Vitamin B12 (cobalamin, Cbl) is an essential nutrient in humans, but it must be metabolized through many steps in order for it to function as a cofactor in cells. At least eight genetically distinct diseases are known that affect newborns or young children in which the metabolism of the vitamin is blocked. Our goal has been to identify the genes and biochemical steps involved in vitamin B12 metabolism and to develop tools for the diagnosis, prevention and treatment of B12 disorders. Our current studies include genetic and biochemical investigations of several genes involved in vitamin B12 metabolism in order to determine the function of these genes and how mutations result in failed utlization of the vitamin. We are also investigating mouse models of a defect in one of the vitamin B12 genes in order to determine the involvement of this gene in metabolism and in the risk of birth defects. Our experiments are leading to an explanation for how low nutrient folate/B12 intake in mothers increases the risk of having babies with spina bifida. We are also opening a new area of vitamin B12 research using the nematode, C. elegans (microscopic worm), and D. discoideum (a slime mold) as models in the effort to identify the remaining genes and metabolic steps in B12 metabolism. We are making use of these organisms because, in both cases, their genomes have been sequenced and their DNA sequences reveal the presence of human-like vitamin B12 pathway genes. Because these organisms have similar metabolism and cellular structures as human cells, we anticipate that B12 genes found in these organisms will lead us to similar genes in humans. The opportunity to probe the genomes of lower organisms as tools for understanding human biology is an important legacy of genome science.

Froese DS, Healy S, McDonald M, Niesen FH, Gravel RA. Thermolability of the MMACHC R161Q mutant in vitamin B₁₂-responsive cblC disorder. Mol Genet Metab Epub PMID: 20219402

Healy S, Perez-Cadahia B, McDonald M, Davie JR (2009) Biotin is not a natural histone modification. Biochim Biophys Acta, 1789:719-733

Froese DS, Zhang J, Healy S, Gravel RA. (2009) Mechanism of vitamin B₁₂-responsiveness in cblC methylmalonic aciduria with homocystinuria. Mol Genet Metab, 98:338-343

Zhang J, Wu X, Padovani D, Schubert HL, Gravel RA. (2009) Ligand-binding by catalytically inactive mutants of the cblB complemenattion group defective in human ATP:cob(I)alamin adenosyltransferase. Mol Genet Metab 98:278-284.

Healy S, Heightman TD, Hohmann L, Schriemer D, Gravel RA (2009) Nonenzymatic biotinylation of histone H2A. Prot Sci 18:314-32

Froese DS, Dobson CM, White AP, Wu X, Padovani D, Banerjee R, Haller T, Gerlt JA, Surette MG,  Gravel RA. (2009) Sleeping beauty mutase (sbm) is expressed and interacts with ygfD in Eschericia coli. Microbiol Res 164:1-8

Muniz, J.R.C., Gileadi, C., Froese, D.S., Yue, W.W., Pike, A.C.W., vonDelft, F., Kochan, G., Chaikuad, A., Pilka, E., Picaud, S., Phillips, C., Guo, K., Krysztofinska, E., Bray, J., Burgess-Brown, N., Arrowsmith, C.H., Weigelt, J., Edwards, A., Bountra, C., Gravel, R.A., Kavanagh, K.L., Oppermann, U. (2009) Crystal structure of methylmalonic acidemia type A protein. Protein Data Bank Accession Number: 2WWW

Perez-Monjaras A, Cervantes-Roldan R, Meneses-Morales I, Gravel RA, Reyes-Carmona S, Solorzano-Vargas S, Gonzalez-Noriega A, Leon-Del-Rio A (2008) Impaired biotinidase activity disrupts holocarboxylase synthetase expression in late-onset multiple carboxylase deficiency. J Biol Chem 283:34150-34158

Froese DS, Wu X, Zhang J, Dumas R, Schoel WM, Amrein M, Gravel RA (2008) Restricted role for methionine synthase reductase defined by subcellular localization. Mol Genet Metab 94:68-77

Seyrantepe V, Canuel M, Carpentier S, Landry K, Durand S, Liang F, Zeng J, Caqueret A, Gravel RA, Marchesini S, Zwingmann C, Michaud J, Morales CR, Levade T, Pshezhetsky AV (2008) Mice deficient in Neu4 sialidase exhibit abnormal ganglioside catabolism and lysosomal storage. Hum Mol Genet. 17:1556-1568.