Vitamin B12 Functional Groups Broken Down

Vitamin B12 can be categorised as a group of 4 corrinoids with similar structures, all with the suffix cobalamin. It is widely regarded as the most complex vitamin, and having only been isolated in 1948, was not synthesised until 1973. It is typically stable and obeys the 18 electron rule. The structural components are all centred on the cobalt atom at the core, with its 6 coordination sites at the octahedral centre allowing plenty of room; four sites are taken up by a corrin ring (red), another by a 5, 6-dimethybenzimidazole (DMB) group (blue) and the sixth coordination site (yellow) has four possibilities, where R = OH, Me, CN or 5-deoxyadenosyl - which create the differing forms of cobalamin. Attached to part of the corrin ring is a nucleotide group, which contains a nitrogenous base, a phosphate group (both green) and a sugar compound. Surrounding the ring the multiple amide side chains play a large role in one of the many roles of B12 - protein binding; it is the organometallic nature of the vitamin, specifically its metal-carbon bond that gives it its major properties. This is unusual for vitamins, with none other than B12 possessing a metal component. The main reason for the stability of this molecule - without which we could not administer it for use as a drug and transport it around the body - is the stabilized pi system created by the extended conjugated system of the double bonds in the corrin ring. They are all within close range of each other and can give rise to resonance forms. This low energy system yields to the cobalt active site being the preferred target for transferring functional groups between the various forms of B12. Of the four types of B12 - methycobalamin (MeCobl), adenosylcobalamin (AdCobl) , hydroxocobalamin (HCobl) and cyanocobalamin (CyCobl) - only the former two are active coenzymes and play a role in the main use of B12 - metabolism in the body. This is made possible due to the 'removable ligand group on the metal active site' (1) of the cobalt. Once inside the body, there are two ways of cleaving this cobalt-carbon band which give rise to different enzyme catalysed reaction; Isomerases These require adenosylcobalamin as the cofactor to the enzyme methylmalonyl-CoA mutase to yield succinyl-CoA for energy extraction and haemoglobin production. The homolytic cleavage of the Co-C bond results in a free radical, which 'allows a hydrogen atom to migrate from a substrate carbon to an adjacent carbon' (2) in exchange for another group. Clearly adenosylcobalamin is the only molecule with the ligand able to do this; thus it is the particular form of B12 that partakes. The cobalt metal can vary between Co (II) and Co (III) oxidation states reversibly whilst more 5-deoxy-5-adenosyl radicals are produced in the active site. Methyltransferases Methylcobalamin is a cofactor to the enzyme methionine synthase which promotes the conversion of the amino acid homocysteine to methionine, a chemical essential for DNA methylation and red blood cell production. It is heterolytically cleaved at the active site, both electrons shifting onto the cobalt. The methyl cation can subsequently be released from the vitamin and transfer to another molecule. The metal-carbon bond is the basis of some of the most crucial functions of cobalamin related to blood and DNA inside the body, and its weak bond enthalpy is the main factor for this. A deficiency of B12 can cause anaemia, with symptoms including tiredness, headaches and problems with mobility and vision. HCobl and CyCobl would be inefficient in these two processes and were they the only forms of B12, anaemia would be a certainty. The vast differences in properties of cobalamin depending on the -R ligand alone enough to have a significant effect on the human body. The most stable and cheapest form of B12 is CyCobl. It is this form that is most widely distributed in multivitamins and food additives although it cannot be used by the body for metabolism. It must be converted into MeCobl by the liver, where its cyanide ligand is replaced by a methyl group. HCobl is also converted into other forms for the same purpose. Its main use as a drug is for treating cyanide poisoning since 'cobalt compounds have the ability to bind and detoxify cyanide' (3). It is able to attach to the cyanide to such an extent that it can 'pull the cyanide out of the mitochondria of the cell to form cyanocobalamin' (4) in place of the hydroxide ligand. This is now the foundation one of the most successful treatments available for cyanide poisoning, with its mechanism of action taking advantage of the strengths of the -R ligands in two forms of B12 and their stabilities with and without cyanide. The conversion of HCobl injected into the body and its affinity to cyanide has led to an effective usage. The CyCobl and all traces of cyanide are safely urinated with minimal side effects. The seven amide chains - three acetamide and four propionamide - attached to the corrin ring enlarge the structure and can be turned into esters via hydrolysis initially to acids. This provides extra oxygen atoms, which increase the hydrogen bonding ability of the molecule and plays a 'key role in the way that cobalamins interact with proteins' (5) in the body. It increases the solubility and allows easier transport and access around the bloodstream. The polyamides are also outstretched and elongated with two or three carbons so as to potentially grab on to molecules when undergoing a reaction. One component that has a crucial role in the vitamins role of creating nucleic acid is the nucleotide chain connected to the seventh amide on the corrin ring, highlighted in green on Figure 1. It comprises of a phosphate group, a sugar and a nitrogenous base. They are specifically used as monomers to DNA, as seen before in methytransferases. The nucleotide is attached to dimethylbenzimidazole which in turn connects as a ligand back to the cobalt centre; a strict restriction in position is required due to this which lowers the stability of the molecule and renders it susceptible to attack. However the dimethylbenzimidazole group, whilst not directly connected to the corrin ring, has a mild increasing effect on the conjugated system which adds to the stability of the molecule.