title: Decyanation of vitamin B12 by a trafficking chaperone.
abstract: The mystery of how the cyanide group in vitamin B(12) or cyanocobalamin, discovered 60 years ago, is removed, has been solved by the demonstration that the trafficking chaperone, MMACHC, catalyzes a reductive decyanation reaction. Electrons transferred from NADPH via cytosolic flavoprotein oxidoreductases are used to cleave the cobalt-carbon bond with reductive elimination of the cyanide ligand. The product, cob(II)alamin, is a known substrate for assimilation into the active cofactor forms, methylcobalamin and 5'-deoxyadenosylcobalamin, and is bound in the "base-off" state that is needed by the two B(12)-dependent target enzymes, methionine synthase and methylmalonyl-CoA mutase. Defects in MMACHC represent the most common cause of inborn errors of B(12) metabolism, and our results explain the observation that fibroblasts from these patients are poorly responsive to vitamin B(12) but show some metabolic correction with aquocobalamin, a cofactor form lacking the cyanide ligand, which is mirrored by patients showing poorer clinical responsiveness to cyano- versus aquocobalamin.
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-0606, USA.
authors.forename: Jihoe
authors.initials: J
authors.lastname: Kim
authors.forename: Carmen
authors.initials: C
authors.lastname: Gherasim
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D002384:Catalysis; D003038:Cobamides / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D005287:Ferredoxin-NADP Reductase / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D014805:Vitamin B 12 / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D003038:Cobamides; D018832:Molecular Chaperones; D011994:Recombinant Proteins; C097751:cob(II)alamin; C508359:MMACHC protein, human; D010088:Oxidoreductases; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D014805:Vitamin B 12
references.citation: Nature. 1948 Apr 24;161(4095):638
references.pmid: 18856623
references.citation: J Biol Chem. 2003 Oct 3;278(40):38310-4
references.pmid: 12871938
references.citation: Nat Genet. 2006 Jan;38(1):93-100
references.pmid: 16311595
references.citation: Science. 1948 Apr 16;107(2781):396-7
references.pmid: 17783930
references.citation: J Biol Chem. 2001 Sep 21;276(38):35558-63
references.pmid: 11466310
references.citation: J Pediatr. 1988 Jan;112(1):32-9
references.pmid: 3257264
references.citation: J Biol Chem. 2000 Jan 14;275(2):1471-8
references.pmid: 10625700
references.citation: ACS Chem Biol. 2006 Apr 25;1(3):149-59
references.pmid: 17163662
references.citation: Biochemistry. 2004 Feb 24;43(7):1988-97
references.pmid: 14967039
references.citation: Structure. 1996 Mar 15;4(3):339-50
references.pmid: 8805541
references.citation: J Am Chem Soc. 2005 Jan 19;127(2):526-7
references.pmid: 15643868
references.citation: Nature. 1956 Jul 14;178(4524):64-6
references.pmid: 13348621
references.citation: J Biol Chem. 2006 Jun 30;281(26):17838-44
references.pmid: 16641088
references.citation: Science. 1994 Dec 9;266(5191):1669-74
references.pmid: 7992050
references.citation: Science. 1976 Dec 10;194(4270):1165-6
references.pmid: 793008
references.citation: J Am Chem Soc. 1992 Jan;114(2):585-92
references.pmid: 20000783
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3059-64
references.pmid: 9501215
references.citation: Can J Neurol Sci. 1992 Nov;19(4):472-86
references.pmid: 1423045
references.citation: J Pediatr. 1998 Jan;132(1):121-4
references.pmid: 9470012
references.citation: Biochem Biophys Res Commun. 1990 Jun 15;169(2):443-50
references.pmid: 2357215
references.citation: Nat Struct Biol. 2003 May;10(5):394-401
references.pmid: 12652322
references.citation: Arch Microbiol. 2000 Mar;173(3):170-7
references.pmid: 10763748
references.citation: Trends Biochem Sci. 2005 Jun;30(6):304-8
references.pmid: 15950874
references.citation: J Biol Chem. 1979 Dec 10;254(23):11847-53
references.pmid: 500677