Caenorhabditis elegans is a nematode that has been widely used as an animal for investigation of diverse biological phenomena. Vitamin B12 is essential for the growth of this worm, which contains two cobalamin-dependent enzymes, methylmalonyl-CoA mutase and methionine synthase. A full complement of gene homologs encoding the enzymes associated with the mammalian intercellular metabolic processes of vitamin B12 is identified in the genome of C. elegans. However, this worm has no orthologs of the vitamin B12-binders that participate in human intestinal absorption and blood circulation. When the worm is treated with a vitamin B12-deficient diet for five generations (15 days), it readily develops vitamin B12 deficiency, which induces worm phenotypes (infertility, delayed growth, and shorter lifespan) that resemble the symptoms of mammalian vitamin B12 deficiency. Such phenotypes associated with vitamin B12 deficiency were readily induced in the worm.
WatanabeFMiyamotoEHydrophilic vitamins. In: ShermaJFriedB (eds). Handbook of thin-layer chromatography, 3rd ed. New York, NY: Marcel Dekker, Inc, 2003, pp. 589–605.
2.
ChenZCrippenKGulatiSBanerjeeR. Purification and kinetic mechanism of a mammalian methionine synthase from pig liver. J Biol Chem1994; 269: 27193–7.
3.
FentonWAHackAMWillardHFGertlerARosenbergLE. Purification and properties of methylmalonyl coenzyme A mutase from human liver. Arch Biochem1982; 228: 323–9.
4.
WatanabeFYabutaYTaniokaYBitoT. Biologically active vitamin B12 compounds in foods for preventing deficiency among vegetarians and elderly subjects. J Agric Food Chem2013; 61: 6769–75.
Institute of Medicine. Vitamin B12 In: Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: Institute of Medicine, National Academy Press, 1998, pp.306–56.
7.
ShibataKFukuwatariTImaiEHayakawaHWatanabeFTakimotoHWatanabeTUmegakiK. Dietary reference intakes for Japanese 2010: water-soluble vitamins. J Nutr Sci Vitaminol2013; 59: S67–82.
8.
van AsseltDZvan den BrokWJLamersCBCorstensFHHoefnagelsWH. Free and protein-bound cobalamin absorption in healthy middle-aged and older subjects. J Am Geriatr Soc1996; 44: 949–53.
O’LearyFSammanS. Vitamin B12 in health and disease. Nutrients2010; 2: 299–316.
11.
González-ManzanoSGonzález-ParamásAMDelgadoLPatiannaSSurco-LaosFDueñasMSantos-BuelgaC. Oxidative status of stressed Caenorhabditis elegans treated with epicatechin. J Agric Food Chem2012; 60: 8911–6.
12.
CulettoESattelleDB. A role for Caenorhabditis elegans in understanding the function and interactions of human disease genes. Hum Mol Genet2000; 9: 869–77.
13.
WatsonEMacNeilLTRitterADYilmazLSRosebrockAPCaudyAAWalhoutAJM. Interspecies systems biology uncovers metabolites affecting C. elegans gene expression and life history traits. Cell2014; 156: 759–70.
14.
WatsonEMacNeilLTArdaHEZhuLJWalhoutAJM. Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response. Cell2013; 153: 253–66.
BitoTMatsunagaYYabutaYKawanoTWatanabeF. Vitamin B12 deficiency in Caenorhabditis elegans results in loss of fertility, extended life cycle, and reduced lifespan. FEBS Open Bio2013; 3: 112–7.
17.
YamadaKKawataTWadaMIsshikiTOnodaJKawanishiTKunouATadokoroTTobimatsuTMaekawaATorayaT. Extremely low activity of methionine synthase in vitamin B12-deficient rats may be related to effects on coenzyme stabilization rather than to changes in coenzyme induction. J Nutr2000; 130: 1894–900.
18.
NakaoMHironakaSHaradaNAdachiTBitoTYabutaYWatanabeFMiuraTYamajiRInuiHNakanoY. Cobalamin deficiency results in an abnormal increase in L-methylmalonyl-coenzyme-A mutase expression in rat liver and COS-7 cells. Br J Nutr2009; 101: 492–8.
QuadrosEVSequeiraJM. Cellular uptake of cobalamin: transcobalamin and the TCblR/CD320 receptor. Biochimie2013; 95: 1008–18.
21.
Youngdahl-TurnerPRosenbergLEAllenRH. Binding and uptake of transcobalamin II by human fibroblasts. J Clin Invest1978; 61: 133–41.
22.
RutschFGailusSMiousseIRSuormalaTSagnéCToliatMRNürnbergGWittkampfTBuersISharifiAStuckiMBeckerCBaumgartnerMRobenekHMarquardtTHöhneWGasnierBRosenblattDSFowlerBNürnbergP. Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism. Nat Genet2009; 41: 234–9.
23.
CoelhoDKimJCMiousseIRFungSdu MoulinMBuersISuormalaTBurdaPFrapolliMStuckiMNürnbergPThieleHRobenekHHöhneWLongoNPasqualiMMengelEWatkinsDShoubridgeEAMajewskiJRosenblattDSFowlerBRutschFBaumgartnerMR. Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nat Genet2012; 44: 1152–5.
24.
Lerner-EllisJP1TironeJCPawelekPDDoréCAtkinsonJLWatkinsDMorelCFFujiwaraTMMorasEHosackARDunbarGVAntonickaHForgettaVDobsonCMLeclercDGravelRAShoubridgeEACoultonJWLepagePRommensJMMorganKRosenblattDS. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet2006; 38: 93–100.
25.
KimJGherasimCBanerjeeR. Decyanation of vitamin B12 by a trafficking chaperone. Proc Natl Acad Sci USA2008; 105: 14551–4.
26.
OlteanuHMunsonTBanerjeeR. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Biochemistry2002; 41: 13378–85.
27.
Takahashi-IniguezTGarcia-ArellanoHTrujillo-RoldanMAFloresME. Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein. Biochem Biophys Res Commun2011; 404: 443–7.
28.
LealNAParkSDKimaPEBobikTA. Identification of the human and bovine ATP:Cob(I)alamin adenosyltransferase cDNAs based on complementation of a bacterial mutant. J Biol Chem2003; 278: 9227–34.
KuwabaraPEO’NeilN. The use of functional genomics in C. elegans for studying human development and disease. J Inherit Metab Dis2001; 24: 127–38.
31.
MarcotteEMXenariosIvan der BliekAMEisenbergD. Localizing proteins in the cell from their phylogenetic profiles. Proc Natl Acad Sci USA2000; 97: 12115–20.
32.
MeissnerBRogalskiTViveirosRWarnerAPlastinoLLorchAGrangerLSegalatLMoermanDG. Determining the sub-cellular localization of proteins within Caenorhabditis elegans body wall muscle. PLoS One2011; 6: e19937–e19937.
33.
ChandlerRJAswaniVTsaiMSFalkMWehrliNStablerSAllenRSedenskyMKazazianHHVendittiCP. Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: evidence for a role of methylalonyl-CoA epimerase in intermediary metabolism. Mol Genet Metab2006; 89: 64–73.
34.
SimmerFMooemanCvan der LindenAMKuijkEvan den BerghePVKamathRSFraserAGAhringerJPlasterkRH. Genome-wide RNAi of C. elegans using the hypersensitive rrf-3 strain reveals novel gene functions. PLoS Biol2003; 1: E12–E12.
35.
LiZGherasimCLesniakNABanerjeeR. Glutathione-dependent one-electron transfer reactions catalyzed by a B12 trafficking protein. J Biol Chem2014; 289: 16489–97.
36.
CabreiroFAuCLeungKYVergara-IrigarayNCocheméHMNooriTWeinkoveDSchusterEGreeneNDGemsD. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell2013; 153: 228–39.
37.
HansenMHsuALDillinAKenyonC. New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet2005; 1: 119–28.
38.
KhünlJBobikTProcterJBBurmeisterCHöpperJWildeILüersenKTordaAEWalterRDLiebauE. Functional analysis of the methymalonyl-CoA epimerase from Caenorhabditis elegans. FEBS J2005; 272: 1465–77.
39.
NicolaouAWaterfieldCJKenyonSHGibbonsWA. The inactivation of methionine synthase in isolated rat hepatocytes by sodium nitroprusside. Eur J Biochem1997; 244: 876–82.
40.
KimJHannibalLGherasimCJacobsenDWBanerjeeR. A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem2009; 284: 33418–24.
41.
BitoTYabutaYIchiyanagiTKawanoTWatanabeF. A dodecylamine derivative of cyanocobalamin potently inhibits the activities of cobalamin-dependent methylmalonyl-CoA mutase and methionine synthase of Caenorhabditis elegans. FEBS Open Bio2014; 4: 722–9.
42.
ShaneBStokstadELR. Vitamin B12-folate interrelationships. Ann Rev Nutr1985; 5: 115–41.
43.
CraigSAS. Betaine in human nutrition. Am J Clin Nutr2004; 80: 539–49.
44.
PajaresMAPérez-SalaD. Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism?Cell Mol Life Sci2006; 63: 2792–803.
45.
BartholomewDWBatshawMLAllenRHRoeCRRosenblattDValleDLFrancomanoCA. Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria. J Pediatr1988; 112: 32–9.
46.
PedenASMacPFeiYJCastroCJiangGMurfittKMiskaEAGriffinJLGanapathyVJorgensenEM. Betaine acts on a ligand-gated ion channel in the nervous system of the nematode C. elegans. Nat Neurosci2013; 16: 1794–801.
47.
ToyoshimaSWatanabeFSaidoHPezackaEHJacobsenDWMiyatakeKNakanoY. Accumulation of methylmalonic acid caused by vitamin B12 deficiency disrupts normal cellular metabolism in rat liver. Br J Nutr1996; 75: 929–38.
48.
ToyoshimaSWatanabeFSaidoHMiyatakeKNakanoY. Methylmalonic acid inhibits respiration in rat liver mitochondria. J Nutr1995; 125: 2846–50.
49.
GeldzilerBDMarcelloMRShakesDCSingsonA. The genetics and cell biology of fertilization. Methods Cell Biol2011; 106: 343–75.
50.
PlatzerUMeinzerHP. Genetic networks in the early development of Caenorhabditis elegans. Int Rev Cytol2004; 234: 47–100.
51.
CalahoroFRuiz-RubioM. Caenorhabditis elegans as an experimental tool for the study of complex neurological diseases: Parkinson’s disease, Alzheimer’s disease and autism spectrum disorder. Invert Neurosci2011; 11: 73–83.
52.
ArdielELRankinCH. An elegant mind: learning and memory in Caenorhabditis elegans. Learn Mem2012; 17: 191–201.
53.
YamadaKKawataTWadaMMoriKTamaiHTanakaNTadokoroTTobimatsuTTorayaTMaekawaA. Testicular injury to rats fed on soybean protein-based vitamin B12-deficient diet can be reduced by methionine supplementation. J Nutr Sci Vitaminol2007; 53: 95–101.
54.
CostelloAMLOsrinD. Micronutrient status during pregnancy and outcomes for newborn infants in developing countries. J Nutr2003; 133: 1757S–64S.
55.
MetzJ. Cobalamin deficiency and the pathogenesis of nervous system disease. Annu Rev Nutr1992; 12: 59–79.
56.
LindballeDLFedosovSSherlikerPHinHClarkeRNexoE. Association of cognitive impairment with combinations of vitamin B12-related parameters. Clin Chem2011; 57: 1436–43.
