Skip to main content
SpringerLink
Log in

Multiple roles of ATP:cob(I)alamin adenosyltransferases in the conversion of B12 to coenzyme B12

  • Mini-Review
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

Our mechanistic understanding of the conversion of vitamin B12 into coenzyme B12 (a.k.a. adenosylcobalamin, AdoCbl) has been substantially advanced in recent years. Insights into the multiple roles played by ATP:cob(I)alamin adenosyltransferase (ACA) enzymes have emerged through the crystallographic, spectroscopic, biochemical, and mutational analyses of wild-type and variant proteins. ACA enzymes circumvent the thermodynamic barrier posed by the very low redox potential associated with the reduction of cob(II)alamin to cob(I)alamin by generating a unique four-coordinate cob(II)alamin intermediate that is readily converted to cob(I)alamin by physiological reductants. ACA enzymes not only synthesize AdoCbl but also they deliver it to the enzymes that use it, and in some cases, enzymes in which its function is needed to maintain the fidelity of the AdoCbl delivery process have been identified. Advances in our understanding of ACA enzyme function have provided valuable insights into the role of specific residues, and into why substitutions of these residues have profound negative effects on human health. From an applied science standpoint, a better understanding of the adenosylation reaction may lead to more efficient ways of synthesizing AdoCbl.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Bagnato JD, Eilers AL, Horton RA, Grissom CB (2004) Synthesis and characterization of a cobalamin-colchicine conjugate as a novel tumor-targeted cytotoxin. J Org Chem 69:8987–8996

    Article  CAS  Google Scholar 

  • Bandarian V, Reed GH (1999) Ethanolamine ammonia-lyase. In: Banerjee R (ed) Chemistry ad Biochemistry of B12. Wiley, New York, pp 811–833

    Google Scholar 

  • Banerjee R (2006) B12 trafficking in mammals: a case for coenzyme escort service. ACS Chem Biol 1:149–159

    Article  CAS  Google Scholar 

  • Banerjee R, Chowdhury S (1999) Methylmalonyl-CoA mutase. In: Banerjee R (ed) Chemistry and Biochemistry of B12. Wiley, New York, pp 707–729

    Google Scholar 

  • Banerjee R, Vlasie M (2002) Controlling the reactivity of radical intermediates by coenzyme B(12)-dependent methylmalonyl-CoA mutase. Biochem Soc Trans 30:621–624

    Article  CAS  Google Scholar 

  • Battersby AR (2000) Tetrapyrroles: the pigments of life. Nat Prod Rep 17:507–526

    Article  CAS  Google Scholar 

  • Bauer CB, Fonseca MV, Holden HM, Thoden JB, Thompson TB, Escalante-Semerena JC, Rayment I (2001) Three-dimensional structure of ATP:corrinoid adenosyltransferase from Salmonella typhimurium in its free state, complexed with MgATP, or complexed with hydroxycobalamin and MgATP. Biochemistry 40:361–374

    Article  CAS  Google Scholar 

  • Buan NR, Escalante-Semerena JC (2005) Computer-assisted docking of flavodoxin with the ATP:co(I)rrinoid adenosyltransferase (CobA) enzyme reveals residues critical for protein-protein interactions but not for catalysis. J Biol Chem 280:40948–40956

    Article  CAS  Google Scholar 

  • Buan NR, Escalante-Semerena JC (2006) Purification and initial biochemical characterization of ATP:cob(I)alamin adenosyltransferase (EutT) enzyme of Salmonella enterica. J Biol Chem 281:16971–16977

    Article  CAS  Google Scholar 

  • Buan NR, Suh SJ, Escalante-Semerena JC (2004) The eutT gene of Salmonella enterica encodes an oxygen-labile, metal-containing ATP:corrinoid adenosyltransferase enzyme. J Bacteriol 186:5708–5714

    Article  CAS  Google Scholar 

  • Buckel W, Bröker G, Bothe H, Pierik A (1999) Glutamate mutase and 2-methylglutarate mutase. In: Banerjee R (ed) Chemistry and Biochemistry of B12. Wiley, New York, pp 757–782

    Google Scholar 

  • Cavicchi C, Donati MA, Funghini S, la Marca G, Malvagia S, Ciani F, Poggi GM, Pasquini E, Zammarchi E, Morrone A (2006) Genetic and biochemical approach to early prenatal diagnosis in a family with mut methylmalonic aciduria. Clin Genet 69:72–76

    Article  CAS  Google Scholar 

  • Ciani F, Donati MA, Tulli G, Poggi GM, Pasquini E, Rosenblatt DS, Zammarchi E (2000) Lethal late onset cblB methylmalonic aciduria. Crit Care Med 28:2119–2121

    Article  CAS  Google Scholar 

  • Dobson CM, Wai T, Leclerc D, Kadir H, Narang M, Lerner-Ellis JP, Hudson TJ, Rosenblatt DS, Gravel RA (2002) Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. Hum Mol Genet 11:3361–3369

    Article  CAS  Google Scholar 

  • Eirich LD, Vogels GD, Wolfe RS (1978) Proposed structure for coenzyme F420 from Methanobacterium. Biochemistry 17:4583–4593

    Article  CAS  Google Scholar 

  • Escalante-Semerena JC, Warren MJ (2008) Biosynthesis and use of cobalamin (B12). In: Böck A, Curtiss R III, Kaper JB, Karp PD, Neidhardt FC, Nyström T, Slauch JM, Squires CL (eds) EcoSal—Escherichia coli and Salmonella: cellular and molecular biology. ASM, Washington, D. C

    Google Scholar 

  • Escalante-Semerena JC, Suh SJ, Roth JR (1990) cobA function is required for both de novo cobalamin biosynthesis and assimilation of exogenous corrinoids in Salmonella typhimurium. J Bacteriol 172:273–280

    CAS  Google Scholar 

  • Eschenmoser A, Wintner CE (1977) Natural product synthesis and vitamin B12. Science 196:1410–1420

    Article  CAS  Google Scholar 

  • Fan C, Bobik TA (2008) Functional characterization and mutation analysis of human ATP:cob(I)alamin adenosyltransferase. Biochemistry 47:2806–2813

    Article  CAS  Google Scholar 

  • Fenton WA, Rosenberg LE (1978) Mitochondrial metabolism of hydroxocobalamin: synthesis of adenosylcobalamin by intact rat liver mitochondria. Arch Biochem Biophys 189:441–447

    Article  CAS  Google Scholar 

  • Fonseca MV, Escalante-Semerena JC (2001) An in vitro reducing system for the enzymic conversion of cobalamin to adenosylcobalamin. J Biol Chem 276:32101–32108

    Article  CAS  Google Scholar 

  • Fonseca MV, Buan NR, Horswill AR, Rayment I, Escalante-Semerena JC (2002) The ATP:co(I)rrinoid adenosyltransferase (CobA) enzyme of Salmonella enterica requires the 2′-OH group of ATP for function and yields inorganic triphosphate as its reaction byproduct. J Biol Chem 277:33127–33131

    Article  CAS  Google Scholar 

  • Fontecave M (1998) Ribonucleotide reductases and radical reactions. Cell Mol Life Sci 54:684–695

    Article  CAS  Google Scholar 

  • Fontecave M, Mulliez E (1999) Ribonucleotide reductases. In: Banerjee R (ed) Chemistry and biochemistry of B12. Wiley, New York, pp 731-–756

    Google Scholar 

  • Hall DA, Jordan-Starck TC, Loo RO, Ludwig ML, Matthews RG (2000) Interaction of flavodoxin with cobalamin-dependent methionine synthase. Biochemistry 39:10711–10719

    Article  CAS  Google Scholar 

  • Hall DA, Vander Kooi CW, Stasik CN, Stevens SY, Zuiderweg ER, Matthews RG (2001) Mapping the interactions between flavodoxin and its physiological partners flavodoxin reductase and cobalamin-dependent methionine synthase. Proc Natl Acad Sci USA 98:9521–9526

    Article  CAS  Google Scholar 

  • Hoover DM, Jarrett JT, Sands RH, Dunham WR, Ludwig ML, Matthews RG (1997) Interaction of Escherichia coli cobalamin-dependent methionine synthase and its physiological partner flavodoxin: binding of flavodoxin leads to axial ligand dissociation from the cobalamin cofactor. Biochemistry 36:127–138

    Article  CAS  Google Scholar 

  • Johnson CL, Pechonick E, Park SD, Havemann GD, Leal NA, Bobik TA (2001) Functional genomic, biochemical, and genetic characterization of the Salmonella pduO gene, an ATP:cob(I)alamin adenosyltransferase gene. J Bacteriol 183:1577–1584

    Article  CAS  Google Scholar 

  • Johnson CL, Buszko ML, Bobik TA (2004) Purification and initial characterization of the Salmonella enterica PduO ATP:cob(I)alamin adenosyltransferase. J Bacteriol 186:7881–7887

    Article  CAS  Google Scholar 

  • Lawrence AD, Deery E, McLean KJ, Munro AW, Pickersgill RW, Rigby SE, Warren MJ (2008) Identification, characterization, and structure/function analysis of a corrin reductase involved in adenosylcobalamin biosynthesis. J Biol Chem 283:10813–10821

    Article  CAS  Google Scholar 

  • Leal NA, Park SD, Kima PE, Bobik TA (2003) Identification of the human and bovine ATP: cob(I)alamin adenosyltransferase cDNAs based on complementation of a bacterial mutant. J Biol Chem 278:9227–9234

    Article  CAS  Google Scholar 

  • Lenhert PG (1968) The structure of vitamin B12 VII. The X-ray analysis of the vitamin B12 coenzyme. Proc R Soc Lond Ser A 303:45–84

    Article  CAS  Google Scholar 

  • Lerner-Ellis JP, Gradinger AB, Watkins D, Tirone JC, Villeneuve A, Dobson CM, Montpetit A, Lepage P, Gravel RA, Rosenblatt DS (2006) Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. Mol Genet Metab 87:219–225

    Article  CAS  Google Scholar 

  • Lexa D, Saveant JM (1976) Electrochemistry of vitamin B12. I. Role of the base-on/base-off reaction in the oxidoreduction mechanism of the B12r-B12s system. J Am Chem Soc 98:2652–2658

    Article  CAS  Google Scholar 

  • Mancia F, Keep NH, Nakagawa A, Leadlay PF, McSweeney S, Rasmussen B, Bosecke P, Diat O, Evans PR (1996) How coenzyme B12 radicals are generated: the crystal structure of methylmalonyl-coenzyme A mutase at 2 Å resolution. Structure 4:339–350

    Article  CAS  Google Scholar 

  • Martens JH, Barg H, Warren MJ, Jahn D (2002) Microbial production of vitamin B12. Appl Microbiol Biotechnol 58:275–285

    Article  CAS  Google Scholar 

  • Mera PE, Escalante-Semerena JC (2010) Dihydroflavin-driven adenosylation of 4-coordinate Co(II) corrinoids: are cobalamin reductases enzymes or electron transfer proteins? J Biol Chem 285:2911–2917

    Article  CAS  Google Scholar 

  • Mera PE, Maurice MS, Rayment I, Escalante-Semerena JC (2007) Structural and functional analyses of the human-type corrinoid adenosyltransferase (PduO) from Lactobacillus reuteri. Biochemistry 46:13829–13836

    Article  CAS  Google Scholar 

  • Mera PE, St Maurice M, Rayment I, Escalante-Semerena JC (2009) Residue Phe112 of the human-type corrinoid adenosyltransferase (PduO) enzyme of Lactobacillus reuteri is critical to the formation of the four-coordinate Co(II) corrinoid substrate and to the activity of the enzyme. Biochemistry 48:3138–3145

    Article  CAS  Google Scholar 

  • Montforts FP, Glasenapp-Breiling M (2002) Naturally occurring cyclic tetrapyrroles. Fortschr Chem Org Naturst 84:1–51

    CAS  Google Scholar 

  • Padovani D, Banerjee R (2009a) A G-protein editor gates coenzyme B12 loading and is corrupted in methylmalonic aciduria. Proc Natl Acad Sci USA 106:21567–21572

    Article  CAS  Google Scholar 

  • Padovani D, Banerjee R (2009b) A rotary mechanism for coenzyme B(12) synthesis by adenosyltransferase. Biochemistry 48:5350–5357

    Article  CAS  Google Scholar 

  • Padovani D, Labunska T, Palfey BA, Ballou DP, Banerjee R (2008) Adenosyltransferase tailors and delivers coenzyme B12. Nat Chem Biol 4:194–196

    Article  CAS  Google Scholar 

  • Park K, Mera PE, Escalante-Semerena JC, Brunold TC (2008) Kinetic and spectroscopic studies of the ATP:corrinoid adenosyltransferase PduO from Lactobacillus reuteri: substrate specificity and insights into the mechanism of Co(II)corrinoid reduction. Biochemistry 47:9007–9015

    Article  CAS  Google Scholar 

  • Rosenblatt DS, Fenton WA (1999) Inborn errors of metabolism. In: Banerjee R (ed) Chemistry and Biochemistry of B12. Wiley, New York, pp 367–384

    Google Scholar 

  • Ruiz-Sanchez P, Mundwiler S, Spingler B, Buan NR, Escalante-Semerena JC, Alberto R (2008) Syntheses and characterization of vitamin B(12)-Pt(II) conjugates and their adenosylation in an enzymatic assay. J Biol Inorg Chem 13:335–347

    Article  CAS  Google Scholar 

  • Sampson EM, Johnson CL, Bobik TA (2005) Biochemical evidence that the pduS gene encodes a bifunctional cobalamin reductase. Microbiology 151:1169–1177

    Article  CAS  Google Scholar 

  • Saridakis V, Yakunin A, Xu X, Anandakumar P, Pennycooke M, Gu J, Cheung F, Lew JM, Sanishvili R, Joachimiak A, Arrowsmith CH, Christendat D, Edwards AM (2004) The structural basis for methylmalonic aciduria. The crystal structure of archaeal ATP:cobalamin adenosyltransferase. J Biol Chem 279:23646–23653

    Article  CAS  Google Scholar 

  • Schubert HL, Hill CP (2006) Structure of ATP-bound human ATP:cobalamin adenosyltransferase. Biochemistry 45:15188–15196

    Article  CAS  Google Scholar 

  • Sheppard DE, Penrod JT, Bobik T, Kofoid E, Roth JR (2004) Evidence that a B12-adenosyl transferase is encoded within the ethanolamine operon of Salmonella enterica. J Bacteriol 186:7635–7644

    Article  CAS  Google Scholar 

  • Spalla C, Grein A, Garofano L, Ferni G (1989) Microbial production of Vitamin B12. In: Vandamme EJ (ed) Biotechnology of vitamins, pigments, and growth factors. Elsevier, London, pp 257–284

    Google Scholar 

  • St Maurice M, Mera PE, Taranto MP, Sesma F, Escalante-Semerena JC, Rayment I (2007) Structural characterization of the active site of the PduO-type ATP:Co(I)rrinoid adenosyltransferase from Lactobacillus reuteri. J Biol Chem 282:2596–2605

    Article  CAS  Google Scholar 

  • St Maurice M, Mera P, Park K, Brunold TC, Escalante-Semerena JC, Rayment I (2008) Structural characterization of a human-type corrinoid adenosyltransferase confirms that coenzyme B12 is synthesized through a four-coordinate intermediate. Biochemistry 47:5755–5766

    Article  CAS  Google Scholar 

  • Stich TA, Buan NR, Brunold TC (2004) pectroscopic and computational studies of Co(2+)corrinoids: spectral and electronic properties of the biologically relevant base-on and base-off forms of Co(2+)cobalamin. J Am Chem Soc 126:9735–9749

    Article  CAS  Google Scholar 

  • Stich TA, Buan NR, Escalante-Semerena JC, Brunold TC (2005a) Spectroscopic and computational studies of the ATP:Corrinoid adenosyltransferase (CobA) from Salmonella enterica: insights into the mechanism of adenosylcobalamin biosynthesis. J Am Chem Soc 127:8710–8719

    Article  CAS  Google Scholar 

  • Stich TA, Yamanishi M, Banerjee R, Brunold TC (2005b) Spectroscopic evidence for the formation of a four-coordinate Co(2+)cobalamin species upon binding to the human ATP:cobalamin adenosyltransferase. J Am Chem Soc 127:7660–7661

    Article  CAS  Google Scholar 

  • Suh S, Escalante-Semerena JC (1995) Purification and initial characterization of the ATP:corrinoid adenosyltransferase encoded by the cobA gene of Salmonella typhimurium. J Bacteriol 177:921–925

    CAS  Google Scholar 

  • Toraya T (1999) Diol dehydratase and glycerol dehydratase. In: Banerjee R (ed) Chemistry and Biochemistry of B12. Wiley, New York, pp 783–809

    Google Scholar 

  • van Beelen P, Stassen AP, Bosch JW, Vogels GD, Guijt W, Haasnoot CA (1984) Elucidation of the structure of methanopterin, a coenzyme from Methanobacterium thermoautotrophicum, using two-dimensional nuclear-magnetic-resonance techniques. Eur J Biochem 138:563–571

    Article  Google Scholar 

  • Veer WL, Edelhausen JH, Wijmenga HG, Lens J (1950) Vitamin B12: I. The relation between vitamins B12 and B12b. Biochim Biophys Acta 6:225–228

    Article  CAS  Google Scholar 

  • Warren MJ, Raux E, Schubert HL, Escalante-Semerena JC (2002) The biosynthesis of adenosylcobalamin (vitamin B12). Nat Prod Rep 19:390–412

    Article  CAS  Google Scholar 

  • Wijmenga HG, Veer WL, Lens J (1950) II. The influence of HCN on some factors of the vitamin B12 group. Biochim Biophys Acta 6:229–236

    Article  CAS  Google Scholar 

  • Wohlfarth G, Diekert G (1999) Reductive dehalogenases. In: Banerjee R (ed) Chemistry and biochemistry of B12. Wiley, New York, pp 871–893

    Google Scholar 

  • Woodward RB (1973) The total synthesis of vitamin B12. Pure Appl Chem 33:145–177

    Article  CAS  Google Scholar 

  • Zhang J, Dobson CM, Wu X, Lerner-Ellis J, Rosenblatt DS, Gravel RA (2006) Impact of cblB mutations on the function of ATP:cob(I)alamin adenosyltransferase in disorders of vitamin B12 metabolism. Mol Genet Metab 87:315–322

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by USPHS grant R37 GM40313 (to J.C.E.-S.).

Author information

Authors and Affiliations

  1. Department of Developmental Biology, Stanford University, 279 Campus Drive, Stanford, CA, 94305, USA

    Paola E. Mera

  2. Department of Bacteriology, University of Wisconsin, 1550 Linden Drive, Madison, WI, 53706, USA

    Jorge C. Escalante-Semerena

Authors
  1. Paola E. Mera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jorge C. Escalante-Semerena
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jorge C. Escalante-Semerena.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mera, P.E., Escalante-Semerena, J.C. Multiple roles of ATP:cob(I)alamin adenosyltransferases in the conversion of B12 to coenzyme B12 . Appl Microbiol Biotechnol 88, 41–48 (2010). https://doi.org/10.1007/s00253-010-2773-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-010-2773-2

Keywords

Search

Navigation