{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T03:13:20Z","timestamp":1777605200342,"version":"3.51.4"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T00:00:00Z","timestamp":1491350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Evidence from several fields of investigation lead to the hypothesis that the sulfur atom is involved in vitamin B12-dependent methyl group transfer. To compile the evidence, it is necessary to briefly review the following fields: methylation, the new field of sulfane sulfur\/hydrogen sulfide (S\u00b0\/H2S), hydrosulfide derivatives of cobalamins, autoxidation of hydrosulfide radical, radical S-adenosylmethionine methyl transfer (RSMT), and methionine synthase (MS). Then, new reaction mechanisms for B12-dependent methyl group transfer are proposed; the mechanisms are facile and overcome difficulties that existed in previously-accepted mechanisms. Finally, the theory is applied to the effect of S\u00b0\/H2S in nerve tissue involving the \u201chypomethylation theory\u201d that was proposed 50 years ago to explain the neuropathology resulting from deficiency of vitamin B12 or folic acid. The conclusions are consistent with emerging evidence that sulfane sulfur\/hydrogen sulfide may be beneficial in treating Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/molecules22040582","type":"journal-article","created":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T10:33:01Z","timestamp":1491388381000},"page":"582","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Possible Involvement of Hydrosulfide in B12-Dependent Methyl Group Transfer"],"prefix":"10.3390","volume":"22","author":[{"given":"John I.","family":"Toohey","sequence":"first","affiliation":[{"name":"Cytoregulation Research, Elgin, ON K0G1E0, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12789","DOI":"10.3390\/molecules190812789","article-title":"Thiosulfoxide (sulfane) sulfur: New chemistry and new roles in biology","volume":"19","author":"Toohey","year":"2014","journal-title":"Molecules"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e00304","DOI":"10.1042\/BSR20150147","article-title":"S-sulfhydration as a cellular redox regulation","volume":"36","author":"Iciek","year":"2015","journal-title":"Biosci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.3390\/molecules21121721","article-title":"Redox signaling regulated by cysteine persufide and protein polysulfidation","volume":"21","author":"Kasamatsu","year":"2016","journal-title":"Molecules"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1021\/ar200202c","article-title":"Radical-mediated enzymatic methylation: A tale of two SAMs","volume":"45","author":"Zhang","year":"2012","journal-title":"Acc. Chem. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1002\/cbic.201600107","article-title":"Emerging diversity of the cobalamin-dependent methyltransferases involving radical-based mechanisms","volume":"17","author":"Wing","year":"2016","journal-title":"ChemBioChem"},{"key":"ref_6","first-page":"497","article-title":"Methionine biosynthesis","volume":"1","author":"Blakely","year":"1984","journal-title":"Methionine Biosynthesis in Folates and Pterins"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/j.1574-6976.1993.tb00027.x","article-title":"Recent advances in elucidation of biological corrinoid functions","volume":"12","author":"Stupperich","year":"1993","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ab.2011.01.044","article-title":"Sulfur signaling: Is the agent sulfide or sulfane","volume":"413","author":"Toohey","year":"2011","journal-title":"Anal. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7606","DOI":"10.1073\/pnas.1321232111","article-title":"Reactive cysteine persulfide and S-polythiolation regulate oxidative stress and redox signaling","volume":"111","author":"Ida","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1139\/o86-103","article-title":"Persulfide sulfur is a growth factor for cells defective in sulfur metabolism","volume":"4","author":"Toohey","year":"1986","journal-title":"Biochem. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0162-0134(93)80004-S","article-title":"Hydrosulfide derivatives of cobalamins","volume":"49","author":"Toohey","year":"1993","journal-title":"J. Inorg. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1002\/ejic.201301340","article-title":"Kinetics and mechanism of the reaction of hydrogen sulfide with cobalamin in aqueous solution","volume":"2014","author":"Salnikov","year":"2014","journal-title":"Eur. J. Inorg. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4123","DOI":"10.1002\/ejic.201402082","article-title":"Kinetics and mechanism of the reaction hydrogen sulfide with diaquacobinamide in aqueous solution","volume":"2014","author":"Salnikov","year":"2014","journal-title":"Eur. J. Inorg. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4093","DOI":"10.1039\/C5NJ00206K","article-title":"Organometallic sulfur complexes: Reactivity of the hydrogen sulfide anion with cobaloximes","volume":"39","author":"Strianese","year":"2015","journal-title":"New J. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5018","DOI":"10.1021\/ja00973a044","article-title":"Reaction of hydroxocobalamin with thiols","volume":"88","author":"Adler","year":"1966","journal-title":"J. Am. Chem. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3676","DOI":"10.1021\/j100162a044","article-title":"Reactions of sulfhydryl and sulfide radicals with oxygen, hydrogen sulfide, hydrosulfide, and sulfide: Formation of SO2\u2212, HSSH\u2212, HSS.2\u2212 and HSS","volume":"95","author":"Zhu","year":"1991","journal-title":"J. Phys. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27193","DOI":"10.1016\/S0021-9258(18)46968-2","article-title":"Purification and kinetic mechanism of a mammalian methionine synthase from pig liver","volume":"269","author":"Chen","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.1016\/S0021-9258(18)93829-9","article-title":"Enzymatic synthesis of the methyl group of methionine: VII Isolation of a cobalamin-containing transmethylase (5\u2032-methyltetrahydrofolate-homocysteine) from mammalian liver","volume":"239","author":"Loughlin","year":"1964","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1021\/bi00796a019","article-title":"Isolation of a cobalamin containing 5-methyltetrahydrofolate-homocysteine transmethylase from mammalian liver","volume":"10","author":"Mangum","year":"1971","journal-title":"Biochemistry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/j.1432-1033.1970.tb01057.x","article-title":"Methionine synthase: Existence and interconversion of two enzyme species","volume":"16","author":"Rudiger","year":"1970","journal-title":"Eur. J. Biochem."},{"key":"ref_21","unstructured":"Toohey, J.I. (1980). Unpublished work."},{"key":"ref_22","unstructured":"(2017, February 05). Xanthogenate Cellulose Structural Formula V1.svg. Available online: https:\/\/commons.wikimedia.org\/wiki\/File:Xanthogenate_Cellulose_Structural_Formula_V1.svg#file."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1021\/bi901844d","article-title":"Characterization of a covalent polysulfane bridge in Cu-Zn superoxide dismutase","volume":"49","author":"You","year":"2010","journal-title":"Biochemistry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6745","DOI":"10.1016\/S0021-9258(19)42122-4","article-title":"Activation of methionine synthase by a reduced triphosphopyridine nucleotide-dependent flavoprotein system","volume":"249","author":"Fuji","year":"1974","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1016\/S0021-9258(18)96120-X","article-title":"N5-Methyltetrahydrofolate-homocysteine transmethylase: Partial purification and properties","volume":"242","author":"Taylor","year":"1967","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1093\/oxfordjournals.jbchem.a127347","article-title":"Enzymatic synthesis of the methyl group of methionine: III Spectral and electrophoretic studies of the prosthetic group of the B12 enzyme","volume":"49","author":"Takeyama","year":"1961","journal-title":"J. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0003-9861(68)90591-2","article-title":"Studies on the nature of the bound cobamide in E. coli N5-methyltetrahydrofolate-homocysteine transmethylase","volume":"126","author":"Ertel","year":"1968","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1021\/bi00837a002","article-title":"Vitamin B12 dependent methionine biosynthesis in cultured mammalian cells","volume":"8","author":"Mangum","year":"1969","journal-title":"Biochemistry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/jcp.1041040211","article-title":"Formation of sulfhydryl groups in the culture medium of human diploid fibroblasts","volume":"104","author":"Bannai","year":"1980","journal-title":"J. Cell. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1021\/bi00304a021","article-title":"Catalysis of thiol oxidation by cobalamins and cobinamides: Reaction products and kinetics","volume":"23","author":"Jacobsen","year":"1984","journal-title":"Biochemistry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1073\/pnas.71.4.1133","article-title":"The effect of replacement of methionine by homocysteine on survival of malignant and normal adult mammalian cell in culture","volume":"71","author":"Halpern","year":"1974","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0305-7372(03)00118-X","article-title":"Methionine dependency and cancer treatment","volume":"29","author":"Cellarier","year":"2003","journal-title":"Cancer Treat. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.ctrv.2012.01.004","article-title":"A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span expansion","volume":"38","author":"Cavuoto","year":"2012","journal-title":"Cancer Treat. Rev."},{"key":"ref_34","first-page":"151","article-title":"Cobalamin metabolism in methionine-dependent human tumour and leukemia cell lines","volume":"21","author":"Watkins","year":"1998","journal-title":"Clin. Investig. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.ymgme.2008.12.011","article-title":"Epigenetic modification of the gene for the vitamin B12 chaperone MMACHC can results in increased tumorigenicity and methionine dependence","volume":"96","author":"Loewy","year":"2009","journal-title":"Mol. Genet. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/0026-0495(93)90080-8","article-title":"The methylcobalamin metabolism of cultured human fibroblasts","volume":"42","author":"Chu","year":"1993","journal-title":"Metabolism"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.ymgme.2009.04.005","article-title":"Processing of alkylcobalamins in mammalian cells: A role of MMACHC (cblC) gene product","volume":"97","author":"Hannibal","year":"2009","journal-title":"Mol. Genet. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6428","DOI":"10.1021\/bi00344a018","article-title":"Methyl transfer from methylcobalamin: A reinvestigation","volume":"24","author":"Hogenkamp","year":"1985","journal-title":"Biochemistry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0076-6879(71)18006-8","article-title":"Preparation of the reduced forms of Vitamin B12 and of some analogs of the Vitamin B12 coenzyme containing a cobalt-carbon bond","volume":"18C","author":"Dolphin","year":"1971","journal-title":"Meth. Enzymol."},{"key":"ref_40","unstructured":"Dolphin, D.H., and Johnson, A.W. (1963). The reaction of cobalamins with thiols: An alternative synthesis of alkyl-cobamide coenzyme analogues. Chem. Soc. Proc., 311\u2013312."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/0006-291X(70)90646-7","article-title":"Spectrophotometric evidence for the formation of an Eschericia coli B12s methyltransferase","volume":"38","author":"Taylor","year":"1970","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8377","DOI":"10.1038\/ncomms9377","article-title":"The thiostrepton A tryptophan methyltransferase TsrM catalyses a Cob(II)alamin-dependent methyl transfer reaction","volume":"6","author":"Benjdia","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S0950-3536(05)80217-3","article-title":"The biochemical basis of the neuropathy in cobalamin deficiency","volume":"8","author":"Weir","year":"1995","journal-title":"Bailliere\u2019s Clin. Haematol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/B978-0-7020-4087-0.00061-9","article-title":"The neurology of folic acid deficiency","volume":"120","author":"Reynolds","year":"2014","journal-title":"Handb. Clin. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.nutres.2015.10.003","article-title":"Metabolic vitamin B12 deficiency: A missed opportunity to prevent dementia and stroke","volume":"36","author":"Spencer","year":"2016","journal-title":"Nutr. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6548","DOI":"10.1007\/s12035-015-9556-9","article-title":"Folic acid alters methylation profile of JAK-STAT and long-term depression signaling pathways in Alzheimer\u2019s disease models","volume":"53","author":"Li","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Montgomery, S.E., Sepchry, A.A., Wangsgaard, J.D., and Koenig, J.E. (2014). The effect of S-adenosylmethionine on cognitive performance in mice; an animal model meta analysis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107756"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1212\/WNL.38.3.459","article-title":"Demyelination and decreased S-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency","volume":"38","author":"Hyland","year":"1988","journal-title":"Neurology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1172\/JCI118862","article-title":"Demyelination of the brain is associated with methionine adenosyltransferase deficiency","volume":"98","author":"Chamberlin","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3233\/JAD-2011-110128","article-title":"A new hope for neurodegeneration: Possible role of hydrogen sulfide","volume":"24","author":"Gong","year":"2011","journal-title":"J. Alzheimers Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/j.jocn.2014.01.006","article-title":"Therapeutic benefits of H2S in Alzheimers disease","volume":"21","author":"Wei","year":"2014","journal-title":"J. Clin. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s00726-004-0072-x","article-title":"Endogenous production of hydrogen sulfide in mammals","volume":"26","author":"Kamoun","year":"2004","journal-title":"Amino Acids"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1042\/bj2060267","article-title":"Characterization of the enyzmic capacity for cysteine desulphhydration in liver and kidney of the rat","volume":"206","author":"Stipanuk","year":"1982","journal-title":"Biochem. J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s00216-016-0003-1","article-title":"High throughput and simultaneous quantitative analysis of homocysteine-methionine cycle metabolites and cofactors in blood plasma and cerebrospinal fluid by isotope dilution LS-MS\/MS","volume":"409","author":"Guiraud","year":"2017","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1089\/ars.2008.2253","article-title":"3-Mercaptopyruvate sulfrtransferase produces hydrogen sulfide and bound sulfur in the brain","volume":"11","author":"Shibuya","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/jnc.12698","article-title":"Contribution of cysteine aminotransferase and mercaptopyruvate sulfurtransferase to hydrogen sulfide produciton in peripheral neurons","volume":"130","author":"Miyamoto","year":"2014","journal-title":"J. Neurochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1038\/srep01986","article-title":"Antioxidant enzyme, 3-mercaptopyruvate sulfurtransferase knockout mice exhibit increased anxiety-like behaviors: A moldel for human mercaptolactate-cysteine disulfidurea","volume":"3","author":"Nagahara","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8360738","DOI":"10.1155\/2016\/8360738","article-title":"AP39, a mitochondria-targeted sulfide donor, supports cellular bioenergetics and protects against Alzheimer\u2019s disease by preserving mitochondrial funcion in APP\/PS1 mice and neurons","volume":"2016","author":"Zhao","year":"2016","journal-title":"Oxid. Med. Cell. Longev."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/4\/582\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:32:03Z","timestamp":1760207523000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/4\/582"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,5]]},"references-count":58,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2017,4]]}},"alternative-id":["molecules22040582"],"URL":"https:\/\/doi.org\/10.3390\/molecules22040582","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,5]]}}}