Cyanocobalamin reductase / alkylcobalamin dealkylase

Definition:

Cobalamin (vitamin B12) cytosolic chaperone that catalyzes the reductive decyanation of cyanocob(III)alamin (cyanocobalamin, CNCbl) to yield cob(II)alamin and cyanide, using FAD or FMN as cofactors and NADPH as cosubstrate. Cyanocobalamin constitutes the inactive form of vitamin B12 introduced from the diet, and is converted into the active cofactors methylcobalamin (MeCbl) involved in methionine biosynthesis, and 5'-deoxyadenosylcobalamin (AdoCbl) involved in the TCA cycle. Forms a complex with the lysosomal transporter ABCD4 and its chaperone LMBRD1, to transport cobalamin across the lysosomal membrane into the cytosol. The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR (methionine synthase) which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine. Also acts as a glutathione transferase by catalyzing the dealkylation of the alkylcob(III)alamins MeCbl and AdoCbl, using the thiolate of glutathione for nucleophilic displacement to generate cob(I)alamin and the corresponding glutathione thioether. The conversion of incoming MeCbl or AdoCbl into a common intermediate cob(I)alamin is necessary to meet the cellular needs for both cofactors. Cysteine and homocysteine cannot substitute for glutathione in this reaction.

References:

[1]. Jihoe Kim, et al. Decyanation of vitamin B12 by a trafficking chaperone. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14551-4. [Content Brief]

[2]. Markos Koutmos, et al. Structural basis of multifunctionality in a vitamin B12-processing enzyme. J Biol Chem. 2011 Aug 26;286(34):29780-7. [Content Brief]

[3]. D S Froese, et al. Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria. Mol Genet Metab. 2009 Dec;98(4):338-43. [Content Brief]

[4]. Jihoe Kim, et al. A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem. 2009 Nov 27;284(48):33418-24. [Content Brief]

[5]. Justin C Deme, et al. Purification and interaction analyses of two human lysosomal vitamin B12 transporters: LMBD1 and ABCD4. Mol Membr Biol. 2014 Nov-Dec;31(7-8):250-61. [Content Brief]

[6]. D Sean Froese, et al. Structure of MMACHC reveals an arginine-rich pocket and a domain-swapped dimer for its B12 processing function. Biochemistry. 2012 Jun 26;51(25):5083-90. [Content Brief]

[7]. Maria Plesa, et al. Interaction between MMACHC and MMADHC, two human proteins participating in intracellular vitamin B₁₂ metabolism. Mol Genet Metab. 2011 Feb;102(2):139-48. [Content Brief]

[8]. Christine Bassila, et al. Methionine synthase and methionine synthase reductase interact with MMACHC and with MMADHC. Biochim Biophys Acta Mol Basis Dis. 2017 Jan;1863(1):103-112. [Content Brief]

[9]. Carmen Gherasim, et al. Pathogenic mutations differentially affect the catalytic activities of the human B12-processing chaperone CblC and increase futile redox cycling. J Biol Chem. 2015 May 1;290(18):11393-402. [Content Brief]

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