting method that has been extensively studied. For detailed discussions of recent research on lactic acid production by genetically modied microorganisms from renewable resources, a review article by the Okano group (2010) can be referred to. The other bottleneck for lactic acid production is the operating cost. For example, sterilization is necessary for fermentative production of lactic acid. Microorganisms, with an optimal fermentation temperature of 3042 C, are usually used for industrial applications (John et al., 2007). Therefore, it is difcult to avoid contamination if the medium is not sterilized. Nonsterilized fermentative production of L-lactic acid by a newly isolated thermophilic strain, Bacillus sp. 26, has been recently reported (Qin et al., 2009). High yield (97.3%), productivity (4.37 g/[l h]), and optical purity of L-lactic acid (99.4%) were obtained in batch and fed-batch open fermentations (Qin et al., 2009). Practically, nonsterilization means eliminating the need for sterilization equipments, reducing energy consumption, and lowering labor cost. The separation and purication processes after fermentation also elevate the cost of lactic acid production. Owing to the inhibitory effects of low pH on cell growth and lactic acid production, CaCO3 must be added to maintain a constant pH. This requires processing for

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t1:1 t1:2 t1:3 t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25

Table 1 Comparison of lactic acid production from renewable raw materials by different organismsa. Organism

Substrate

Lactic acid Concentration (g/l) 129.9 126.7 123.3 123.2 175.4 24.0 92.0 28.0 166 73.0 90.0 27.0 10.9 32.5 62.8 74.7 40.7 42 118 207 Yield (g/g) 1.04 1.01 0.99 0.99 0.71 0.76 0.77 0.78 0.87 0.97 0.90 0.90 0.36 0.88 0.83 0.50 0.43 0.38 0.95 0.93 Productivity (g/l/h) 1.5 1.5 1.7 1.4 1.8 0.51 0.96 0.28 4.2 2.9 2.3 6.7 0.17 5.4 1.2 0.38 0.87 1.7 3.8
Type

O
L L L L L L L L L L L L L L L L L L D D

Enterococcus faecalis RKY1

Lactobacillus rhamnosus strain CASL Lactobacillus pentosus Bacillus coagulan strains 36D1 Lactobacillus delbrueckii IFO 3202 Lactobacillus delbrueckii mutant Uc-3 Lactobacillus rhamnosus ATCC 7469 Lactobacillus delbrueckii Uc-3 Lactobacillus sp. RKY2 Lactococcus lactis IO-1 Lactobacillus rhamnosus CECT-288 Lactobacillus bifermentans Bacillus sp. strain Bacillus coagulans DSM 2314 Lactobacillus rhamnosus CECT-288 Lactobacillus delbrueckii Sporolactobacillus sp. CASD

Corn starch Tapioca starch Potato starch Wheat starch Cassava powder Trimming vine shoots Paper sludge Rice bran Molasses Cellobiose and cellotriose Lignocellulosic hydrolysates Sugar cane bagasse Apple pomace Wheat bran hydrolysate Corncob molasses Lime-treated wheat straw Cellulosic biosludges Sugarcane juice Peanut meal, glucose

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For detailed discussion of the other researches on lactic acid production from renewable raw materials before 2006, review written by the groups of John et al. (2007), can be consulted.

Please cite this article as: Gao C, et al, Biotechnological routes based on lactic acid production from biomass, Biotechnol Adv (2011), doi:10.1016/j.biotechadv.2011.07.022

Reference

(Wee et al., 2008)

(Wang et al., 2010a) (Moldes et al., 2006) (Budhavaram and Fan, 2009) (Tanaka et al., 2006) (Dumbrepatil et al., 2008) (Marques et al., 2008) (Adsul et al., 2007) (Wee and Ryu, 2009) (Laopaiboon et al., 2010) (Gullon et al., 2008) (Givry et al., 2008) (Wang et al., 2010b) (Maas et al., 2008) (Romani et al., 2008) (Calabia and Tokiwa, 2007) (Wang et al., 2011)

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the regeneration of precipitated calcium lactate (Datta and Henry, 2006). To solve this problem, a sodium lactate-tolerant mutant strain, Bacillus sp. Na-2, was obtained by ion beam implantation, a new mutagenesis method for the breeding of crops and microbes in agriculture and industry, and applied to the sodium hydroxide-based L-lactic acid production process (Qin et al., 2010). On the other hand, some new processes that do not produce calcium lactate such as reverse osmosis, ultraltration, electrodialysis, and solvent extraction have been concurrently developed (Datta and Henry, 2006). Lactic acid is one of the primary platform chemicals that can be used to synthesize a wide variety of useful products. Although further efforts are needed to increase the efciency and cost-effectiveness of the lactic acid production process, considerable pioneering investigations have been performed by a few researchers in the development of lactic acid production technologies. Those studies laid a solid foundation for lactic acid production from renewable biomass as well as offered the possibility for the ultimate green production of lactic acid derivatives. 3. Biotechnological production of lactic acid derivatives 3.1. Esterication of lactic acid Lactate esters are traditionally produced by homogeneous catalysts such as anhydrous hydrogen chloride, sulfuric acid, phosphoric acid, and other conventional acids (Corma et al., 2007). However, this method has some aws. For example, lactic acid contains hydroxy and carboxy groups that act as both acyl donors and nucleophiles, and they undergo self-polymerization in chemical systems (Hasegawa et al., 2008b). To solve this problem, drastic reaction conditions are required. Biocatalysis, because of its mild reaction condition, high activity, and low-pollution environment, emerges as a good choice that can replace the chemical method. Lipases (triacylglycerol hydrolases, EC 3.1.1.3) catalyze the hydrolysis of triacylglycerols and other carboxy esters in aqueous solutions (Sim et al., 2009). In the absence of water, they catalyze the condensation of organic acids and alcohols to produce esters (Tan et al., 2010). Thus, lipases are suitable catalysts for esterication of lactic acid (From et al., 1997). Lipase-catalyzed esterication of lactic acid with butanol, ethanol, glycoside, or straight-chain alcohols has been previously studied (Hasegawa et al., 2008a, 2008b; Pirozzi and Greco, 2006; Roenne et al., 2005; Torres et al., 1999; Wei et al., 2003). These lactate esters have been widely used in food, pharmaceutical, and cosmetic formulations owing to their hygroscopic and emulsifying properties. For example, esters of lactic acid and alcohols (particularly methanol, ethanol, and butanol) have recently been highlighted as environment-friendly (biodegradable and biologically derived) green solvents and could potentially replace toxic and halogenated solvents for a wide range of industrial uses (Corma et al., 2007). Esters of lactic acid and glycoside are also useful in the preparation of herbicidal formulations because they are not irritants to human skin, unlike free acids (Wei et al., 2003). The esterication reactions mentioned above are conducted in a nonaqueous system. Because of the high polarity of lactic acid, it is immiscible with hydrophobic organic solvents that are commonly used for nonaqueous enzyme reactions (Hasegawa et al., 2008b). The strong acidity of lactic acid would also cause acid inactivation of enzymes. Lipase-catalyzed esterication of lactic acid has thus only achieved limited success. Numerous studies have been undertaken to enhance the efciency of lipase-catalyzed lactic acid esterication. Hasegawa et al. utilized particular polar organic solvents such as 1,4-dioxane to suppress the enzyme inactivation and nonenzymatic esterication caused by the acidity (Hasegawa et al., 2008a). With immobilized lipase from Candida antarctica as the catalyst, esterication of lactic acid (1.0 mol/l) could be continued for up to 4 weeks without any loss of enzyme activity

(Hasegawa et al., 2008a). They also used hydrophobic ethers and ketones as reaction media. Those solvents are miscible with lactic acid and show less toxicity to enzymes than do polar solvents. The use of hydrophobic ethers (diethyl ether, diisoproryl ether, and tert-butyl methyl ether) and ketones (ethyl methyl ketone, diethyl ketone, di-npropyl ketone, and methyl isobutyl ketone) that have basic reaction media prevented acid inactivation of the enzyme and led to successful esterication of lactic acid (Hasegawa et al., 2008b). Lactic acid could also esterify itself and produce 2 primary esterication products: the linear lactic acid lactate (2-lactyloxypropanoic acid) and cyclic lactide (3,6-dimethyl-1,4-dioxane-2,5-dione). Different catalysts for the preparation of lactide have been reported (Corma et al., 2007). Lactide is the monomer for the production of polylactic acid (PLA), a biodegradable plastic that is extensively discussed below. 3.2. Polymerization of lactic acid

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PLA is a representative bio-based plastic with good biocompatibility and biodegradability (Auras et al., 2004; Tsuji, 2005). There is a growing demand for PLA derivatives that can substitute for conventional plastic materials as well as be used in health-demanded new materials. Owing to the competing depolymerization reaction, lactic acid does not polymerize directly to a large extent, and this limits the molecular weight of the resulting polymer. Currently, the major industrial method to produce PLA is ring-opening polymerization, which is catalyzed by heavy metal catalysts, typically tin (Albertsson et al., 2000; Kricheldorf, 2001). The Food and Drug Administration (FDA) has set a limit of 20 ppm of residual tin in commercially used medical polymers. Although different processes have been developed for the tin-catalyzed ring-opening reactions, it is impossible to add less tin to the reactions because it is the initiator of the reaction (Stjerndahl et al., 2007). Thus, the solution for not exceeding that limit is to use an efcient cleaning procedure. For example, for the reaction of the polymer with 1,2-ethanedithiol, Stjerndahl et al. reduced the residual amount of tin in poly--caprolactone from over 1000 to 23 ppm, which is close to the limit of 20 ppm set by the FDA (Stjerndahl et al., 2007). Another way to avoid tin residues is to use an initiator containing atoms other than tin, for example, zinc (Schwach et al., 1996). However, the molecular weight of the resulting polymer produced with these polymerizations is too low for the polymer to be useful in industrial applications (Stjerndahl et al., 2007). Lactic acid-based polyesters could also be produced by enzymatic catalysis (Kikuchi et al., 2000; Matsumura et al., 1997). For example, lipase-catalyzed ring-opening polymerization of cyclic lactides is applicable for the synthesis of PLA (Kobayashi, 2009). Thus, this is a simple replacement of the heavy metal catalyst with an enzyme (Matsumoto and Taguchi, 2010). Poly[L-lactic acid] (PLLA) and poly[Dlactic acid] (PDLA) could be produced from either enantiomers of lactic acid by lipase with strict specicity for certain enantiomers. Selection of a proper lipase that catalyzes the polymerization of D- and L-lactic acid could also produce PDLLA, a polymer that is known to show superior thermal stability than each homopolymer alone. Although lipasecatalyzed ring-opening polymerization is applicable to lactides, exploration of the lipases with high polymerizing activity toward lactides might still be necessary to improve the efciency of the lipase-catalyzed production of PLA (Matsumoto and Taguchi, 2010). The preparation of PLA by lipase still consists of 2 steps, chemical production of lactide and enzymatic polymerization. Therefore, the lipase-catalyzed polymer production is not a completely green process. Thus, PLA production from biomass-derived lactic acid by a 1-step bioprocess without the need for any subsequent chemical processes, including extraction of lactic acid, synthesis of lactides, and successive ring-opening polymerization, has attracted researchers' attention. However, direct polymerization of lactic acid in vivo is a

Please cite this article as: Gao C, et al, Biotechnological routes based on lactic acid production from biomass, Biotechnol Adv (2011), doi:10.1016/j.biotechadv.2011.07.022

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very challenging target. A PLA-producing microorganism remains to be discovered (Taguchi et al., 2008). Polyhydroxyalkanoates (PHAs), which are structurally analogous to PLA, could be wholly synthesized in vivo via monomer supply (Jo et al., 2007). In this regard, the bacterial PHA synthetic system might also be used in in vivo lactic acid polymerization. Some intensive efforts have been made to create such a system (Matsumoto and Taguchi, 2010; Taguchi et al., 2008; Tajima et al., 2009). Taguchi et al. discovered a PHA synthase with polymerizing activity of the lactic acid moiety in lactate-CoA. They rst constructed a lactate-CoAproducing Escherichia coli strain with a CoA transferase gene. Subsequently, the PHA synthase gene was introduced into the resultant recombinant strain. One-step biosynthesis of the lactateincorporated copolyester with 6% lactic acid and 94% 3-hydroxybutyric acid was realized (Fig. 2) (Taguchi et al., 2008). Although lactate-incorporated copolyester could be produced, the complete biosynthesis of a homopolymer, i.e., PLA, is still very difcult. In in vitro experiments, no polymer was generated when only lactate-CoA was supplied as a substrate of PHA synthase. This result indicated that the presence of 3-hydroxybutyryl-CoA is essential to the incorporation of lactic acid unit into the polymer backbone by those PHA synthases (Matsumoto and Taguchi, 2010). Thus, generation of an engineered synthase that polymerizes lactateCoA in vitro might be the rst task at the current stage. Enhancement of the lactic acid fraction in the copolymer was also attempted. For example, Shozui et al. used a lactic acid-overproducing

strain, E. coli JW0885, as the host for lactate-incorporated copolyester production. The lactic acid fraction of the copolyester was enhanced to 28% (Shozui et al., 2010). On the other hand, because the production of lactic acid is promoted under anaerobic conditions while 3hydroxybutyryl-CoA is aerobically supplied, a 2-step culture of the recombinant E. coli was also introduced by Yamada et al. (2009). This evaluated the lactic acid fraction of the copolyester up to 47%. Thus, the groundwork for generating a lactic acid-enriched copolymer has been laid. Perhaps eventually, a homopolymer of lactic acid might be produced directly from biomass in the near future (Matsumoto and Taguchi, 2010). 3.3. Hydrogenation of lactic acid

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1,2-Propanediol (propylene glycol) is a major commodity chemical with a variety of uses. It is currently produced by a synthetic process from propylene oxide, a nonrenewable petrochemical derivative (Corma et al., 2007). Production of 1,2-propanediol by direct hydrogenation of bio-based lactic acid can be an alternative route to the petroleum-based process. Generally, hydrogenation of lactic acid by chemical catalysts requires esterication of lactic acid and successive hydrogenation. Currently, the major method for the hydrogenation of lactate esters to 1,2-propanediol was performed at 423523 K at high hydrogen pressure (2030 MPa) over copper/chromium oxide and by using Raney nickel catalysts (Corma et al., 2007). This process is energy

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Please cite this article as: Gao C, et al, Biotechnological routes based on lactic acid production from biomass, Biotechnol Adv (2011), doi:10.1016/j.biotechadv.2011.07.022

Fig. 2. Metabolic pathway for the production of lactate-incorporated copolyester in recombinant E. coli (Taguchi et al., 2008).

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intensive and requires the use of chemical catalysts, and is thus controversial regarding issues of environmental protection and sustainable process development. It is clear that the development of green lactic acid hydrogenation techniques is required. The reduction of lactic acid to 1,2-propanediol involves 2 separate steps: hydrogenation of lactic acid to produce lactaldehyde and successive reduction of lactaldehyde to produce 1,2-propanediol. As shown in Fig. 3, these 2 reactions could be catalyzed by 2 different enzymes: NAD-dependent lactaldehyde dehydrogenase and NADdependent 1,2-propanediol dehydrogenase, respectively. The NAD-dependent lactaldehyde dehydrogenases are present in different strains (Grochowski et al., 2006). These enzymes catalyzed the oxidation of lactaldehyde to the corresponding carboxylic acid: lactic acid. After heterologous expression and purication of the lactaldehyde dehydrogenase from E. coli, the crystal structure of the lactaldehyde dehydrogenaseNADH-lactate complex was recently elucidated by a study (Di Costanzo et al., 2007), the ndings of which imply the possibility of the NADH-dependent lactate reduction to lactaldehyde at low pH and sufcient NADH supply (Oude Elferink et al., 2001). The conversion of lactaldehyde to 1,2-propanediol could be performed by NAD-dependent 1,2-propanediol dehydrogenase (Bennett and San, 2001; Chen and Lin, 1984). On the other hand, the alcohol dehydrogenase in Saccharomyces cerevisiae could also catalyze the NADH-dependent reduction of lactaldehyde (Hoffman, 1999). These enzymes have been introduced into the metabolically engineered E. coli for enhancement of the production of 1,2-propanediol (Altaras and Cameron, 2000). Although the NAD-dependent lactaldehyde dehydrogenase and NAD-dependent 1,2-propanediol dehydrogenase exist in different strains, they are generally regarded as the enzymes responsible for 1,2-propanediol metabolism through lactic acid. For example, the pathway of lactic acid formation from 1,2-propanediol has been elucidated for E. coli (Cocks et al., 1974). In this process, 2 mol of NAD was converted to NADH by the 2 enzymes with per mol of lactic acid formation. 1,2-Propanediol production from lactic acid was only studied in some lactobacilli (Nishino et al., 2003; Oude Elferink et al., 2001). During the anaerobic conversion of lactic acid, the lactate-converting ability is strongly inuenced by the pH, and acidic conditions are needed to induce lactic acid conversion. In addition, the reduction of lactic acid to 1,2-propanediol requires the consumption of NADH. Oude Elferink et al. proposed a pathway for anaerobic degradation of lactic acid by Lactobacillus buchneri in which 2 mol of lactic acid was degraded to 1 mol of acetic acid and 1 mol of 1,2-propanediol (Oude Elferink et al., 2001). For each mole of lactic acid that is degraded to acetic acid, 2 mol of NAD is converted to NADH. The NADH generated could be used for the NADH-dependent reduction of lactic acid to 1,2propanediol. Thus, the yield of 1,2-propanediol from lactic acid was only 50%. For the efcient production of 1,2-propanediol, enhancement of the lactic-acid-converting capacity and an effective pathway for the NADH supply are needed.

Fermentation is currently the predominant pathway for biotechnological production of 1,2-propanediol (Bennett and San, 2001). Compared with fermentative methods with sugars as substrates, the method with lactic acid as the substrate for 1,2-propanediol production is modest. However, the report mentioned above indicates that it might be possible to produce 1,2-propanediol from lactic acid by using appropriate bacteria. With the help of powerful strain screening and directed evolution techniques, more selective and realistic strains might be prepared for the hydrogenation of lactic acid to produce 1,2-propanediol. 3.4. Dehydrogenation of lactic acid Pyruvic acid is an important starting material widely applied in chemical, pharmaceutical, and agrochemical industries (Koh-Banerjee et al., 2005; Li et al., 2001; Xu et al., 2007). Commercial pyruvic acid is produced by chemical or fermentation processes (Causey et al., 2003; Li et al., 2001; van Maris et al., 2004). Chemical production of pyruvic acid occurs through the dehydration and decarboxylation of tartaric acid (Li et al., 2001). In this process, pyruvic acid is distilled from a mixture of tartaric acid and potassium hydrogen sulfates at 220 C. Thus, this method is simple to realize but not cost-effective (Li et al., 2001). Fermentative methods currently play a dominant role in biotechnological pyruvic acid production (Li et al., 2001). However, pyruvate occupies the central position in carbon metabolism, and the fermentation of sugars to produce pyruvate results in a fairly low yield. Thus far, the van Maris group has obtained the highest pyruvate concentration of 135.0 g/l by the directed evolution of pyruvate decarboxylase-negative S. cerevisiae, but with a disappointingly low overall yield at 0.54 g/g from glucose (van Maris et al., 2004). On the other hand, the fermentative pyruvic acid production was primarily based on the activities of 2 microorganisms, a multivitamin auxotroph of the yeast Torulopsis glabrata and a lipoic acid auxotroph of E. coli containing a mutation in the F1ATPase component of (F1F0)H+-ATP synthase (Causey et al., 2003). Both strains require precise regulation of media components during fermentation and complex supplements. The recovery of pyruvic acid from such a complex fermentation broth is generally difcult and expensive (Li et al., 2001). Thus, pyruvic acid production by enzymatic conversion of lactic acid is becoming competitive with the fermentative process, not only because of the low cost and high conversion rate but also because of the lower level of byproduct formation as well as the convenience of recovery. Pyruvic acid production from lactic acid is a simple dehydrogenation process that can be performed using several types of reactions. Excluding chemical catalysts, many biocatalysts could be employed in the production of pyruvic acid by dehydrogenation of lactic acid in an aqueous solution (Fig. 4). NAD-dependent lactate dehydrogenases (nLDHs), which catalyze the reduction of pyruvate to lactate by using NADH as a coenzyme, have been widely studied (Garvie, 1980). nLDHs could also catalyze the oxidation of lactate at high pH in the presence of high lactate and

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Fig. 3. Summary of the enzymes involved in lactic acid hydrogenation (Oude Elferink et al., 2001).

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NAD concentrations (Garvie, 1980). Owing to the high costs of the cofactors, it is difcult to use these enzymes to obtain lactate on the preparative scale, because stoichiometric amounts of NAD have to be used (Schmid et al., 2001; vander Donk and Zhao, 2003). Whole cells have some reserves of NAD and provide a continuous source of cofactors. Therefore, whole cells expressing the nLDHs might be applied in the production of pyruvate from lactate. However, during the catalytic process, lactate is oxidized to pyruvate, and NAD is reduced to NADH. Thus, after 1 cycle of the reaction course, NAD is depleted, whereas NADH is accumulated. An efcient NAD regeneration method is an inevitable prerequisite to obtain a high yield of pyruvate. In 2010, Xiao et al. developed a whole-cell system in which the unique H2O-producing NADH oxidase (NOX, catalyzing NADH into NAD) was used as the NAD-regenerating enzyme (Xiao et al., 2010). By using this system, the production of chiral acetoin from 2,3butanediol by NAD-dependent 2,3-butanediol dehydrogenase catalyzing the oxidation reaction has been actualized. This research provided a suitable method for NAD regeneration, and construction of a whole-cell biocatalyst with the NAD-dependent lactate dehydrogenase for pyruvate might become rather possible. Glycolate oxidase and lactate oxidase belong to the family of hydroxyacid-oxidizing enzymes. These enzymes catalyzed the oxidation of L-lactate with oxygen to generate pyruvate and H2O2. They catalyzed the direct formation of pyruvate from lactate without requiring NAD as a cofactor, and thus, several groups have reported the production of pyruvate by glycolate oxidase or lactate oxidase (Xu et al., 2008). For example, Burdick et al. reported the oxidation of L-lactate to pyruvate by lactate oxidase (Burdick and Schaeffer, 1987). However, the oxidation of L-lactate to pyruvate led to the production of hydrogen peroxide as a byproduct. Hydrogen peroxide can metabolize pyruvate to acetate, CO2, and water, and hence lower the production yield. To resolve this problem, co-immobilization of lactate oxidase with catalase, which metabolizes hydrogen peroxide to oxygen and water, was conducted. By using the lactate oxidase-catalase immobilized in gelatin with different crosslinking agents as the catalyst, a yield of pyruvate up to 47% was obtained (Burdick and Schaeffer, 1987). On the other hand, Payne et al. obtained high levels of spinach glycolate oxidase from a methylotrophic yeast Pichia pastoris (Payne et al., 1995). To decompose hydrogen peroxide produced during the biocatalysis process, genetically modied strains that express both glycolate oxidase and catalase have been constructed. The combination of glycolate oxidase with catalase leads to a high bioconversion ratio of L-lactate to pyruvate (Gellissen et al., 1996). Among the family of -hydroxyacid-oxidizing enzymes, in addition to glycolate oxidase and lactate oxidase, NAD-independent

lactate dehydrogenases (iLDHs) have been extensively studied. These enzymes are widely distributed in bacteria, yeasts, and protists (Ma et al., 2007). iLDHs catalyze the oxidation of lactate in a avindependent manner (avin mononucleotide and avin adenine dinucleotide for L- and D-iLDH, respectively). Similar to glycolate oxidase and lactate oxidase, iLDHs do not require NAD as a cofactor. However, they could not directly catalyze the oxidization of lactate by using oxygen as the electron acceptor. The use of natural or articial electron acceptors was needed for the application of iLDHs for pyruvate production (Xu et al., 2008). Dehydrogenation of lactate by using the enzyme (2R)-hydroxycarboxylate-viologen-oxidoreductase (HVOR), a type of iLDH, has been studied in Proteus vulgaris cells (Schinschel and Simon, 1993). HVOR can react with many articial redox mediators as electron acceptors for lactate dehydrogenation. Combined with redox mediators, 20 g (dry weight) of HVOR-containing cell can convert 0.65 M lactate to 94% pyruvate in 1 h. However, the reoxidation of electron acceptors is necessary because oxidized cofactors are required in the reaction system. The regeneration of oxidized cofactors could be achieved by chemical or electrochemical methods. The lactate dehydrogenation using HVOR in an enzyme-membrane reactor with coupled electrochemical regeneration of the mediator has been previously reported (Hekmat et al., 1999). The natural electron acceptor of iLDHs is a membrane quinone (E. coli) or cytochrome c (S. cerevisiae) (Philippe et al., 2004). The reduced forms of quinone and cytochrome c could be regenerated through the electron transport chain. Compared with nLDHs, glycolate oxidase, or lactate oxidase, this lactate oxidation mechanism prevents the hydrogen peroxide formation and the cofactor regeneration. Hence, iLDHs containing whole cells might have a great potential for application in the commercial production of pyruvate (Liu et al., 2010). For example, Pseudomonas stutzeri SDM, which has the ability to produce pyruvate from lactate through iLDHs, has been reported (Hao et al., 2007). A high yield of pyruvic acid (22.6 g/l) is obtained from 25.5 g/l DL-lactic acid in 24 h. The major problem restricting iLDHs containing biocatalysts for commercial production of pyruvate is that the inducement of iLDHs in different strains requires the addition of lactate, and this increases the biocatalyst preparation cost (Gao et al., 2010). With a target of lowcost biocatalyst preparation, a mutant with constitutive iLDH of Pseudomonas sp. XP-M2 was screened in our previous work. The iLDHs containing biocatalysts were prepared using the cheaper substrate glucose as the carbon source from the mutant. The costeffective biocatalyst prepared from glucose showed a high yield of pyruvate from lactate (0.96 mol/mol) (Gao et al., 2010).

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Fig. 4. Enzymes utilized in the lactic acid oxidation process. nLDH: NAD-dependent lactate dehydrogenase; LOX: lactate oxidase; iLDH: NAD-independent lactate dehydrogenase.

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Compared with fermentative methods, the applications of biocatalysis for the production of pyruvic acid are still not feasible, perhaps because of the limitations of those biocatalysts mentioned above, such as expensive cofactor utilization, byproduct production, and the enzyme inducement process. With the help of powerful enzyme discovery methods, accumulated genetic information, and directed evolution techniques, preparation of more selective and realistic biocatalysts for more environment-friendly and sustainable production of pyruvate should be possible. 3.5. Dehydration of lactic acid Acrylic acid is one of the most important industrial chemicals with a considerable value (Lunelli et al., 2007; Shen et al., 2009). For example, acrylic acid and its ester derivatives are the principal raw materials for the production of acrylate polymers (Danner et al., 1998; Zhang et al., 2008). Currently, acrylic acid is produced by the petrochemical industry, mostly via the direct oxidation of propene (Corma et al., 2007). Dehydration of lactic acid is an attractive target for the production of bio-based acrylic acid. Currently, most lactic acid conversion studies have focused on this reaction. During the dehydration of lactic acid by chemical catalysts, decarbonylation and decarboxylation yield acetaldehyde, and hydrogenation that results in the formation of propanoic acid also occurs (Corma et al., 2007). Those reactions compete with dehydration and decrease the acrylic acid yield. The production of acrylic acid as a biochemical intermediate has been described in a few reports (Dalal et al., 1980; O'Brien et al., 1990; Schweiger and Buckel, 1985; Seeliger et al., 2002). Anaerobic formation of acrylic acid occurs through the direct reduction pathway of lactic acid (Akedo et al., 1983; Danner et al., 1998). The related metabolic pathway is shown in Fig. 5. Lactyl-CoA is rst formed from lactic acid catalyzed by CoA-transferase, and then it is dehydrated to

N C O

produce acrylyl-CoA. The dehydration reaction is catalyzed by lactylCoA dehydratase, which has been partially puried from Clostridium propionicum (Schweiger and Buckel, 1985). Normally, acrylyl-CoA is then catalyzed into propionyl-CoA by propionyl-CoA dehydrogenase (Danner et al., 1998). When C. propionicum uses lactic acid as the energy source, 3 mol of lactic acid is converted into 1 mol of acetate and 2 mol of propionate via the direct reduction pathway. Acrylic acid was produced only after the direct reduction of acrylyl-CoA was blocked. Direct observations of free acrylic acid are rare in biological systems. The major problems of acrylate formation from lactic acid are the regeneration of reduction equivalents and the sufcient inhibition of propionyl-CoA dehydrogenase (Danner et al., 1998). It is known that 3-butynoic acid, a structural analog of acrylic acid, can inhibit the activity of propionyl-CoA dehydrogenase. With the addition of 3butynoic acid, the formation of acrylic acid from lactic acid was detected in the anaerobic rumen bacterium Megasphaera elsdenii (Sanseverino et al., 1989). The presence of the reduction equivalents (e.g., ferredoxin, rubedoxin, avodoxin) can inhibit the growth of microorganisms. Danner et al. established a method for the regeneration of reduction equivalents by using methylene blue as the electron acceptor (Danner et al., 1998). However, the acrylic acid concentration never exceeded 1% of the initial substrate concentrations (Sanseverino et al., 1989; Xu et al., 2006). In recent years, Huang's group developed a series of NaY zeolite catalysts for the dehydration of lactic acid. Through modication of the NaY zeolites by potassium or rare earth metals (lanthanum, cerium, samarium, and europium), catalytic dehydration of lactic acid to acrylic acid was enhanced (Sun et al., 2009; Sun et al., 2010; Wang et al., 2008; Yan et al., 2010; Yu et al., 2011). These excellent studies made the application of lactic acid dehydration to produce acrylic acid possible. Compared to the NaY zeolite catalysts with improved selectivity to acrylic acid during lactic acid dehydration, the biotechnological methods mentioned above have never yielded high amounts of acrylic acid. However, biological conversion of lactic acid to produce acrylic acid is still a hopeful process. In fact, from the industrial point of view, the biotechnological production of acrylic acid from lactic acid is presented as an environment-friendly process because of its bio-based substrate and moderate reaction conditions. The understanding of the metabolic pathway and the identication of enzymes involved in acrylic acid production have facilitated the biological dehydration of lactic acid. For example, because of the existence of acrylic acid pathways in some microorganisms, strain improvement and metabolic engineering methods such as the insertion of a lactyl-CoA dehydratase gene into C. propionicum provide the potential to produce acrylic acid directly from lactic acid (Danner et al., 1998). On the other hand, selective removal of the acrylate in situ by a consecutive process would also be a practical method to drive the conversion of lactate to acrylate (Alvarez et al., 2007; Straathof et al., 2005).

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Fig. 5. Metabolic pathway of lactic acid dehydration: direct reduction pathway (Danner et al., 1998).

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3.6. Comparison between the biotechnological and chemical processes Both chemical and biotechnological processes could be used in the production of lactic acid derivatives. A comparison of these different methods is summarized in Table 2. Chemical processes now occupy the dominant position in the production of lactic acid derivatives. Cost effectiveness and life cycle assessment of some processes including biotechnological production of lactic acid and chemical production of lactic acid derivatives, especially the PLA, have been disclosed in previous studies (Akerberg and Zacchi, 2000; Datta et al., 1995; Gonzalez et al., 2007; Groot and Born, 2010; Vink et al., 2003). As for the biotechnological production of lactic acid derivatives, most of the reported methods could only be conducted on a laboratory scale. For the practical application of those biotechnological processes, researches on their cost effectiveness and life cycle assessment should also been conducted.

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Table 2 Comparison between the biotechnological and chemical processes. Reaction Esterication Chemical process Reactions are traditionally catalyzed by homogeneous catalysts. To reduce the self-polymerization of lactate, drastic reaction conditions are required (Corma et al., 2007). Biotechnological process

t2:5

t2:6

t2:7

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t2:8

Reactions are catalyzed by lipases in a nonaqueous system. The reaction conditions are moderate. To reduce the lactic acid caused inactivation of enzymes, particular polar organic solvents should been used (Hasegawa et al., 2008a, 2008b). Polymerization Heavy metal catalysts, such as tin, catalyzed ring-opening polymerization is Lipase-catalyzed ring-opening polymerization is a simple replacement of the the major industrial method to produce PLA (Albertsson et al., 2000; heavy metal catalyst with an enzyme (Matsumoto and Taguchi, 2010). Kricheldorf, 2001). To reduce the residual tin in commercially used medical Whole-cell synthesis of lactate-containing polyesters has been accomplished. polymers, efcient cleaning procedure is needed (Stjerndahl et al., 2007). However, the complete biosynthesis of a homopolymer, i.e., PLA, is still difcult (Taguchi et al., 2008). 1,2-Propanediol production from lactic acid was studied in some Lactobacilli Hydrogenation Hydrogenation of lactic acid requires esterication of lactic acid and successive hydrogenation. The hydrogenation of lactate esters is an energy strains with a yield of 50% (Nishino et al., 2003; Oude Elferink et al., 2001). For the intensive process that performs at drastic reaction conditions (Corma et al., efcient production of 1,2-propanediol, more selective and realistic strains with enhanced lactic-acid-converting capacity are needed. 2007). Dehydrogenation A few attempts concerning the direct oxidative dehydrogenation of lactic acid Many biocatalysts could be employed in the dehydrogenation of lactic acid in have been reported. Most of the chemical catalysts catalyze the oxidative C\C an aqueous solution. The bioprocess produces pyruvate with high conversion bond ssion, converting the major part of lactic acid to acetaldehyde and CO2 rate, high yield and low level of byproduct formation. Environment-friendly and sustainable production of pyruvate using biocatalysts might be possible rather than to pyruvic acid (Li et al., 2001). in future (Xu et al., 2008). Dehydration Numerous studies have focused on the dehydration of lactic acid. During the Anaerobic formation of acrylic acid through the direct reduction pathway of lactic acid has been described in a few reports. The major problems of acrylic production of acrylic acid by chemical catalysts, decarbonylation, acid formation from lactic acid are the regeneration of reduction equivalents and decarboxylation, and hydrogenation of lactic acid also occur. Those side the sufcient inhibition of propionyl-CoA dehydrogenase (Danner et al., 1998). reactions decrease the acrylic acid yield (Corma et al., 2007).

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Acknowledgments

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References

The work was supported by National Natural Science Foundation of China (30821005, 31000014 and 31070062), by National Basic Research Program of China (2007CB707803), and by Chinese National Programs for High Technology Research and Development (2011AA02A207).

In addition to its traditional application in the food industry, lactic acid is currently considered as the most potential feedstock monomer for chemical conversions. Because it contains 2 reactive functional groups, a carboxylic group and a hydroxyl group, lactic acid can undergo a variety of chemical reactions to yield potentially useful chemicals. All of the derivatives of lactic acid mentioned in this review article can be produced through biotechnological routes. Owing to environmental concerns and the limited nature of petrochemical feedstocks, a completely green process would be the preferred method for the production of those lactic acid derivatives. Although some of the reactions are still not applicable at this stage, with the improvement and expansion of the lactic acid production industry, the biotechnological processes for the production of bio-based lactic acid derivatives will attract researchers' attention and may replace the chemically derived methods in the future.

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