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Scientific
Publications - Work Done by Microbiology Reader
Niklas von Weymarn, Process development for mannitol production by lactic acid bacteria, Technical Biochemistry Report 1/2002, Helsinki University of Technology, Department of Chemical Technology, Laboratory of Bioprocess Engineering, Dissertation for the degree of Doctor of Science in Technology to be presented with due permission of the Department of Chemical Technology for public examination and debate in Auditorium KE 2 (Komppa Auditorium) at Helsinki University of Technology (Espoo, Finland) on the 12th of April, 2002, at 12 noon, 114 pp. ABSTRACT D-Mannitol (here: mannitol) is a naturally occurring sugar alcohol with six carbon atoms. It is only half as sweet as sucrose. However, mannitol and other sugar alcohols exhibit reduced caloric values compared to the respective value of most sugars, which make them applicable as sweeteners in so-called “light” foods. Moreover, sugar alcohols are metabolized independently of insulin and are thus also applicable in diabetic food products. Besides applications in the food industry, mannitol is also used in the pharmaceutical industry. In medicine, mannitol is used to decrease cellular edema (excessive accumulation of fluid) and increases the urinary output. In this doctoral thesis, the development of a new bioprocess for the production of mannitol is described. For this purpose, aspects such as strain selection, choice of process method, optimization of process parameters, scale-up, and metabolic engineering were studied. At present, mannitol is produced commercially by catalytic hydrogenation of fructose-containing syrups. The existing chemical production methods are, however, characterized by several drawbacks. The uppermost being that when fructose is catalytically hydrogenated only about 50% of it is converted into mannitol, whereas the rest is converted into another sugar alcohol, sorbitol. In addition, ultra-pure (expensive) raw materials (fructose and hydrogen gas) are required for efficient conversion. When more cost-effective raw materials, such as glucose-fructose syrups are used as starting material for catalytic hydrogenation, the main product is sorbitol and mannitol is formed as a by-product. Hence, mannitol production becomes very dependent on the market demand of sorbitol. Furthermore, mannitol is relatively difficult to purify from sorbitol. In addition, ion exchange is required for removal of the metal catalyst from the production solution. This results in even higher production costs and decreased yields. The microbial mannitol production process described in this thesis is based on high cell density cultures of slowly growing heterofermentative lactic acid bacteria. The bioconversion of fructose to mannitol was performed in a slowly agitated membrane cell-recycle bioreactor equipped with pH and temperature control. Neither aeration nor nitrogen flushing of the bioconversion medium was required, which drastically lowers the investment costs of such a plant. An important detail in the new bioprocess was the re-use of cell biomass in successive bioconversions. In a semicontinuous production experiment, the initial cell biomass provided stable mannitol productivities and yields for at least 14 successive batches. Moreover, using a simple purification protocol comprising cooling crystallization of a supersaturated solution and crystal recovery by means of drum centrifugation, high yields of high-purity (>98%) mannitol crystals were obtained. Moreover, in scale-up trials the microbial mannitol production process was successfully run at a small pilot-scale (100 L). The yield of crystalline mannitol from the initial sugar consumed in the bioprocess was about 52% (w/w). This compares favorably to a commercial chemical process with a yield of about 39%. Hence, under optimized conditions the best production strain (Leuconostoc mesenteroides) converted up to 95% (mol/mol) of fructose consumed into mannitol. Unfortunately, this is only achieved when a significant amount of glucose is co-metabolized by the cells. The catabolism of glucose enables cofactor regeneration in the cells and is thus, essential for the bioconversion of fructose to mannitol. Moreover, some mannitol is also lost in the purification steps. Another significant improvement brought about by the new bioprocess was a reduced by-product burden. In the commercial chemical process, a total of 1.58 kg by-products are formed for each kilogram of mannitol crystals produced. In the bioprocess, only 0.67 kg by-products are produced per kilogram crystalline mannitol. Using tools of genetic engineering, two key enzymes involved in the primary metabolism of another efficient mannitol-producer, Lactobacillus fermentum, were inactivated. A mutant deficient in D-lactate dehydrogenase and grown in a fructoseglucose medium produced high levels of both mannitol and pure L-lactate. Inactivation of both lactate dehydrogenases resulted in major rerouting of glucose catabolism, which led to the accumulation of pyruvate and production of 2,3- butanediol. Moreover, mutants with lowered fructokinase activity and deficient in acetate kinase were constructed and studied.
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CONCLUSIONS Mannitol has a steady market, but the methods for producing mannitol are still evaluated and developed. Commercial production of mannitol relies on catalytic hydrogenation of fructose or fructose-glucose mixtures. However, the hydrogenation process has several drawbacks. In the hydrogenation process, fructose is reacting with a metal catalyst under high pressure and temperature. The hydrogen needed is supplied in the form of hydrogen gas. With the best metal catalysts available, only about 50% of fructose is reduced to mannitol, while the rest is reduced to sorbitol. Metal catalysts are non-specific in regards to the substrates, i.e. they catalyze a variety of reactions depending on the substrates present in the reactor. Besides that the catalyst must be of high quality, also the fructose and hydrogen gas must be of high purity to avoid further yield losses and unwanted side-reactions. A complicated purification process adds additional costs to the catalytic hydrogenation process. First, ion exchange must be used to remove the metal catalyst. Second, high temperature reactions result in color formation and extra purification steps are needed to remove the color impurities. Third, although a big solubility difference between mannitol and sorbitol favors efficient separation of these two compounds, production of high purity mannitol (or sorbitol) requires additional purification steps. Moreover, pure fructose is seldom used as a starting material in commercial production. Instead cheaper fructose-glucose mixtures are used, in which case mannitol becomes the side product of the process. It is thus obvious that the current chemical mannitol production methods are both laborious, ineffective and relatively expensive. Alternative production methods based on both enzymatic and microbial techniques have been studied. Enzymatic processes for mannitol production often applies socalled cofactor regeneration systems, but the use of these systems on a commercial level, is restricted by factors such as strong end product inhibition, high Km value of key enzyme for fructose and low volumetric productivities. A noteworthy microbial production process was developed by Ojamo et al. (2000). High yields and volumetric productivities were achieved with this bioprocess alternative. However, some drawbacks remained, like cell leakage from the reactor column and slow fructose consumption at low concentrations. In this work, a well-known enzymatic reaction, in which heterofermentative LAB reduce fructose into mannitol, was applied to develop a commercially competitive mannitol bioprocess. Several LAB species were compared in their ability to produce mannitol and based on the resulting data, an efficient strain belonging to the L. mesenteroides species was identified. When this strain was grown in a simple batch process good yields but only moderate productivities were achieved. To increase the productivity, more sophisticated bioprocess alternatives were studied. Using membrane cell-recycle bioreactor techniques and optimizing the critical process parameters, productivities over 20 g/L/h were achieved. In Table 16, the new bioprocess is compared to the traditional catalytic hydrogenation process.
Table 16. Comparison of a catalytic hydrogenation process and the bioprocess described in this thesis.
Regardless of whether the yield or productivity carry more weight from an economical point of view, both parameters ought to be met by the new bioprocess. It is naturally important to remember that a supply of glucose is also needed in the bioprocess and hence, the maximum theoretical yield for the bioreaction phase is only about 67% of mannitol from the sugar consumed (the real yield for the new bioprocess was about 61-62%). The functionality of the new bioprocess was tested on two levels. First, on a laboratory- scale, the process was run in a semi-continuous mode a total of 14 batches. Hence, it was shown that stable yields and productivities were possible to achieve in successive batches using the same initial biomass. Second, moving from a 2-L laboratory-scale to a small pilot-scale (100 L), no changes in essential process parameters were observed. It is thus assumed that the new bioprocess will pass further scale-up phases and is applicable for commercial production-scale. Moreover, the scalability of this process concept is expected to be better than e.g. the process using immobilized cells. The capital costs for the new bioprocess are low compared to the capital costs of typical bioprocesses. Due to a low contamination risk not much effort must be put into maintaining aseptic conditions and only moderately equipped reactors are needed. Also, no gassing systems are required and only the basic parameters (temperature and pH) need to be controlled. Moreover, the purification comprises basic well-established unit operations. The production costs of the new mannitol bioprocess, on the other hand, are strongly dependent on the price of fructose. One key benefit of microbial processes, in general, is that low-purity raw materials can be used without affecting the yields or productivities. In the case of mannitol production, this will drastically reduce the production costs and is a highly relevant factor, when the new bioprocess alternative is evaluated against the chemical hydrogenation processes. Furthermore, the use of L. mesenteroides, especially in the food industry, is commonly accepted. The use of LAB as hosts for production of recombinant proteins will most likely grow in importance in the future as new cloning tools are developed. Significant progress has been made with homofermentative LAB, where e.g. Lc. lactis has become a very popular cloning host. Cloning of heterofermentative LAB is also a topic of current research efforts (e.g. Bourel et al., 2001). In order to find applications for the glucose catabolism of the new mannitol bioprocess, metabolic engineering techniques were applied. For instance, mutants producing mannitol and either optically pure L-lactate or pyruvate were constructed. Hence, the total yield of valuable products from sugar consumed was significantly improved in both cases. In the future, efforts should be placed in finding sources of readily available lowpurity fructose syrups. Ideally this syrup would contain both fructose and glucose (e.g. side streams from a glucose to fructose isomerization process). The effects of using a low purity raw material source must then be carefully validated. After the sugars were depleted from the medium, the cells were observed to slowly consume mannitol. Hence, correct timing of the product recovery by filtration is vital. However, without an on-line sugar analysis system, the correct timing was difficult to estimate. Although some indications were obtained from the base consumption rate, in the future, other on-line analysis methods must be considered and studied. Finally, the reaction rates by which fructose was reduced to mannitol were surprisingly high. Hence, it would be sensible to study the use of this reduction power for reduction of other substrates to their respective high-value reduced forms.
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