Bacterial synthesis of vitamins

The K vitamins include vitamin Ki, phylloquinone or phytonadione, and vitamin K2 which is a group of compounds, the menaquinones. Menadione, vitamin K3, is a precursor of menaquinone-4. Vitamin K is present in alfalfa and fish livers. Other dietary sources include green vegetables, soybean oil and eggs. A normal diet together with the bacterial synthesis of vitamin K in the gut are usually sufficient to prevent deficiencies in healthy adults. 

Alterations in gut flora by antimicrobials may potentiate oral anticoagulant by reducing bacterial synthesis of vitamin K (usually only after antimicrobials are given orally in high dose, e.g. to treat Helicobacter pylori). 

Not fully understood. Sulfamethoxazole is a known inhibitor of the cytochrome P450 isoenzyme CYP2C9, by which S-warfarin in predominantly metabolised. The finding that co-trimoxazole caused a modest 22% increase in S-warfarin levels supports this mechanism. Acenocoumarol and phenprocoumon are also metabolised by CYP2C9 and might be expected to be similarly affected. Plasma protein binding displacement has been suggested as a mechanism, but on its own it does not provide an adequate explanation because the interaction is sustained. Sulfonamides can drastically reduce the intestinal bacterial synthesis of vitamin K, but this is not normally an essential source of the vitamin unless dietary sources are exceptionally low, see also Coumarins + Antibacterials , p.365. 

The aecmnulated literature hitherto cited on animals leaves little room for doubt that bacterial synthesis of vitamins in the intestinal tract of different species of animals does take place to a considerable degree. The quantity synthesized of a particular vitamin appears to be of considerable importance. In many instances it is enough to supply the need of the animal for that vitamin with an adequate margin of safety. In other instances, the synthesis is totally inadequate to supply the quantity required for normal... 

Cobalt is one of twenty-seven known elements essential to humans (28) (see Mineral NUTRIENTS). It is an integral part of the cyanocobalamin [68-19-9] molecule, ie, vitamin B 2> only documented biochemically active cobalt component in humans (29,30) (see Vitamins, VITAMIN Vitamin B 2 is not synthesized by animals or higher plants, rather the primary source is bacterial flora in the digestive system of sheep and cattle (8). Except for humans, nonmminants do not appear to requite cobalt. Humans have between 2 and 5 mg of vitamin B22, and deficiency results in the development of pernicious anemia. The wasting disease in sheep and cattle is known as bush sickness in New Zealand, salt sickness in Florida, pine sickness in Scotland, and coast disease in AustraUa. These are essentially the same symptomatically, and are caused by cobalt deficiency. Symptoms include initial lack of appetite followed by scaliness of skin, lack of coordination, loss of flesh, pale mucous membranes, and retarded growth. The total laboratory synthesis of vitamin B 2 was completed in 65—70 steps over a period of eleven years (31). The complex stmcture was reported by Dorothy Crowfoot-Hodgkin in 1961 (32) for which she was awarded a Nobel prize in 1964. 

The determination of vitamin K requirements is complicated by the intestinal bacterial synthesis of menaquinones and the extent to which these are absorbed and utilized (Section 5.1). Prolonged use of antibiotics leads to impaired blood clotting, but simple dietary restriction of vitamin K results in prolonged prothrombin time and increased circulating preprothrombin so it is apparent that bacterial synthesis is inadequate to meet requirements in the absence of a dietary intake of phylloquinone. Preprothrombin is elevated at intakes between 40 to 60 /xg per day, but not at intakes above 80 /rg per day (Suttie etal., 1988). 

Dietary deficiency is relatively widespread, yet is apparently never fatal there is not even a clearly characteristic riboflavin deficiency disease. In addition to intestinal bacterial synthesis of the vitamin, there is very efficient conservation and reutilization of riboflavin in tissues. Flavin coenzymes are tightly enzyme bound, in some cases covalently, and control of tissue flavins is largely at the level of synthesis and catabolism of flavin-dependent enzymes. 

As a result of this resorption and the protein binding of plasma biotin, which reduces filtration at the glomerulus, renal clearance of biotin is only 40% of that of creatinine. This efficient conservation of biotin, together with the recycling of biocytin released from the catabolism of biotin-containing enzymes, may be as important as intestinal bacterial synthesis of the vitamin in explaining the rarity of deficiency. 

Vitamin K> (3-difamesylmenadione), as bacterial growth factor, VI, 208 bacterial synthesis of, VI, 208 biological conversion to menadione, VI, 34... 

Somewhat ironically, the Eschenmoser-Claisen rearrangement was not employed in Woodward s and Eschenmoser s synthesis of Vitamin 8,2, for which it was initially developed [79]. However, the reaction figured prominently in Mulzer s approach toward the molecule (cf. Scheme 7.5) [15] and has found extensive applications in Montforfs studies on bacterial chlorines [80-82]. For instance, in a synthesis of heme dl, a twofold Eschenmoser-Claisen rearrangement was used to convert porphyrin 102 into chlorin 103, setting the quaternary stereocenters of the target (Scheme 7.35) [83]. 

The establishment of allowances for vitamin B-6 is complicated by the following facts (1) the requirement varies with dietary protein intake—there is increased need for vitamin B-6 with increased intakes of protein (2) the uncertainty of the availability of the vitamin in the diet and (3) the uncertainty as to the extent of intestinal bacterial synthesis of the vitamin, and the degree to which it is utilized by the body. Also, there is evidence of increased need of the vitamin in pregnancy and lactation, in the elderly, and in various pathologic and genetic disturbances. Nevertheless, the NRC has set recommended allowances to assure a safety margin and to make a deficiency unlikely under most circumstances. Discussion follows ... 

The contribution of the gut flora to the available pantothenate for humans is unknown, but there is some evidence that bacterial synthesis of the vitamin may be important in animals, especially ruminants, since severe deficiency can only be achieved by using antibiotics or antagonists. Clinical conditions such as ulcers or colitis can adversely affect pantothenate status and excretion rates, and dietary fiber may affect its absorption. 

FIGURE 8.18 Dolichol phosphate is an initiation point for the synthesis of carbohydrate polymers in animals. The analogous alcohol in bacterial systems, undecaprenol, also known as bactoprenol, consists of 11 isoprene units. Undecaprenyl phosphate delivers sugars from the cytoplasm for the synthesis of cell wall components such as peptidoglycans, lipopolysaccharides, and glycoproteins. Polyprenyl compounds also serve as the side chains of vitamin K, the ubiquinones, plastoquinones, and tocopherols (such as vitamin E). 

A healthy diet usually covers average daily vitamin requirements. By contrast, malnutrition, malnourishment (e.g., an unbalanced diet in older people, malnourishment in alcoholics, ready meals), or resorption disturbances lead to an inadequate supply of vitamins from which hypovitaminosis, or in extreme cases avitaminosis, can result. Medical treatments that kill the intestinal flora—e. g., antibiotics—can also lead to vitamin deficiencies (K, Bi2, H) due to the absence of bacterial vitamin synthesis. 

Vitamin K is found in cabbage, cauliflower, spinach, egg yolk, and liver. There is also extensive synthesis of the vitamin by the bacteria in the gut. There is no RDA for vitamin K, but 70 to 140 mg/day is recommended as an adequate level. The lower level assumes one half of the estimated requirement comes from bacterial synthesis, whereas the upper figure assumes no bacterial synthesis. 

Factors which cause a decrease in bioavailability include 111 high urinary excretion (2) destruction by certain mlesiinal bacteria (2) increased urinary excretion caused by vitamin C (4) presence of sulfonamides which block intestinal synthesis and (5) a decrease in absorption mechanisms. Increase in bioavailability can be provided by stimulating intestinal bacterial synthesis in certain species. No toxicity due to folic acid has been reported in humans. 

This vitamin is not synthesized in animals, but rather it results from the bacterial or fungal fermentation in the rumen, after which it is absorbed and concentrated during metabolism. Among the known vitamins, this exclusive microbial synthesis is of great interest. One of the major results of vitamin Bn deficiency is pernicious anemia. This disease, however, usually does not result from a dietary deficiency of the vitamin, but rather by an absence of a glycoprotein ( gastric intrinsic factor ) in the gastric juices that facilitates absorption of the vitamin in the intestine. Control of the diseases hence is either by injection of Bn or by oral administration of the intrinsic factor, with or without the vitamin injection. 

Inhibitors are substances that tend to decrease the rate of an enzyme-catalysed reaction. Although some act on the substrate, the discussion here will be restricted to those inhibitors which combine directly with the enzyme. Inhibitors have many uses, not only in the determination of the characteristics of enzymes, but also in aiding research into metabolic pathways where an inhibited enzyme will allow metabolites to build up so that they are present in detectable levels. Another important use is in the control of infection where drugs such as sulphanilamides competitively inhibit the synthesis of tetrahydrofolates which are vitamins essential to the growth of some bacteria. Many antibiotics are inhibitors of bacterial protein synthesis (e.g. tetracyclin) and cell-wall synthesis (e.g. penicillin). 

The vitamin B12 that occurs in nature is produced almost entirely by bacterial synthesis in animals but not in humans (Battersby, 1994). The richest dietary sources of vitamin B12 are organ meats, such as fiver and kidney. Lesser amounts are present in shellfish, chicken, fish, muscle meats, and dairy products (the principal source in lacto-vegetarians). Plants contain no vitamin B12 unless they are contaminated by bacteria, and foods that contain microorganisms often provide the only source of vitamin B12 for strict vegetarians, such as the vegans of southern India. 

Spent liquors from streptomycin and other antibiotic fermentations contain appreciable amounts of vitamin B12. Bacterial strains producing high amounts have been specially selected for commercial production. Today vitamin B 2 is obtained from fermentations using selected strains of Propionibacterium or Pseudomonas cultures. A full chemical synthesis process for vitamin B 2 is known. However, it requires some 70 steps and for all practical purposes is of little value. 

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