Vitamin B12, synthesis

Only microorganisms are able to synthesize vitamin B12. Microbiological vitamin B12 synthesis in humans takes place, however, in the lower intestine where the... 

Once the "synthesis tree" has been elaborated, we must proceed to the evaluation of the alternative pathways and compare them with possible synthetic schemes in order to optimise the chosen route and make it as self-consistent as possible. However, all synthetic plans must be flexible enough to allow new alternative solutions when things do not happen as anticipated. In this sense. Woodward referred very often to opportunism and of taking advantage of the "surprises" which may occur during the execution of a synthesis. Through the different stages of a synthesis new aspects may evolve and even important discoveries may be made. Such was the case, for instance, in the vitamin B12 synthesis in which the considerations of the stereochemistry of an intermediate, opposite to the one anticipated, led Woodward to the discovery of the principle of conservation of orbital symmetry [29]. 

The high nucleophilicity of sulfur atoms is preserved, even if it is bound to electron withdrawing carbonyl groups. Thiocarboxyiates, for example, substitute bromine, e.g. of a-bromo ketones. In the presence of bases the a-acylthio ketones deprotonate and rearrange to episulfides. After desulfurization with triphenyiphosphine, 1,3-diketones are formed in good yield. Thiolactams react in the same way, and A. Eschenmoser (1970) has used this sequence in his vitamin B12 synthesis (p. 261). 

In chapter 27 we analysed the synthesis of the bicyclic lactone 7 needed by Eschenmoser for his vitamin B12 synthesis.2 The next step was a chain extension by the Amdt-Eistert procedure to the ester 9. 

For this reason, in his vitamin B12 synthesis, Woodward initially predicted the wrong stereochemistry for the electrocyclization of a hexatriene. This led to the discovery of the conservation of orbital symmetry (Woodward R. B., in Aromaticity, Special Publication No. 21, Chemical Society, London, 1967, 217). 

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. 

It appears that cobalt plays a particularly important role in the growth of cyanobacteria (Saito et al, 2002 Sunda and Huntsman, 1995b). Both Prochlorococcus and Synechococcus show an absolute cobalt requirement that zinc cannot substitute for (Figure 18(a)). The growth rate of Synechococcus is little affected by low zinc concentrations, except in the presence of cadmium which then becomes extremely toxic (Saito et al, personal communication). The biochemical processes responsible for the major cellular utilization of zinc and cobalt in marine cyanobacteria are unknown, however. These metals may be involved in carbonic anhydrase and/or other hydrolytic enzymes. Cobalamin (vitamin B12) synthesis is a function of cobalt in these organisms, yet B12 quotas tend to be very small (on the order of only 0.01 p.mol (mol C) ) and hence are not likely represent a significant portion of the cellular cobalt (Wilhelm and Trick, 1995). 

The bicyclic double lactone (14) was used by Eschenmoser as the precursor for all four heterocyclic rings in his vitamin B12 synthesis. Disconnecting both lactones reveals a ketone (15). 

In Chapter 27 we analysed the synthesis of bicyclic lactone (6). In his vitamine B12 synthesis Eschenmoser needed to lengthen the acetic acid side chain of (6) into the propionic side chain of (7). This he accomplished by the Arndt-Eistert procedure. 

Ashe Sutherland Braye Woodward and Eschenmoser Ginsberg and Lindsell Franz Synthesis of phosphabenzene (phosphinine) C3H3P Importance of c-AMP established Phospholide anion characterised Synthesis of vitamin B12 Synthesis of first P4 complex with an M-P bond Development of the herbicide Glyphosate... 

Microbiota keeps an important role in human metabolism. It must be considered a metabolizing organ, with impact oti endo- and xenobiotic metabolism, beyond its metabolic relevance for vitamin B12 synthesis, and carbohydrate breakdown, between other important functions. 

On the other hand, it has been shown (Kanopkaite and Gibavichyute, 1965) that the addition of ATP to the medium increases vitamin B12 synthesis. Similarly, adding amino acids to minimal medium causes the growth rates of cultures producing excessive quantities of vitamin Bn to approach those of cultures synthesizing optimal amounts (Fig. 5.5) (Iordan et al., 1984). 

The competition of vitamin B12 synthesis for amino acids has an effect on protein synthesis, as shown by the rate of incorporation of labeled leucine in cellular proteins (Fig. 5.6). In cells containing corrinoids at levels that are either higher or lower than the optimal (physiological) level, protein synthesis is reduced (Iordan et al, 1984). Apparently, vitamin B is indirectly involved in protein synthesis, since the protein content in vitamin Bi2-deficient cells is 67% of the control cells. The decrease in protein content may be a consequence of the inhibition of synthesis and activity of a number of enzymes (first of all SH-dependent enzymes) in vitamin Bn-deficient cells. 

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