Bacterial Biosynthesis of Vitamin

Vitamin B12 is synthesized only by bacteria and possibly some algae. There are no plant sources of the vitamin, and no plant enzymes are known to require vitamin B12 as a coenzyme. A number of reports have suggested that vitamin Bi2 occurs in some algae, but this maybe the result of bacterial contamination of the water in which they were grown. Nori, made from the edible seaweed Porphyra tenera, has been reported to contain biologically active cobalamin when it is fresh but, on drying, there is a considerable loss of the vitamin as a result of the formation of inactive corrinoids (Yamada et al., 1999). 

The precursor for vitamin B12 synthesis is uroporphyrinogen 111, the common precursor for aU porphyrins, including heme and chlorophyll. Uroporphyrinogen III is synthesized by condensation between succinyl coenzyme A (CoA) and glycine to yield 5-aminolevulinic acid. Two molecules of (5-amino-levulinic acid then condense to form the pyrrole phorphobilinogen, and four molecules of porphobilinogen condense to yield uroporphobilinogen III. 

Uroporphobilinogen III then undergoes the following sequence of reactions (Raux et al., 2000 Roessner et al., 2001)  

successive methylations, in which S-adenosyl methionine is the methyl donor  

excision of C-20 to give the direct fused link between the A and D pyrrole rings  

attachment of 5 -deoxyadenosine to the cobedt atom, yielding cobyrinic acid  

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Ruminants require cobalt for the bacterial biosynthesis of vitamin B12 in the first stomach. Cobalt-deficient sheep or cattle show diminished feed intakes and weight loss. In cows, milk production declines and the fre-... 

Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body, but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing folate, more precisely DHF, from precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim. 

On the other hand, disturbance of digestion and absorption in the intestinal tract probably is a major cause of impairment of nutritional health in the host, both general and possibly with regard to specific nutrients. Helminths are likely, at least periodically, to cause irritation and inflammation. Intestinal hurry and diarrhea not only leave less time for the absorption of nutrients but may also partly remove or disturb the intestinal bacterial flora whose biosynthesis of vitamins is of benefit to the host. Smith and Woodruff (1951) recorded that more than half their cases of dysentery among prisoners of war developed beriberi. This was, of course, an effect of bacterial invasion, but it is reasonable to suppose that helminths may interfere with absorption of nutrients in a similar nonspecific manner. 

The mode of action of the sulfonamides as antagonists of 4-aminobenzoic acid (PAB) is well documented, as is the effect of physicochemical properties of the sulfonamide molecule, e.g. pK, on potency (B-81MI10802). Sulfonamides compete with PAB in the biosynthesis of folic acid (44), a vital precursor for several coenzymes found in all living cells. Mammalian cells cannot synthesize folic acid (44), and rely on its uptake as an essential vitamin. However, bacteria depend on its synthesis from pteridine precursors, hence the selective toxicity of sulfonamides for bacterial cells. Sulfonamides may compete with PAB at an enzyme site during the assembly of folic acid (44) or they may deplete the pteridine supply of the cell by forming covalently-bonded species such as (45) or they may replace PAB as an enzyme substrate to generate coupled products such as (46) which are useless to the cell. 

Raux E, Schubert HE, and Warren MJ (2000) Biosynthesis of cobalamin (vitamin B12) a bacterial conundrum. Cellular and Molecular Life Scierwes 57,1880-93. 

The sulfonamides act as competitive enzyme inhibitors and block the biosynthesis of the vitamin folic acid in bacterial cells (Fig. 10.14). They do this by inhibiting the... 

The complete biosynthesis of cobalamin requires somewhere around 30 enzyme-mediated steps, which compares favorably to the total chemical synthesis of the compound where, for instance, 37 steps are involved in the photochemical route to synthetic cobyric acid, ° an intermediate that represents only the corrin component of the final cobalamin molecule. For this reason vitamin B12 is produced commercially by bacterial culture and is the most expensive of the water-soluble vitamins to produce because of the comparatively low yields obtained. 

Given this structural similarity, it should not be surprising to learn that sulfanilamide competes with p-aminobenzoic acid for a binding site on the surface of dihydropteroate synthetase. Put another way, sulfanilamide binds to the enzyme where p-aminobenzoic acid should bind but no reaction occurs. The consequence is that a step in folic acid biosynthesis is disrupted and the bacterial cell is deprived of adequate folic acid. Nucleic acid synthesis, among other things, is disrupted, leading to a cessation of cell growth and division. The human immune system can mop up what remains. No similar consequences befall the human host since it cannot make folic acid in the first place and must get an adequate supply of this vitamin in the diet. 

The effect of pH is a composite of separate effects on synthesis, on enzyme activities, and on vitamin Bn storage in the cell (below pH 5.5 the vitamin is washed out of the cell). In general, the process of biosynthesis is more sensitive to changes in pH than bacterial growth. This fact has a special... 

Ford SH and Friedmann HC (1976) Vitamin B12 biosynthesis in vitro formation of cobinamide from cobyric acid and L-threonine. Arch Biochem Biophys 175 121-130 Forrest WW and Walker DJ (1964) Change in entropy during bacterial metabolism. Nature 20L49-52... 

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