Pseudovitamin B12

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Pseudovitamin B12
Pseudovitamin B12 skeletal.svg
Pseudovitamin B12 in its cyano form
Names
Other names
  • β-Cobalamin
  • Adenine cobamide
  • Coα-[α-(7-adenyl)]-Coβ-cobamide
Identifiers
3D model (JSmol)
10761681
ChEBI
ChemSpider
PubChem CID
  • InChI=1S/C58H85N16O14P.CN.Co/c1-26(87-89(84,85)88-47-34(23-75)86-53(46(47)83)74-25-69-52-45(74)51(65)67-24-68-52)22-66-42(82)16-17-55(6)32(18-39(62)79)50-58(9)57(8,21-41(64)81)31(12-15-38(61)78)44(73-58)28(3)49-56(7,20-40(63)80)29(10-13-36(59)76)33(70-49)19-35-54(4,5)30(11-14-37(60)77)43(71-35)27(2)48(55)72-50;1-2;/h19,24-26,29-32,34,46-47,50,53,75,83H,10-18,20-23H2,1-9H3,(H17,59,60,61,62,63,64,65,66,67,68,70,71,72,73,76,77,78,79,80,81,82,84,85);;/q;;+2/p-2/t26-,29-,30-,31-,32+,34-,46-,47-,50-,53+,55-,56+,57+,58+;;/m1../s1 Yes check.svgY
    Key: SEIQEEFQSMTJKO-IOOXTKEKSA-L Yes check.svgY
  • N#[C-][Co+3]1234[N]5=CN(C=6C(=NC=NC65)N)C7OC(CO)C(OP(=O)([O-])OC(C)CNC(=O)CCC8(C9=C(C%10=[N]4C(=CC%11=[N]3C(=C(C%12=[N]2C(C)(C([N-]91)C8CC(=O)N)C(C)(CC(=O)N)C%12CCC(=O)N)C)C(C)(CC(=O)N)C%11CCC(=O)N)C(C)(C)C%10CCC(=O)N)C)C)C7O
Properties
C59H83CoN17O14P
Molar mass 1344.325 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Pseudovitamin B12 is a structural analog of cobalamin, a natural corrinoid with a structure similar to the vitamin B12 group of vitamers. It has no vitamin activity in humans, but can act as a cofactor in some microbial enzymes. [1] [2] Pseudovitamin B12 is the majority corrinoid in spirulina, an algal dietary supplement sometimes erroneously claimed as having this vitamin activity. [3]

Chemical structure

Pseudovitamin B12 is a coordination complex of cobalt, which occupies the center of a corrin ligand and is further bound to an adenosine-containing sidechain. The sixth ("upper") ligand for the metal is alternatively cyano, methyl, hydroxo, or a second adenosyl group. [4] [5] All these analogs are biologically inactive in humans. [1]

Compared to cobalamin (vitamin B12), pseudovitamin B12 has the "lower" ligand, 5,6-dimethylbenzimidazole (DMB), replaced with adenine. [6]

Occurrence

Most cyanobacteria, including Spirulina, and some algae, such as Porphyra tenera (used to make a dried seaweed food called nori in Japan), have been found to contain mostly pseudovitamin B12 instead of biologically active B12. [3] [7] These pseudo-vitamin compounds can be found in some types of shellfish, [1] in edible insects, [8] and at times as metabolic breakdown products of cyanocobalamin added to dietary supplements and fortified foods. [2] [9]

Pseudovitamin B12 can act as a coenzyme in a similar way to normal vitamin B12 when a microbiological assay with Lactobacillus delbrueckii subsp. lactis is used, as that bacteria can utilize the pseudovitamin despite it being unavailable to humans. To get a reliable reading of B12 content, more advanced techniques are available. One such technique involves pre-separation by silica gel and then assessment with B12-dependent E. coli bacteria. [1]

Pseudovitamin B12 is the main corrin cofactor produced by Clostridium cochlearium , [4] Limosilactobacillus reuteri , and the methanogenic methanococcales and Methanoplanus [10] under anaerobic conditions, and by the cyanobacteria Nostoc commune and Aphanizomenon flos-aquae . [11] [12]

Despite production of this compound in groups as distantly related as lactic acid bacteria [13] and cyanobacteria, DMB is preferred over adenine by the vast majority of versions of CobT , the enzyme responsible for making the active phosphoribosylated lower sidechain of cobalamin. [6]

Salmonella enterica is able to make either B12 or pseudovitamin B12 depending on the availability of DMB. Its enzymes prefer DMB, but it remains able to grow when DMB is unavailable and pseudo-B12 has to be made instead. [11]

Activity as enzyme cofactor

In organisms that produce pseudovitamin B12, it takes the same role as vitamin B12 does in humans: as a corrin cofactor that facilitates the function of enzymes. [11] Pseudovitamin B12 is also functional in some non-corrin-producing relatives of organisms that produce pseudovitamin B12. This includes Lactobacillus delbrueckii subsp. lactis (LLD), which is in the same family as Limosilactobacillus reuteri. [1] LLD is also able to use factor S and factor A (see § Other human-inactive cobamides below). [14]

Cobalamide-dependent growth behavior of Sinorhizobium meliloti largely correlates with the cofactor binding selectivity of its methylmalonyl-CoA mutase (MCM). Among adenyl-cobamides, paseudovitamin B12 does not bind to its MCM, factor A (see below) does slightly, and vitamin B12 binds well. [15]

Human apo-methionine synthase (MS) is able to be activated by methyl-pseudovitamin B12in vitro (in solution). Apo-MS is extremely unselective of cofactors: It is activated by all tested cobamides (vitamin B12). It appears to only require the central cobalt atom to have an oxidation state of +2. [16] Hydroxo-pseudovitamin B12 is able to activate the MS in COS-7 cells, but unlike hydroxo-vitamin B12, it does not increase the translation of MS (hydroxo-B12 achieves this by binding to the internal ribosome entry site of MS mRNA). [5]

Human methylmalonyl-CoA mutase (MCM) normally relies on the adenosyl form of vitamin B12. It binds and works with some vitamin B12 analogs in vitro (in solution), but not purinyl ones such as pseudovitamin B12. [17] Adenyl-pseudovitamin B12 does not function as a cofactor or inhibitor of MCM in COS-7 cells. [5]

Interaction with vitamin B12-binding proteins and transporters

Human (mamallian in general) intrinsic factor binds pseudovitamin B12 with 500-fold lower affinity than to its usual target, vitamin B12. This prevents mammals from absorbing trace amounts of pseudovitamin B12 from food. [11] Factor III (see below) has a remarkable 80% affinity relative to vitamin B12. [18]

Another protein involved in the absorption of vitamin B12 is haptocorrin. Human haptocorrin binds pseudovitamin B12 with the same affinity as vitamin B12. It is the least selective protein among all three human vitamin B12-binding proteins. [18]

Transcobalamin II (TCN2) is responsible for carrying vitamin B12 around in blood and into cells. It is relatively unselective, with pseudovitamin B12 showing 80% relative affinity. [18] There is a concern that excess pseudovitamin B12 may compete with vitamin B12 for available TCN2. In COS-7 cells, 10  nM of pseudovitamin B12 in the culture medium inhibits the uptake of 1 nM vitamin B12. Pseudovitamin B12 is not able to show inhibition when vitamin B12 is more abundant.. [5]

Other vitamin B12 analogs

Alternative bases found in vitamin B12 (1), factor III (2), factor IIIm (3), pseudovitamin B12 (4), factor A (5) and factor S (6) Vitamin B12 alternative bases.svg
Alternative bases found in vitamin B12 (1), factor III (2), factor IIIm (3), pseudovitamin B12 (4), factor A (5) and factor S (6)

Other human-inactive cobamides

Factor S (2-methylmercaptoadenyl cobamide), which differs from pseudo-B12 by the addition of a methylmecropto (-S-CH3) group, is found alongside pseudovitamin B12 in crickets. It is presumed to have been made by the gut bacteria of crickets. [19] It is also the predominant corrinoid in human feces. It is also found in escargot. [20]

Factor A (2-methyladenyl cobamide), which differs from pseudo-B12 by the addition of a methyl (-CH3) group, is found in crickets. [14]

Factor IIIm (methoxybenzimidazolyl cobamide) is found in escargot. It differs from vitamin B12 by the removal of a methyl (-CH3) group and the replacement of a methyl group with a methoxy (-O-CH3) group. [20] Factor III (5-hydroxybenzimidazolyl-cobamide), which differs from factor IIIm by the replacement of methoxy with hydroxy (-OH), is common in methanogenic bacteria. [10]

Thermal decomposition of all six of these corrinoids results in the same material, since the sidechain cleaves at the phosphate ester which attaches them to the main heterocycle. [14]

Antivitamin B12

A related concept is antivitamin B12– compounds (often synthetic) that not only have no vitamin action, but also actively interfere with the activity of true vitamin B12. The design of these compounds mainly involves the replacement of the metal ion with rhodium, nickel, or zinc; the attachment may have an inactive ligand such as 4-ethylphenyl. These compounds may be used to analyze B12 utilization pathways or to attack B12-dependent pathogens. [21]

References

  1. 1 2 3 4 5 Watanabe F, Bito T (2018). "Determination of Cobalamin and Related Compounds in Foods". Journal of AOAC International. 101 (5): 1308–1313. doi:10.5740/jaoacint.18-0045. PMID   29669618.
  2. 1 2 Moravcová M, Siatka T, Krčmová LK, et al. (2025). "Biological properties of vitamin B12". Nutrition Research Reviews. 38 (1): 338–370. doi: 10.1017/S0954422424000210 . PMID   39376196.
  3. 1 2 Watanabe F, Katsura H, Takenaka S, et al. (1999). "Pseudovitamin B12 is the Predominant Cobamide of an Algal Health Food, Spirulina Tablets". Journal of Agricultural and Food Chemistry. 47 (11): 4736–4741. Bibcode:1999JAFC...47.4736W. doi:10.1021/jf990541b. PMID   10552882.
  4. 1 2 Hoffmann B, Oberhuber M, Stupperich E, et al. (2000). "Native Corrinoids from Clostridium cochlearium Are Adeninylcobamides: Spectroscopic Analysis and Identification of Pseudovitamin B12and Factor A". Journal of Bacteriology. 182 (17): 4773–4782. doi: 10.1128/jb.182.17.4773-4782.2000 . PMC   111353 . PMID   10940017.
  5. 1 2 3 4 Bito T, Bito M, Hirooka T, et al. (17 July 2020). "Biological Activity of Pseudovitamin B(12) on Cobalamin-Dependent Methylmalonyl-CoA Mutase and Methionine Synthase in Mammalian Cultured COS-7 Cells". Molecules (Basel, Switzerland). 25 (14): 3268. doi: 10.3390/molecules25143268 . PMC   7396987 . PMID   32709013.
  6. 1 2 Hazra AB, Tran JL, Crofts TS, et al. (October 2013). "Analysis of Substrate Specificity in CobT Homologs Reveals Widespread Preference for DMB, the Lower Axial Ligand of Vitamin B12". Chemistry & Biology. 20 (10): 1275–1285. doi:10.1016/j.chembiol.2013.08.007. PMID   24055005.
  7. ↑ Yamada, Yamada, Fukuda, et al. (1999). "Bioavailability of Dried Asakusanori (Porphyra tenera) as a Source of Cobalamin (Vitamin B12)". International Journal for Vitamin and Nutrition Research. 69 (6): 412–418. doi:10.1024/0300-9831.69.6.412. PMID   10642899.
  8. ↑ Schmidt A, Call LM, Macheiner L, et al. (2019). "Determination of vitamin B12 in four edible insect species by immunoaffinity and ultra-high performance liquid chromatography". Food Chemistry. 281: 124–129. doi:10.1016/j.foodchem.2018.12.039. PMID   30658738.
  9. ↑ Yamada K, Shimodaira M, Chida S, et al. (2008). "Degradation of Vitamin B12 in Dietary Supplements". International Journal for Vitamin and Nutrition Research. 78 (45): 195–203. doi:10.1024/0300-9831.78.45.195. PMID   19326342.
  10. 1 2 Stupperich E, Kreutler B (January 1988). "Pseudo vitamin B12 or 5-hydroxybenzimidazolyl-cobamide are the corrinoids found in methanogenic bacteria". Archives of Microbiology. 149 (3): 268–271. doi:10.1007/BF00422016.
  11. 1 2 3 4 Taga ME, Walker GC (February 2008). "Pseudo-B12 joins the cofactor family". Journal of Bacteriology. 190 (4): 1157–9. doi: 10.1128/JB.01892-07 . PMC   2238202 . PMID   18083805.
  12. ↑ Walworth NG, Lee MD, Suffridge C, et al. (2018). "Functional Genomics and Phylogenetic Evidence Suggest Genus-Wide Cobalamin Production by the Globally Distributed Marine Nitrogen Fixer Trichodesmium". Frontiers in Microbiology. 9: 189. doi: 10.3389/fmicb.2018.00189 . PMC   5816740 . PMID   29487583.
  13. ↑ Santos F, Vera JL, Lamosa P, et al. (16 October 2007). "Pseudovitamin is the corrinoid produced by Lactobacillus reuteri CRL1098 under anaerobic conditions". FEBS Letters. 581 (25): 4865–4870. doi:10.1016/j.febslet.2007.09.012. hdl: 11336/58580 . PMID   17888910.
  14. 1 2 3 Fedosov SN, Nexo E, Heegaard CW, et al. (30 October 2023). "Protein binding assays for an accurate differentiation of vitamin B12 from its inactive analogue. A study on edible cricket powder". Food Chemistry: X. 19: 100824. doi:10.1016/j.fochx.2023.100824. PMC   10534188 . PMID   37780289.
  15. ↑ Sokolovskaya OM, Mok KC, Park JD, et al. (29 October 2019). "Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme". mBio. 10 (5). doi:10.1128/mbio.01303-19. PMC   6759758 . PMID   31551329.
  16. ↑ Kolhouse J, Utley C, Stabler S, et al. (December 1991). "Mechanism of conversion of human apo- to holomethionine synthase by various forms of cobalamin". Journal of Biological Chemistry. 266 (34): 23010–23015. doi: 10.1016/S0021-9258(18)54455-0 .
  17. ↑ Sokolovskaya OM, Plessl T, Bailey H, et al. (April 2021). "Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase". Biochimie. 183: 35–43. bioRxiv   10.1101/2020.03.20.997551 . doi:10.1016/j.biochi.2020.06.014. PMC   8682075 . PMID   32659443.
  18. 1 2 3 Stupperich E, Nexø E (15 July 1991). "Effect of the cobalt-N coordination on the cobamide recognition by the human vitamin B12 binding proteins intrinsic factor, transcobalamin and haptocorrin". European Journal of Biochemistry. 199 (2): 299–303. doi:10.1111/j.1432-1033.1991.tb16124.x. PMID   2070790.
  19. ↑ Okamoto N, Nagao F, Umebayashi Y, et al. (June 2021). "Pseudovitamin B12 and factor S are the predominant corrinoid compounds in edible cricket products". Food Chemistry. 347: 129048. doi:10.1016/j.foodchem.2021.129048. PMID   33493835.
  20. 1 2 Watanabe F, Bito T (January 2018). "Vitamin B 12 sources and microbial interaction". Experimental Biology and Medicine. 243 (2): 148–158. doi:10.1177/1535370217746612. PMC   5788147 . PMID   29216732.
  21. ↑ Kräutler B (2020). "Antivitamins B12—Some Inaugural Milestones". Chemistry – A European Journal. 26 (67): 15438–15445. doi:10.1002/chem.202003788. PMC   7756841 . PMID   32956545.
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