More and more research is being conducted on methylcobalamin (MeCbl). We will update this page with current research as soon as it becomes available.
Methylcobalamin as an endogenous coenzyme plays as important a role in transmethylation of methionine synthetase in the synthesis of methionine from homocysteine. It is transported to nerve cell organelles, and promotes nucleic acid and protein synthesis. Transportation of methylcobalamin to nerve cell organelles is better than both hydroxocobalamin and cyanocobalamin. It is involved in the synthesis of thymidine from deoxyuridine, promotion of deposited folate utilisation and metabolism of nucleic acid. It promotes nucleic acid and protein synthesis more than adenosylcobalamin does. Methylcobalamin promotes axonal transport and axonal regeneration. Methylcobalamin normalises axonal skeletal protein transport in nerve cells in animal models of diabetes mellitus. It exhibits neuropathological and electrophysiological protective effect on nerve degeneration in animal models of axonal degeneration (adriamycin, acrylamide, and vincristine-induced neuropathies) with spontaneous diabetes mellitus. It promotes myelination (phospholipid synthesis). It promotes the synthesis of lecithin, the main constituent of medullary sheath lipids, and increases myelination of neurons in tissue culture, more than adenosylcobalamin does. It restores delayed synaptic transmission and diminished neurotransmitters to normal.
These abstracts are available on PubMed and where we have included more than the abstract below, it is from an open access article.
Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment.
Functional Magnetic Resonance Imaging of the Brain (FMRIB) Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. firstname.lastname@example.org
Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer’s disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamintreatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.
Genetic disorders of vitamin B₁₂ metabolism: eight complementation groups–eight genes.
Structural Genomics Consortium, University of Oxford, Oxford, UK.
Vitamin B12 (cobalamin, Cbl) is an essential nutrient in human metabolism. Genetic diseases of vitamin B12 utilisation constitute an important fraction of inherited newborn disease. Functionally, B12 is the cofactor for methionine synthase and methylmalonyl CoA mutase. To function as a cofactor, B12 must be metabolised through a complex pathway that modifies its structure and takes it through subcellular compartments of the cell. Through the study of inherited disorders of vitamin B12 utilisation, the genes for eight complementation groups have been identified, leading to the determination of the general structure of vitamin B12 processing and providing methods for carrier testing, prenatal diagnosis and approaches to treatment.
Structure of vitamin B12 (cobalamin). (a) The ‘R group’ corresponds to substitutions at the upper or β-axial ligand (5′-deoxyadenosyl-, methyl-, hydroxo-, cyano-). The dimethylbenzimidazole constituent (DMB) is shown coordinated to the cobalt in the lower α-axial position (‘base-on’ structure). DMB is linked to the corrin ring through a phosphoribosyl attached to a propionamide side chain. (b) Structure of methylcobalamin (MeCbl) with DMB displaced from the cobalt by a histidine residue in methionine synthase (MS; the ‘base-off/His-on’ structure). A similar configuration is observed for adenosylcobalamin (AdoCbl) bound to methylmalonyl-CoA mutase. Structures are from http://www.genome.jp using the ‘SIMCOMP Search’ utility (query C00576, vitamin B12; C06410, MeCbl-MS).
Intracellular processing of vitamin B12 showing sites of defects in complementation groups. Complementation groups are in blue and are positioned at sites of metabolic blocks (shown in red). Cobalamin intermediates are in red. Excreted metabolites due to genetic defects are in shaded boxes. Pathway details are described in the text. In the lysosome, cobalamin is released from transcobalamin (TC) through its degradation (arrow pointing to dots). In the cytosol, R groups are released by the cblC protein with the cob(II)alamin [Cob(II)] product remaining bound (dotted line emanating from the cblC protein denotes complex with cobalamin forms). The three versions of the cblD protein (cblD, cblD-1, cblD-2) illustrate the role of the protein in directing cobalamin to the mitochondrial or cytosolic pathway. In the mitochondrion, the cblB protein adds the 5′-deoxyadenosyl group, generating the active cofactor [adenosylcobalamin (AdoCbl)], which is transferred to the mut [methylmalonyl-CoA mutase (MCM)] protein. The cblA protein is proposed to act as a gatekeeper to ensure that the cofactor form that is accepted and retained by MCM is AdoCbl. In the cytosolic pathway, cob(II)alamin is bound to the cblG [methionine synthase (MS)] protein. The cblE [methionine synthase reductase (MSR)] protein catalyses generation of the active cofactor, methylcobalamin (MeCbl), or its regeneration if oxidised to cob(II)alamin during reaction cycles.
Although we have gained much insight into the pathway of vitamin B12 metabolism, the goal of the medical geneticist has been to gain insight into managing the vitamin B12 disorders, providing access to carrier testing and prenatal diagnosis, and, in the best of outcomes, preventing or successfully treating symptomatic disease. The remarkable feature of vitamin B12 utilisation disorders has been their potential for treatment. The discovery that high-dose vitamin B12 can overcome pathway deficits in some patients has given new life to individuals with an otherwise potentially severe or fatal disease. The early discovery that OHCbl is effective in the treatment of cblC disorder while CNCbl is not is a powerful illustration of the complexity of vitamin B12 biochemistry. The more recent finding that AdoCbl or MeCbl may have a significant stabilising effect on MMACHC protein, despite ultimately being hydrolysed to cob(II)alamin, reminds us that there is still much to be learned on behalf of the patient. Strikingly, the most recent success with gene therapy to treat mice with knockout of the Mut gene (Ref. 151) has opened up a new avenue for treatment that might ultimately benefit patients with metabolically ‘unresponsive’ disorders. The application of widespread newborn screening for homocysteine and methylmalonate underscores the opportunity to identify and treat these patients before the onset of potentially irreversible disease.
Advances in the understanding of cobalamin assimilation and metabolism.
Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA. Edward.Quadros@downstate.edu
The haematological and neurological consequences of cobalamin deficiency define the essential role of this vitamin in key metabolic reactions. The identification of cubilin-amnionless as the receptors for intestinal absorption of intrinsic factor-bound cobalamin and the plasma membrane receptor for cellular uptake of transcobalamin bound cobalamin have provided a clearer understanding of the absorption and cellular uptake of this vitamin. As the genes involved in the intracellular processing of cobalamins and genetic defects of these pathways are identified, the metabolic disposition of cobalamins and the proteins involved are being recognized. The synthesis of methylcobalamin and 5′-deoxyadenosylcobalamin, their utilization in conjunction with methionine synthase and methylmalonylCoA mutase, respectively, and the metabolic consequences of defects in these pathways could provide insights into the clinical presentation of cobalamin deficiency.
Pathways and proteins involved in the assimilation of cobalamin and inborn or acquired defects () in these pathways.
Br J Haematol. 2010 January;148(2):195-204.
J Neurol Sci. 1994 Apr;122(2):140-3.
Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamideneuropathy.
Department of Neurology, Kyoto University Hospital, Japan.
Despite intensive searches for therapeutic agents, few substances have been convincingly shown to enhance nerve regeneration in patients with peripheral neuropathies. Recent biochemical evidence suggests that an ultra-high dose ofmethylcobalamin (methyl-B12) may up-regulate gene transcription and thereby protein synthesis. We examined the effects of ultra-high dose of methyl-B12 on the rate of nerve regeneration in rats with acrylamide neuropathy, using the amplitudes of compound muscle action potentials (CMAPs) after tibial nerve stimulation as an index of the number of regenerating motor fibers. After intoxication with acrylamide, all the rats showed equally decreased CMAP amplitudes. The animals were then divided into 3 groups; rats treated with ultra-high (500 micrograms/kg body weight, intraperitoneally) and low (50 micrograms/kg) doses of methyl-B12, and saline-treated control rats. Those treated with ultra-high dose showed significantly faster CMAP recovery than saline-treated control rats, whereas the low-dose group showed no difference from the control. Morphometric analysis revealed a similar difference in fiber density between these groups. Ultra-high doses of methyl-B12 may be of clinical use for patients with peripheral neuropathies.
Exp Neurol. 2010 Apr;222(2):191-203. doi: 10.1016/j.expneurol.2009.12.017. Epub 2010 Jan 4.Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model.
Department of Orthopaedics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Methylcobalamin is a vitamin B12 analog and is necessary for the maintenance of the nervous system. Although some previous studies have referred to the effects of methylcobalamin on neurons, the precise mechanism of this effect remains obscure. Here we show that methylcobalamin at concentrations above 100 nM promotes neurite outgrowth and neuronal survival and that these effects are mediated by the methylation cycle, a metabolic pathway involving methylation reactions. We also demonstrate that methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle. In a rat sciatic nerve injury model, continuous administration of high doses of methylcobalamin improves nerve regeneration and functional recovery. Therefore, methylcobalamin may provide the basis for better treatments of nervous disorders through effective systemic or local delivery of high doses of methylcobalamin to target organs.