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Vitamin B12: Biosynthesis of the Corrin Ring

  • Chapter
Tetrapyrroles

Part of the book series: Molecular Biology Intelligence Unit ((MBIU))

Abstract

Vitamin B12 is a cobalt-containing modified tetrapyrrole, whose structural complexity and beguiling chemistry has fascinated scientists for over 80 years. As with all modified tetrapyrroles, its structure is derived from uroporphyrinogen III. This transformation requires a large number of enzyme-mediated steps that result in peripheral methylation, cobalt chelation, ring contraction, decarboxylation, amidation and adenosylation. There are two related though genetically distinct routes for cobalamin biosynthesis, which are referred to as the aerobic and anaerobic pathways. In this chapter the biosynthesis of the corrin ring component of vitamin B12 along these two routes is described.

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References

  1. Stabler SP, Allen RH. Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr 2004; 24: 299–326.

    Article  PubMed  CAS  Google Scholar 

  2. Roth JR, Lawrence JG, Bobik TA. Cobalamin (coenzyme B12): synthesis and biological significance. Annu Rev Microbiol 1996; 50:137–181.

    Article  PubMed  CAS  Google Scholar 

  3. Warren MJ, Scott AI. Tetrapyrrole assembly and modification into the ligands of biologically functional cofactors. Trends Biochem Sci 1990; 15: 486–491.

    Article  PubMed  Google Scholar 

  4. Warren MJ, Raux E, Schubert HL et al. The biosynthesis of adenosylcobalamin (vitamin B12). Nat Prod Rep 2002; 19: 390–412.

    Article  PubMed  CAS  Google Scholar 

  5. Roessner CA, Santander PJ, Scott AI. Multiple biosynthetic pathways for vitamin B12: variations on a central theme. Vitamins and Hormones 2001; 61: 267–297.

    Article  PubMed  CAS  Google Scholar 

  6. Raux E, Schubert HL, Warren MJ. Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum. Cell Mol Life Sci 2000; 57: 1880–1893.

    Article  PubMed  CAS  Google Scholar 

  7. Blanche F, Cameron B, Crouzet J et al. Vitamin B12: How the problem of its biosynthesis was solved. Angew Chem Int Ed Engl 1995; 34(4):383–411.

    Article  CAS  Google Scholar 

  8. Battersby A.R. How nature builds the pigments of life: the conquest of vitamin B12. Science 1994; 264(5165):1551–1557.

    Article  PubMed  CAS  Google Scholar 

  9. Uzar HC, Battersby AR, Carpenter TA et al. Biosynthesis of porphyrins and related macrocycles. 28. Development of a pulse labeling method to determine the c-methylation sequence for vitamin-B12. Chem. Soc Perkin Trans I 1987; 1689–1696.

    Google Scholar 

  10. Blanche F, Debussche L, Thibaut D et al. Purification and characterization of S-adenosyl-L-methionine: uroporphyrinogen III methyltransferase from Pseudomonas denitrificans. J Bacteriol 1989; 171(8):4222–4231.

    PubMed  CAS  Google Scholar 

  11. Robin C, Blanche F, Cauchois L et al. Primary structure, expression in Escherichia coli, and properties of S-adenosyl-L-methionine:uroporphyrinogen III methyltransferase from Bacillus megaterium. J Bacteriol 1991; 173(15): 4893–4896.

    PubMed  CAS  Google Scholar 

  12. Blanche F, Robin C, Couder M et al. Purification, characterization, and molecular cloning of S-adenosyl-L-methionine: uroporphyrinogen III methyltransferase from Methanobacterium ivanovii. J Bacteriol 1991; 173(15):4637–4645.

    PubMed  CAS  Google Scholar 

  13. Vevodova J, Graham RM, Raux E et al. Structure/function studies on a S-adenosyl-L-methionine-dependent uroporphyrinogen III C methyltransferase (SUMT), a key regulatory enzyme of tetrapyrrole biosynthesis. J Mol Biol 2004; 344(2): 419–433.

    Article  PubMed  CAS  Google Scholar 

  14. Stroupe ME, Leech HK, Daniels DS et al. CysG structure reveals tetrapyrrole-binding features and novel regulation of siroheme biosynthesis. Nat Struct Biol 2003; 10(12): 1064–1073.

    Article  PubMed  CAS  Google Scholar 

  15. Schubert HL, Wilson KS, Raux E et al. The X-ray structure of a cobalamin biosynthetic enzyme, cobaltprecorrin-4 methyltransferase. Nat Struct Biol 1998; 5(7): 585–592.

    Article  PubMed  CAS  Google Scholar 

  16. Schubert HL, Blumenthal RM, Cheng X. Many paths to methyltransfer: a chronicle of convergence. Trends Biochem Sci 2003; 28(6):329–335.

    Article  PubMed  CAS  Google Scholar 

  17. Roth JR, Lawrence JG, Rubenfield M et al. Characterization of the cobalamin (vitamin B12) biosynthetic genes of Salmonella typhimurium. J Bacteriol 1993; 175(11): 3303–3316.

    PubMed  CAS  Google Scholar 

  18. Debussche L, Thibaut D, Cameron B et al. Biosynthesis of the corrin macrocycle of coenzyme B12 in Pseudomonas denitrificans. J Bacteriol 1993; 175(22): 7430–7440.

    PubMed  CAS  Google Scholar 

  19. Thibaut D, Couder M, Crouzet J et al. Assay and purification of S-adenosyl-L-methionine:precorrin-2 methyltransferase from Pseudomonas denitrificans. J Bacteriol 1990; 172(11): 6245–6251.

    PubMed  CAS  Google Scholar 

  20. Warren MJ, Roessner CA, Ozaki S et al. Enzymatic synthesis and structure of precorrin-3, a trimethyldipyrrocorphin intermediate in vitamin B12 biosynthesis. Biochemistry 1992; 31(2):603–609.

    Article  PubMed  CAS  Google Scholar 

  21. Scott AI, Roessner CA, Stolowich NJ et al. Biosynthesis of vitamin B12. Discovery of the enzymes for oxidative ring contraction and insertion of the fourth methyl group. Febs Letters 1993; 331(l–2):105–108.

    Article  PubMed  CAS  Google Scholar 

  22. Spencer JB, Stolowich NJ, Santander PJ et al. Mechanism of the ring contraction step in vitamin-B12 biosynthesis—the origin and subsequent fate of the oxygen functionalities in precorrin-3X. J Am Chem Soc 1994; 116:4991–4992.

    Article  CAS  Google Scholar 

  23. Debussche L, Thibaut D, Danzer M et al. Biosynthesis of vitamin B12: Structure of precorrin-3B, the trimethylated substrate of the enzyme catalysing ring contraction. J Chem Soc Chem Commun 1993; 1100–1103.

    Google Scholar 

  24. McGoldrick HM, Roessner CA, Raux E et al. Identification and characterization of a novel vitamin B12 (cobalamin) biosynthetic enzyme (CobZ) from Rhodobacter capsulatus, containing flavin, heme, and Fe-S cofactors. J Biol Chem 2005; 280(2): 1086–1094.

    Article  PubMed  CAS  Google Scholar 

  25. Roessner CA, Spencer JB, Ozaki, S et al. Overexpression in Escherichia coli of 12 vitamin B12 biosynthetic enzymes. Protein Expression and Purification 1995; 6(2):155–163.

    Article  PubMed  CAS  Google Scholar 

  26. Thibaut D, Debussche L, Frechet D et al. Biosynthesis of vitamin-B12—the structure of factor-IV, the oxidized form of precorrin-4. J Chem Soc Chem Commun 1993; 513–515.

    Google Scholar 

  27. Min CH, Atshaves BP, Roessner CA et al. Isolation, structure, and genetically-engineered synthesis of precorrin-5, the pentamethylated intermediate of vitamin-B12 biosynthesis. J Am Chem Soc 1993; 115:10380–10381.

    Article  CAS  Google Scholar 

  28. Thibaut D, Debussche L, Blanche F. Biosynthesis of vitamin B12: isolation of precorrin-6x, a metal-free precursor of the corrin macrocycle retaining five S-adenosylmethioninederived peripheral methyl groups. Proc Natl Acad Sci USA 1990; 87(22):8795–8799.

    Article  PubMed  CAS  Google Scholar 

  29. Thibaut D, Debussche L, Blanche F. Biosynthesis of vitamin B12: structure of precorrin-6x octamethyl ester. Proc Natl Acad Sci USA 1990; 87(22):8800–8804.

    Article  PubMed  CAS  Google Scholar 

  30. Weaver GW et al. Biosynthesis of vitamin-B12—the site of reduction of precorrin-6X. J Chem Soc Chem Commun 1991; 976–979.

    Google Scholar 

  31. Kiuchi F, Thibaut D, Debussche L et al. Biosynthesis of vitamin-B12—stereochemistry of transfer of a hydride equivalent from NADPH by precorrin-6X reductase. J Chem Soc Chem Commun 1992; 306–308.

    Google Scholar 

  32. Blanche F, Famechon A, Thibaut D et al. Biosynthesis of vitamin B12 in Pseudomonas denitrificans: the biosynthetic sequence from precorrin-6y to precorrin-8x is catalyzed by the cobL gene product. J Bacteriol 1992; 174(3): 1050–1052.

    PubMed  CAS  Google Scholar 

  33. Keller JP, Smith PM, Benach J et al. The crystal structure of MT0146/CbiT suggests that the putative precorrin-8w decarboxylase is a methyltransferase. Structure (Camb) 2002; 10(11): 1475–1487.

    Article  CAS  Google Scholar 

  34. Thibaut D, Couder M, Famechon A et al. The final step in the biosynthesis of hydrogenobyrinic acid is catalyzed by the cobH gene product with precorrin-8x as the substrate. J Bacteriol 1992; 174(3):1043–1049.

    PubMed  CAS  Google Scholar 

  35. Thibaut D, Kiuchi F, Debussche L et al. Biosynthesis of vitamin-B12—structural studies on precorrin-8X, an octamethylated intermediate and the structure of its stable tautomer. J Chem Soc Chem Commun 1992; 982–985.

    Google Scholar 

  36. Shipman LW, Li D, Roessner CA et al. Crystal Structure of Precorrin-8x Methyl Mutase. Structure with Folding & Design 2001; 9(7):587–596.

    CAS  Google Scholar 

  37. Debussche L, Thibaut D, Cameron B et al. Purification and characterization of cobyrinic acid a,c-diamide synthase from Pseudomonas denitrificans. J Bacteriol 1990; 172(11):6239–6244.

    PubMed  CAS  Google Scholar 

  38. Cameron B, Blanche F, Rouyez MC et al. Genetic analysis, nucleotide sequence, and products of two Pseudomonas denitrificans cob genes encoding nicotinate-nucleotide: dimethylbenzimidazole phosphoribosyltransferase and cobalamin (5′-phosphate) synthase. J Bacteriol 1991; 173(19):6066–6073.

    PubMed  CAS  Google Scholar 

  39. Crouzet J, Levyschil S, Cameron B et al. Nucleotide sequence and genetic analysis of a 13.1-kilobase-pair Pseudomonas denitrificans DNA fragment containing five cob genes and identification of structural genes encoding Cob(I)alamin adenosyltransferase, cobyric acid synthase, and bifunctional cobinamide kinase-cobinamide phosphate guanylyltransferase. J Bacteriol 1991; 173(19):6074–6087.

    PubMed  CAS  Google Scholar 

  40. Debussche L, Couder M, Thibaut D et al. Assay, purification, and characterization of cobaltochelatase, a unique complex enzyme catalyzing cobalt insertion in hydrogenobyrinic acid a,c-diamide during coenzyme B12 biosynthesis in Pseudomonas denitrificans. J Bacteriol 1992; 174(22):7445–7451.

    PubMed  CAS  Google Scholar 

  41. Fodje MN, Hansson A, Hansson M et al. Interplay between an AAA module and an integrin I domain may regulate the function of magnesium chelatase. J Mol Biol 2001; 311(1):111–122.

    Article  PubMed  CAS  Google Scholar 

  42. Leech HK, Raux E, McLean KJ et al. Characterization of the cobaltochelatase CbiXL: evidence for a 4Fe-4S center housed within an MXCXXC motif. J Biol Chem 2003; 278(43):41900–41907.

    Article  PubMed  CAS  Google Scholar 

  43. Blanche F, Maton L, Debussche L et al. Purification and characterization of Cob(II)yrinic acid a,c-diamide reductase from Pseudomonas denitrificans. J Bacteriol 1992; 174(22):7452–7454.

    PubMed  CAS  Google Scholar 

  44. Debussche L, Couder M, Thibaut D et al. Purification and partial characterization of Cob(I)alamin adenosyltransferase from Pseudomonas denitrificans. J Bacteriol 1991; 173(19):6300–6302.

    PubMed  CAS  Google Scholar 

  45. Blanche F, Couder M, Debussche L et al. Biosynthesis of vitamin B12: stepwise amidation of carboxyl groups b, d, e, and g of cobyrinic acid a,c-diamide is catalyzed by one enzyme in Pseudomonas denitrificans. J Bacteriol 1991; 173(19):6046–6051.

    PubMed  CAS  Google Scholar 

  46. Crouzet J, Cauchois L, Blanche F et al. Nucleotide sequence of a Pseudomonas denitrificans 5.4-kilobase DNA fragment containing five cob genes and identification of structural genes encoding S-adenosyl-L-methionine: uroporphyrinogen III methyltransferase and cobyrinic acid a,c-diamide synthase. J Bacteriol 1990; 172(10):5968–5979.

    PubMed  CAS  Google Scholar 

  47. Roessner CA, Huang KX, Warren MJ et al. Isolation and characterization of 14 additional genes specifying the anaerobic biosynthesis of cobalamin (vitamin B12) in Propionibacterium freudenreichii (P. shermanii). Microbiology 2002; 148(Pt 6):1845–1853.

    PubMed  CAS  Google Scholar 

  48. Raux E, Schubert HL, Roper JM et al. Vitamin B12; insights into biosynthesis’s Mount improbable. (Review) Bioorganic Chem 1999; 27:100–118.

    Article  CAS  Google Scholar 

  49. Raux E, Leech HK, Beck R et al. Identification and functional analysis of enzymes required for precorrin-2 dehydrogenation and metal ion insertion in the biosynthesis of sirohaem and cobalamin in Bacillus megaterium. Biochem J 2003; 370(Pt 2):505–516.

    Article  PubMed  CAS  Google Scholar 

  50. Brindley AA, Raux E, Leech HK et al A story of chelatase evolution: identification and characterization of a small 13–15-kDa “ancestral” cobaltochelatase (CbiXS) in the archaea. J Biol Chem 2003; 278(25):22388–22395.

    Article  PubMed  CAS  Google Scholar 

  51. Raux E, Thermes C, Heathcote P et al. A role for Salmonella typhimurium cbiK in cobalamin (vitamin B12) and siroheme biosynthesis. J Bacteriol 1997; 179(10):3202–3212.

    PubMed  CAS  Google Scholar 

  52. Schubert HL, Raux E, Wilson KS et al. Common chelatase design in the branched tetrapyrrole pathways of heme and anaerobic cobalamin synthesis. Biochemistry 1999; 38(33): 10660–10669.

    Article  PubMed  CAS  Google Scholar 

  53. Al-Karadaghi S, Hansson M, Nikonov S et al. Crystal structure of ferrochelatase: the terminal enzyme in heme biosynthesis. Structure 1997; 5(11):1501–1510.

    Article  PubMed  CAS  Google Scholar 

  54. Blackwood ME, Rush TS, Romesberg F et al. Alternative modes of substrate distortion in enzyme and antibody catalyzed ferrochelation reactions. Biochemistry 1998; 37(3):779–782.

    Article  PubMed  CAS  Google Scholar 

  55. Lecerof D, Fodje M, Hansson A et al. Structural and mechanistic basis of porphyrin metallation by ferrochelatase. J Mol Biol 2000; 297(1):221–232.

    Article  PubMed  CAS  Google Scholar 

  56. Roessner CA, Warren MJ, Santander PJ et al. Expression of 9 Salmonella typhimurium enzymes for cobinamide synthesis. Identification of the 11-methyl and 20-methyl transferases of corrin biosynthesis. FEBS Lett 1992; 301(1):73–78.

    Article  PubMed  CAS  Google Scholar 

  57. Spencer P, Stolowich NJ, Sumner LW et al. Definition of the redox states of cobalt-precorrinoids: investigation of the substrate and redox specificity of CbiL from Salmonella typhimurium. Biochemistry 1998; 37(42):14917–14927.

    Article  PubMed  CAS  Google Scholar 

  58. Frank S, Deery E, Brindley AA et al. Elucidation of substrate specificity in the cobalamin (vitamin B12) biosynthetic methyltransferases; structure and function of the C20 methyltransferase (CbiL) from Methanothermobacter thermautotrophicus. J Biol Chem 2007; 282(33):23957–23969

    Article  PubMed  CAS  Google Scholar 

  59. Wang J, Stolowich NJ, Santander PJ et al. Biosynthesis of vitamin B12: concerning the identity of the two-carbon fragment eliminated during anaerobic formation of cobyrinic acid. Proc Natl Acad Sci USA 1996; 93(25): 14320–14322.

    Article  PubMed  CAS  Google Scholar 

  60. Scott AI, Stolowich NJ, Wang J et al. Biosynthesis of vitamin B12: Factor IV, a new intermediate in the anaerobic pathway. Proc Natl Acad Sci USA 1996; 93:14316–14319.

    Article  PubMed  CAS  Google Scholar 

  61. Santander PJ, Roessner CA, Stolowich NJ et al. How corrinoids are synthesized without oxygen: nature’s first pathway to vitamin B12. Chem Biol 1997; 4(9):659–666.

    Article  PubMed  CAS  Google Scholar 

  62. Santander PJ, Stolowich NJ, Scott AI. Chemoenzymatic synthesis of an unnatural tetramethyl cobalt corphinoid. Bioorg Med Chem 1999; 7(5):789–794.

    Article  PubMed  CAS  Google Scholar 

  63. Roessner CA, Scott AI. Fine-tuning our knowledge of the anaerobic route to cobalamin (vitamin B12). J Bacteriol 2006; 188(21):7331–7334.

    Article  PubMed  CAS  Google Scholar 

  64. Kajiwara Y, Santander PJ, Roessner CA et al. Genetically engineered synthesis and structural characterization of cobalt-precorrin 5A and-5B, two new intermediates on the anaerobic pathway to vitamin B12: definition of the roles of the CbiF and CbiG enzymes. J Am Chem Soc 2006; 128(30):9971–9978.

    Article  PubMed  CAS  Google Scholar 

  65. Scott AI Discovering nature’s diverse pathways to vitamin B12: A 35-year odyssey. J Org Chem 2003; 68(7): 2529–2539.

    Article  PubMed  CAS  Google Scholar 

  66. Roessner CA, Williams HJ, Scott AI. Genetically engineered production of 1-desmethylcobyrinic acid, 1-desmethylcobyrinic acid a,c-diamide, and cobyrinic acid a,c-diamide in Escherichia coli implies a role for CbiD in C-1 methylation in the anaerobic pathway to cobalamin. J Biol Chem 2005; 280(17): 16748–16753.

    Article  PubMed  CAS  Google Scholar 

  67. Raux E, Lanois A, Rambach A et al. Cobalamin (vitamin B12) biosynthesis: functional characterization of the Bacillus megaterium cbi genes required to convert uroporphyrinogen III into cobyrinic acid a,c-diamide. Biochem J 1998; 335(Pt 1):167–173.

    PubMed  CAS  Google Scholar 

  68. Raux E, Lanois A, Warren MJ et al. Cobalamin (vitamin B12) biosynthesis: identification and characterization of a Bacillus megaterium cobI operon. Biochem J 1998; 335(Pt 1): 159–166.

    PubMed  CAS  Google Scholar 

  69. Santander PJ, Kajiwara Y, Williams HJ et al. Structural characterization of novel cobalt corrinoids synthesized by enzymes of the vitamin B12 anaerobic pathway. Bioorg Med Chem 2006; 14(3):724–731.

    Article  PubMed  CAS  Google Scholar 

  70. Fresquet V, Williams L, Raushel FM. Mechanism of cobyrinic acid a,c-diamide synthetase from Salmonella typhimurium LT2. Biochemistry 2004; 43(33):10619–10627.

    Article  PubMed  CAS  Google Scholar 

  71. Raux E, Lanois A, Levillayer F et al. Salmonella typhimurium cobalamin (vitamin B12) biosynthetic genes: functional studies in S. typhimurium and Escherichia coli. J Bacteriol 1996; 178(3): 753–767.

    PubMed  CAS  Google Scholar 

  72. Williams L, Fresquet V, Santander PJ et al. The Multiple Amidation Reactions Catalyzed by Cobyric Acid Synthetase from Salmonella typhimurium Are Sequential and Dissociative. J Am Chem Soc 2007; 129(2):294–295.

    Article  PubMed  CAS  Google Scholar 

  73. Blanche F, Thibaut D, Debussche L et al. Parallels and decisive differences in vitamin B12 biosyntheses. Angew Chem Int Ed Engl 1993; 32(11):1651–1653.

    Article  Google Scholar 

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Authors and Affiliations

  1. School of Medicine and Pharmacology, University of Western Australia Fremantle Hospital, Fremantle, Australia

    Ross M. Graham

  2. Protein Science Group, Department of Bioscience, University of Kent, Canterbury, Kent, CT2 7NJ, UK

    Evelyne Deery & Martin J. Warren

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  1. Ross M. Graham
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  2. Evelyne Deery
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  3. Martin J. Warren
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Correspondence to Martin J. Warren .

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Graham, R.M., Deery, E., Warren, M.J. (2009). Vitamin B12: Biosynthesis of the Corrin Ring. In: Tetrapyrroles. Molecular Biology Intelligence Unit. Springer, New York, NY. https://doi.org/10.1007/978-0-387-78518-9_18

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