Cobalamin potentials

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. 

Cobalt complexes with square planar tetradentate ligands, including salen, cor-rin, and porphyrin types, all catalyse the reduction of alkyl bromides and iodides. Most preparative and mechanistic work with these reactions has used cobalamines, including vitamin-B,. A generalised catalytic cycle is depicted in Scheme 4.10 [219]. At potentials around -0.9 V vs. see, the parent ligated Co(lll) compound un-... 

Scheme 4.10. Calalyttc cycle for the reduction of alkyl halides by cobalamins. The outer circle represents the combined photo and electrochemical process, "fhe inner shunt is the wholly electrochemical process at more negative potentials. Ligands are omitted for clarity.

Cobalamin catalysed electrochemical reduction of the 2-chloroethanol ester 68 at negative potentials, without photochemical assistance, leads to a 1,2-elimination process (see p. 115) [228]. This contrasts with the lack of 1,2-elimination during reaction of 66 and 67, Thus in the purely electrochemical carbon-cobalt bond... 

Assaf-Anid, N., Hayes, K. F. Vogel, T. M. (1994). Reductive dechlorination of carbon tetrachloride by cobalamin(II) in the presence of dithiothreitol mechanistic study, effect of redox potential and pH. Environmental Science Technology, 28, 246-52. Ballard, T. M. (1971). Role of humic carrier substance in DDT movement through forest soil. Soil Science Society of America Proceedings, 35, 145-7. 

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-... 

Thermochemical. Application to the estimation of the enthalpy of a process such as that depicted by Equation 15 requires determination of the heats of formation of LnM—R, R , and LnM . The latter usually is not accessible to measurement although it is in the case of alkyl-cobalamins (where LnM- corresponds to vitamin B12r, a stable and accessible compound). Thus, thermochemical approaches, in principle, are potentially applicable to the estimation of the Co-C bond dissociation energy in coenzyme B12. However, the practical difficulties are considerable and the probable accuracy of the result is questionable. 

The direct extension of similar approaches to other systems, notably alkyl-cobalamins and related alkyl-cobalt compounds, is constrained by the instability of the corresponding hydrides, which are consequently unsuitable as radical traps. Modification of the approach to utilize other radical traps (e.g., 02) potentially is feasible but needs further investigation in view of possible complicating features such as reaction between the trapping agent and the parent metal-alkyl and ambiguities between homolytic dissociation and other (e.g., concerted) mechanisms (26, 27). 

Scalabrino G (2005) Cobalamin (vitamin B12) in subacute combined degeneration and beyond tiadional interpretations and novel theories. Exp Neurol 192(2) 463 79 Scalabrino G, BucceUato FR, Veber D, Mutti E (2003) New basis of the neurotrophic action of vitamin B12. Clin Chem Lab Med 41(11) 1435-1437 Shih JJ, Kornblum H, Shewmon DA (1996) Global brain dysfunction in an infant with pyridox-ine dependency evaluation with EEG, evoked potentials, MRI, and PET. Neurology 47(3) 824-826... 

The half-wave potential for the enzyme-bound Co VCo cobalamin couple of the methionine synthase from E. coli at 526 mV versus SHE is about 80 mV lower than that of the Co /Cokcobalamin couple in neutral aqueous solution. Access to the catalytic cycle of the enzyme by one-electron reduction of Co kcobalamin (and reactivation upon occasional adventitious formation of Co -cobalamin) is indicated to be accomplished by a unique mechanism. The (thermodynamically unfavorable) reduction with intermediate formation of the enzyme-bound Cokcobalamin is driven by a rapid methylation of the highly reduced Co -center of the reduced corrin with Y-adenosyhnethionine. The modular nature of methionine synthase allows for the control of the methyl-group transfer processes by modulating and alternating conformational equilibria. ... 

Hydroxocobalamin (vitamin another antidote, is a potential alternative to sodium nitrite treatment. It works by binding with cyanide to form nontoxic cyano-cobalamin (vitamin Bj ). Although effective and relatively safe in experimental models, the concentration available in the United States requires large infusion volumes and has a short shelf life due to light instability, and reports of anaphylactoid reactions have limited its use (8,13,21). Further studies using higher concentrations available in European formulations may eventually lead to its use as an outpatient alterative to sodium nitrite treatment in the United States (7,32). Other alternatives currently used or undergoing clinical trials in Europe include cobalt salts, limited by their toxicity, aldehydes, and aminophenol derivatives. These alternative treatments are not currently available in the United States (7). 

The measurement of holotranscobalamin II is potentially useftil as a specific marker of biologically available vitamin Bi2, because only cobalamin bound to Tell is specifically available for uptake by aU cells. Other methods have been described for the measurement of holotranscobalamin in serum, one using an immobilized monoclonal antibody to human transcobalamin, followed by measurement of released cobalamin by CPB, This method is currently available as a commercial kit. The other method uses magnetic beads coated with cobalamin to precipitate apotranscobalamin followed by measurement of the holotranscobalamin in the supernatant by ELISA. Though these methods are claimed to be precise and simple to perform, there remains doubt over the interpretation of the measured concentrations, and over their sensitivity and specificity in the diagnosis of vitamin B deficiency. ... 

Other potentially useful tests include antibody testing and serum gastrin levels. Positive anti-intrinsic factor antibodies may be present in approximately half of patients with pernicious anemia, but is highly specific for the disease. Additionally, an estimated 85% of patients have anti-parietal cell antibodies, but they are nonspecific, as 3% to 10% of healthy patients have these antibodies. Fasting serum gastrin levels are elevated in more than 70% of patients with cobalamin deficiency and may be useful in assessing patients with borderline... 

Potential adverse effects with vitamin Bn replacement therapy are rare. Uncommon side effects include hyperuricemia and hypokalemia. Rebound thrombocytosis may precipitate thrombotic events. Another side effect of vitamin Bn therapy is sodium retention. This effect is more likely to occur in the patient with compromised cardiovascular status, because of an expansion in intravascular volume secondary to the sudden increase in the production of RBCs. Rare cases of anaphylaxis with parenteral administration of cobalamin have been reported. 

The structure in Figure 28 contains information potentially pertaining to translocation of the methylene group of the 5-deoxyadenosyl radical from Co of cobalamin to the substrate 6 A away. The structure shows two conformations of the ribosyl ring in 5-deoxyadenosine, the C2 -endo and the CV-endo conformations. The two conformations project the 5 -methyl group 3.1 and 4.5 A, respectively, from Co. The orientation in the Cy-endo conformation, if replicated in the 5-deoxyadenosyl radical, would allow the methylene radical to... 

Cobalt(II) complexes (such as cob(II)alamin, formerly called B,2,) can be obtained by several methods including controlled potential reduction [14,15], anaerobic photolysis of some organocobalt species [16] (see Section 5.2(b)), partial oxidation of cobalt(I) complexes, in some cases acidification of solutions of cobalt(I) complexes (see below) and chemical reduction. Chemical reduction of cobalt(III) cobalamins to the +2 oxidation state has been achieved with hydrogen over platinum oxide [16], with neutral and acidic solutions of vanadium(III) [17], with chromous acetate at pH 3 [18] and with amalgamated zinc in 0.1 M aqueous perchloric acid [19]. All such cobalt(II) species are probably 5-coordinate, and are low spin d systems containing an unpaired electron and thus displaying an ESR spectrum [20]. 

If folate is given without cobalamin to a B 12-deficient patient, the drug only partially corrects the megaloblastic anemia because it will bypass the methyl-folate trap and provide adequate FH4 coenzyme for the conversion of dUMP to dTMP and for a resurgence of purine synthesis. As a result, normal DNA synthesis, DNA repair, and cell division occur. However, the neurologic syndrome, resulting from hypomethylation in nervous tissue, may progress unless the physician realizes that B12 supplementation is required. In Jean Ann s case, in which the serum B12 concentration was borderline low and in which the dietary history supported the possibility of a B12 deficiency, a combination of folate and B12 supplements is required to avoid this potential therapeutic trap. 

The fact that the nature of the ligands bound axially to the cobalt atom in the cobalamins and cobinamides profoundly influences the reactivity of the metal has received further confirmation from Hogenkamp and Holmes. They have measured the polarographic half-wave potential of several cobalamins and cobinamides and have shown that the differences in reactivity between the two series cannot be due solely to steric factors. 

A standard potential vs. pH diagram correlates the thermodynamics of the aquocobalamin (4+)-Bi2r (23)-Bi2s (40") system (see Fig. 5). The interconversion between the different oxidation states of B -derivatives can usually be monitored effectively by UV-vis spectroscopy, and the relevant data were obtained from potentiostatic measurements, which were followed by UV-vis spectroscopy [90,94], Within the pH range - 1 to 11 and applied potentials = 0.5 V and -1.2 V vs. SCE, seven solution cobalamins are thermodynamically predominant spanning a range of the three formal oxidation states of Bi2 [90]. 

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