Cobalamins oxidation

The total syntheses have yielded cobyric acid and thence cyanocobalamin. Routes to other cobalamins, eg, methylcobalamin and adenosylcobalamin, are known (76—79). One approach to such compounds involves the oxidative addition of the appropriate alkyl haUde (eg, CH I to give methylcobalamin) or tosylate (eg, 5 -A-tosyladenosine to yield adenosylcobalamine) to cobalt(I)alamine. 

Mechanistic aspects of the action of folate-requiring enzymes involve one-carbon unit transfer at the oxidation level of formaldehyde, formate and methyl (78ACR314, 8OMI2I6OO) and are exemplified in pyrimidine and purine biosynthesis. A more complex mechanism has to be suggested for the methyl transfer from 5-methyl-THF (322) to homocysteine, since this transmethylation reaction is cobalamine-dependent to form methionine in E. coli. 

A spore-forming strain of Desulfitobacterium chlororespirans was able to couple the dechlorination of 3-chloro-4-hydroxybenzoate to the oxidation of lactate to acetate, pyruvate, or formate (Sanford et al. 1996). Whereas 2,4,6-trichlorophenol and 2,4,6-tribro-mophenol supported growth with the production of 4-chlorophenol and 4-bromophenol, neither 2-bromophenol nor 2-iodophenol was able to do so. The membrane-bound dehalogenase contains cobalamin, iron, and acid-labile sulfur, and is apparently specific for ortho-substituted phenols (Krasotkina et al. 2001). 

There are many biomimetic model Co complexes of the cobalamins.1149 The primary criterion for an effective B12 model has been that the complex may be reduced to the monovalent state and undergo facile oxidative addition to generate a stable alkylcobalt(III) complex. The two main classes of B12 model complexes that have been investigated are Co oximes and Schiff base complexes. The former class shares the planar CoN4 array of their biological analogs whereas the majority of effective Schiff base Bi2 model complexes comprise equatorial czj-N202 donor sets. 

The activation parameters AS" and for formation and dissociation of the nitric oxide adduct of cobalamin... 

The NO/NO+ and NO/NO- self-exchange rates are quite slow (42). Therefore, the kinetics of nitric oxide electron transfer reactions are strongly affected by transition metal complexes, particularly by those that are labile and redox active which can serve to promote these reactions. Although iron is the most important metal target for nitric oxide in mammalian biology, other metal centers might also react with NO. For example, both cobalt (in the form of cobalamin) (43,44) and copper (in the form of different types of copper proteins) (45) have been identified as potential NO targets. In addition, a substantial fraction of the bacterial nitrite reductases (which catalyze reduction of NO2 to NO) are copper enzymes (46). The interactions of NO with such metal centers continue to be rich for further exploration. 

Other pubKcations dealing with the catalytic ability of electrogenerated cobalt(I) species have appeared. Cob(I)alamin reacts with 1,4-dibromobutane to yield a tet-ramethylene-1,4-di-Co -cobalamin complex [138]. Alkyl radicals (which arise from the oxidative addition of cobalt(I) tetraphenyl porphyrin to an alkyl halide) have been found to migrate from the cobalt center to a nitrogen of a pyrrole ring [139]. 

Vitamin Bjj (8.50, cobalamin) is an extremely complex molecule consisting of a corrin ring system similar to heme. The central metal atom is cobalt, coordinated with a ribofuranosyl-dimethylbenzimidazole. Vitamin Bjj occurs in liver, but is also produced by many bacteria and is therefore obtained commercially by fermentation. The vitamin is a catalyst for the rearrangement of methylmalonyl-CoA to the succinyl derivative in the degradation of some amino acids and the oxidation of fatty acids with an odd number of carbon atoms. It is also necessary for the methylation of homocysteine to methionine. 

Oxidation under acidic conditions gives a c-lactone instead of a c-lactam. The 7-acetamide reacts readily but the 7-acetic ester resists the cyclization. If an excess of oxidant is used, C-10 halogenation follows the lactonization (Scheme 94). The two reactions are competitive for cobalamins, and the course of the reaction depends on the / ligand and the reaction conditions. 

Chronic nitrous oxide abuse can remove a lot of vitamin B12 from the bloodstream. B12 (cobalamin) is necessary for the creation of blood cells and neurotransmitters, as well as the protective layers that cover nerves. This results in nerve damage and pain balancing, walking, and concentration difficulties mental impairment mood disturbances (such as depression) and other physical problems. Chronic nitrous oxide use may also interfere with the production in bone marrow of white blood cells and red blood cells. Treatment with intramuscular injections of B12 may reverse these symptoms. 

Coenzymes can be either inorganic species such as coenzyme F450 and or purely organic as in coenzyme A (2.7), the coenzyme that carries acyl groups in the synthesis and oxidation of fatty acids, and is responsible for oxidation of pyruvate in the citric acid cycle. Vitamins are commonly coenzymes or their precursors. Coenzyme A is vitamin B5 and we will look in detail at cobalamin, vitamin B12, by way of an example in the next section. Some examples of vitamin and non-vitamin coenzymes are shown in Table 2.3. 

C13. Chanarin, I., Cobalamins and nitrous oxide A review. ]. Clin. Pathol. 33, 909-916... 

K5. Kondo, H., Osborne, M. L., Kolhouse, J. F., Binder, M. J., Podell, E. R., Utley, C. S., Abrahams, R. S., and Allen, R. H., Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian Cobalamin-dependent enzymes in rats. J. Clin. Invest. 67, 1270-1283 (1981). 

L8. Lumb, M., Perry, J., Deacon. R., and Chanarin, I., Recovery of tissue folates after inactivation of cobalamin by nitrous oxide. The significance of dietary folate. Am. /. Clin. Nutr. 34, 2418-2422 (1981). 

Other biomimetic reactions are based on the catalytic properties of metal ions. Many enzymes require metal ions that function, in one way or another, in oxidation-reduction processes. The wide range of such metal-ion reactions precludes mentioning more than a few in addition to the iron-porphyrin class, and in addition to chlorophyll, a number of enzymes require cobalamin as cofactor ferridoxin and high-potential iron proteins require iron-sulfur clusters, and nitrog-... 

Wolak M, Zahl A, Schneppensieper T, Stochel G, van Eldik R. Kinetics and mechanism of the reversible binding of nitric oxide to reduced cobalamin. J Am Chem Soc 2001 123 9780-91. 

Figure 21-3. The methionine synthase reaction. Methionine synthase catalyzes the remethylation of homocysteine to methionine. In the first half reaction (1), a methyl group is transferred from 5-methyl tetrahydrofolate (5-MTHF) to the reduced form of cobalamin [Cob(I)], generating methyl-cobalamin [Methyl-Cob(III)] and tetrahydrofolate (THF). During the second half reaction (2), the methyl group is transferred from methylcobalamin to homocysteine, generating methionine. During the catalytic reaction, Cob(I) occasionally becomes oxidized, producing an inactive form of cobalamin, cob(II)alamin [Cob(II)]. The enzyme methionine synthase reductase (MTRR) then reactivates Cob(II) through reductive methylation, producing methyl-Cob(III). SAM, 5-adenosylmethionine SAH, 5-adeno-sylhomocysteine.

---