AMINO ACIDS, PRODUCTION PROCESS
INTRODUCTION
Sodium L-glutamate (MSG) was found by Ikea in 1908 as a flavoring component, or sea tangle. This was the start of the later development of the amino acid industry. Initially, MSG was produced industrially by extraction from a protein hydroxylate, more specifically, first from wheat gluten hydroxylate with hydrochloric acid, and then from fat removed soybean hydroxylate or by conversion from pyrrolidone-5-carboxylic acid in beet molasses, for use as a seasoning agent. This latter process was not sufficient to meet the increasing demand because it involved the problem of by-products disposal, requiring the development of new production processes. In 1956, it is discovered that microbial process for acid production by direct fermentation of a microorganism from sugar and ammonia (1). Consequently, industrial production of MSG as a seasoning was rapidly enlarged, and at the same time, a new industry of amino acid production by fermentation of microorganisms emerged. In 1958, researchers found that an autotrophic mutant requiring homo serine accumulated L-lysine in a medium (2), which enabled industrial production of Lysine by fermentation. Establishing the basis for the development of the amino acid fermentation industry, this technology suggested the possibility of producing various other amino acids by autotrophic mutants and also the importance of research in fermentation production of biological components with regulatory mutants. Since then, direct fermentation of various amino acids has been broadly studied. Reduction of the cost of amino acids, owing to the development of fermentation techniques together with the establishment of their production processes, facilitated extended application of amino acids to uses other than as a seasoning. Particularly, L-lysine, an essential amino acid that is lacking in several food proteins, has been enjoying remarkably increased demand as a feed additive. Most of the amino acids produced in large quantities are still manufactured by fermentation, except for glycine, which does not have optical isomers, and methionine, which has a similar effect as a feed additive in both L- and DL-forms. In addition to being used as a seasoning agent and a feed additive, amino acids are currently used widely as a raw material for the sweetener Aspartame, for pharmaceuticals and agrichemicals, for infusion and oral nutrition,
for surfactants, and so forth, based on their nutritional, pharmacological, and flavoring effects. In connection with amino acid fermentation, many reports have been published on the physiological properties
of amino acid–producing microorganisms. The following discussions stress problems from the standpoint of practically manufacturing amino acids on an industrial scale.
FERMENTATION PROCESSES
Amino acid fermentation may be defined in two ways. One is a definition in the narrow sense and refers to direct accumulation of amino acids in a medium containing a sugar, ammonia, and other nutrients, and the other is a broad definition that covers the fermentation process involving the addition of specific precursors and amino acid production by reaction using enzymatic functions of microorganisms.
Here, mainly direct fermentation of the former type is discussed. Fermentation processes generally have a number of advantages and benefits that accrue to the user of the process. They have disadvantages too. Both are summarized as follows:
Benefits
• Mild conditions are used both in fermentation and in product recovery; hence, little product degradation takes place.
• Fermentation requires relatively less complex operation.
• Once the plant is built and operation has begun, there are relatively low maintenance costs.
• Only L-form amino acids are obtained.
Problems
• Operations provide low product concentrations compared with chemical synthesis processes and require large volumes of water, large fermentor capacity, and
comparatively high capital investment.
• The requirements for strict sterility add to capital costs and operation costs.
• Large amounts of energy for oxygen transfer and mixing are required.
• Product recovery may be complex, difficult, and expensive.
• The process time necessary to reach maximum concentrations of the desired product is usually comparatively long. The aforementioned narrow-sense definition of direct fermentation of amino acids includes three types of fermentation: batch-type, fed-batch-type, and continuous.
Batch Fermentation
Industrial fermentation is mostly performed using batch processes. In a batch process, a large volume of a medium containing nutrients and substrate material is inoculated with a viable culture of one or more appropriate microorganisms. Microbial growth and biochemical synthesis are allowed to proceed until an optimum yield of metabolite or a desired biochemical transformation has been obtained.
Although this process is the basic form of fermentation, it is not frequently practiced on an industrial scale because productivity is limited by the amount and nature of the nutrients present at the time of inoculation. In most amino acid fermentation, enhanced product concentration is important to improve production efficiency and requires more advanced fermentation processes.
Fed-Batch Fermentation
This fermentation method is aimed at efficiently carrying out fermentation and is characterized by a low concentration of components in the initial medium to minimize metabolic regulation. During inoculation, the medium promotes initial growth of microbes; subsequent supplies of more raw materials drive the desirable increase in metabolite biosynthesis. Feeding is effected either periodically or continuously. Industrial fermentation of most amino acids is skilled with this method. Fed-batch fermentation requires feeding equipment in addition to the equipment required for batch fermentation, and therefore leads to more fixed costs. However, the process can result in improved productivity as a whole because of the enhanced yield and less fermentation time. The nitrogen source is completed all the way through pH control with ammonia. This process is of particular importance in industrial operations hence, continuous fermentation cannot be practiced, unlike in the case of glutamic acid fermentation from cane molasses using penicillin, described next.
Continuous Fermentation
In continuous fermentation, a complete medium is fed to a fermentor after an appropriate period of batch fermentation, and the same quantity of broth is continuously taken from the fermentor to maintain the fermentation broth at a fixed volume. This may be performed either by the chemo stat method using a substrate or limiting substance, or by the another stat method, in which the cell level is adjusted to maintain constant cell mass. Because the continuous fermentation process allows improvement of productivity compared with the ordinary fermentor, the initial investment in equipment is small relative to the production volume, and operation cost is low. However, one disadvantage is that it is not suitable for small-scale production, and the challenges of sterile operation and equipment maintenance are very necessary than they are for batch and fed-batch fermentation. This process move from batch fermentation to continuous fermentation when productivity per unit time in the former is relatively high. There are many reports examining the steady-state condition in continuous fermentation.
Most of them relate to cell culture, but a few reports are available specifically on amino acid fermentation (5). One of the cause may be that studies on amino acid fermentation have been mainly led to the influence of metabolic regulation, as in the case of the penicillin addition method in glutamic acid fermentation, or because some amino acid processes have a distinct growth phase and production
phase, and continuous culture cannot be used. Many of the microbial strains used in amino acid fermentation are released from metabolic regulation to a remarkable
extent. This makes it easier to examine continuous processes and thereby develop them. It is necessary to study optimum conditions for each process and to optimize
their industrial application. Unlike processes of chemical synthesis, continuous fermentation processes have their own limitations and duration. This is because microbes endure spontaneous mutation within the system, and an increase in the fraction of microbes with declined productivity may lead to rapid reduction in productivity. Hence, it is important to have a strain with high genetic stability.
Enzymatic Method
Of the amino acid production processes using direct enzymatic transformation, some results have led to standard industrial processes. Although the enzymatic production process did not result in practical application, this technology is interesting because of its use of petrochemical products for fermentation raw materials.
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