Fermentation products

All the fermentation-based modifications of lactose are probably not really economical because lactose is not cost-competitive with alternative 

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PhCHa benzylpenicillin = penicillin G (usual fermentation product)... 

Marecek and colleagues developed a new electrochemical method for the rapid quantitative analysis of the antibiotic monensin in the fermentation vats used during its production. The standard method for the analysis, which is based on a test for microbiological activity, is both difficult and time-consuming. As part of the study, samples taken at different times from a fermentation production vat were analyzed for the concentration of monensin using both the electrochemical and microbiological procedures. The results, in parts per thousand (ppt), are reported in the following table. 

Two-Phase Aqueous Extraction. Liquid—Hquid extraction usually involves an aqueous phase and an organic phase, but systems having two or more aqueous phases can also be formed from solutions of mutually incompatible polymers such as poly(ethylene glycol) (PEG) or dextran. A system having as many as 18 aqueous phases in equiHbrium has been demonstrated (93). Two-phase aqueous extraction, particularly useful in purifying biological species such as proteins (qv) and enzymes, can also be carried out in combination with fermentation (qv) so that the fermentation product is extracted as it is formed (94). 

Although a tremendous number of fermentation processes have been researched and developed to various extents, only a couple of hundred ate used commercially. Fermentation industries have continued to expand in terms of the number of new products on the market, the total volume (capacity), and the total sales value of the products. The early 1990s U.S. market for fermentation products was estimated to be in the 9-10 x 10 range. The total world market is probably three times that figure, and antibiotics continue to comprise a primary share of the industry. Other principal product categories are enzymes, several organic acids, baker s yeast, ethanol (qv), vitamins (qv), and steroid hormones (qv). 

There are thousands of breweries worldwide. However, the number of companies using fermentation to produce therapeutic substances and/or fine chemicals number well over 150, and those that grow microorganisms for food and feed number nearly 100. Lists of representative fermentation products produced commercially and the corresponding companies are available (1). Numerous other companies practice fermentation in some small capacity because it is often the only route to synthesize biochemical intermediates, enzymes, and many fine chemicals used in minor quantities. The large volume of L-phenylalanine is mainly used in the manufacture of the artificial dipeptide sweetener known as aspartame [22389-47-0]. Prior to the early 1980s there was httle demand for L-phenyl alanine, most of which was obtained by extraction from human hair and other nonmicrobiological sources. 

Table 4. Worldwide 1992 Production and Sale Price for Fermentation Products ...

Urethane [51-79-6] (ethyl carbamate) occurs as a natural by-product in fermented products such as wine, Hquors, yogurt, beer, bread, oHves, cheeses, and soy sauces. Whereas urethane has a known cancer etiology in experimental animals, no such relationship has yet been proven in humans (108,109). Alcohol may act by blocking the metaboHsm of urethane, and thus exert a protective effect in humans consuming alcohoHc beverages (110). 

Lactic acid is also the simplest hydroxy acid that is optically active. L (+)-Lactic acid [79-33-4] (1) occurs naturally ia blood and ia many fermentation products (7). The chemically produced lactic acid is a racemic mixture and some fermentations also produce the racemic mixture or an enantiomeric excess of D (—)-lactic acid [10326-41-7] (2) (8). 

Avermectins and Ivermectin. The avermectias are pentacycHc lactones isolated from fermentation products of Streptomjces avermitilis and ivermectin is a semisynthetic chemical, 22,23-dihydroavermectia (46). Ivermectin is effective in very low doses for the control of red spider mites on deciduous fmits, in baits for the control of imported fire ants, and as a parasiticide for Onchocerca volvulus in humans and for catde gmbs. These insecticides appear to function as agonists for the neuroinhibitory transmitter y-aminobutyric acid (GABA) (see Antiparasitic agents, avermectins). 

Fermented Products. Fermented meat products such as semidried and dried sausages are generally recognized as safe, if critical points during processing are controlled properly. Some of the sausage processors use a small amount of fermented product as the starter for a new batch of product. 

In the 1950s, a group of coryneform bacteria which accumulate a large amount of L-glutamic acid in the culture medium were isolated (21). The use of mutant derivatives of these bacteria offered a new fermentation process for the production of many other kinds of amino acids (22). The amino acids which are produced by this method are mostiy of the T.-form, and the desired amino acid is singly accumulated. Therefore, it is very easy to isolate it from the culture broth. Rapid development of fermentative production and en2ymatic production have contributed to the lower costs of many protein amino acids and to their availabiUty in many fields as economical raw materials. 

Fig. 5. Fermentative production of amino acids (140). A, pure culture B, inoculation C, boiler D, air compressor E, air filter F, seed tank G, ammonia water for pH control H, fermenter I, sterilizer , culture media K, preparation tank L, centrifugal separator M, ion-exchange column N, crystallizing...

Table 6. Fermentative Production of Amino Acids and Their Related Substances from Carbohydrates ...

Ivermectin is the catalytic reduction product of avermectin, a macroHde containing a spiroketal ring system. Two other related antibiotics having significantly different stmctural features and biological properties, moxidectin and milbemycin oxime, were more recentiy introduced into the market. Although these compounds have no antimicrobial activity, they are sometimes referred to as antibiotics because they are derived from fermentation products and have very selective toxicities. They have potent activity against worms or helminths and certain ectoparasites such as mites and ticks. 

Shordy thereafter, the M-4365 complex of six factors (A —A and G —G ), produced by M. capillata (275,276), was reported. From the izenamicin complex of seven factors produced by a M.icromonospora species, three were new fermentation products (277). Many compounds isolated are identical juvenimicin A, M-4365 A2, and izenamicin A are the same as rosaramicin. Stmctures have been proven by chemical interconversions (261,277,278) and microbial transformations (279). 

Most of the fermentation and isolation processes for manufacture of the tetracyclines are described in patents (71,72). Manufacture begins with the cultivated growth of selected strains of Streptomjces in a medium chosen to produce optimum growth and maximum antibiotic production. Some clinically useful tetracyclines (2—4) are produced directly in these fermentations others (5—7) are produced by subjecting the fermentation products to one or more chemical alterations. The purified antibiotic produced by fermentation is used as the starting material for a series of chemical transformations (59). 

Euactioaahty of whey proteia coaceatrates varies with whey type and concentration. Table 5 gives compositional data for whey proteia coaceatrates from differeat sources of whey. These coaceatrates are used ia a limited number of products ice cream and other fro2en desserts, fermented products, coffee whiteners, and whipped toppiags. 

In spite of the considerable progress in developing methods for total synthesis, this route to cephalosporins cannot compete with fermentation or penicillin rearrangement (see Sections 5.10.4.1 and 2) for the industrial production of cephalosporin antibiotics. While total synthesis does provide access to nuclear analogs not readily obtainable from fermentation products, none of the totally synthetic materials have displayed sufficient advantages to Warrant their development as new drug products (b-81MI51000). 

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