The Secrets and Wonders of Vitamin B12

A Short History of Vitamins

Vitamins are essential components of the diet required in very small amounts for normal development, composed of organic, low-molecular weight molecules that act as catalysts in the human body. Since these molecules are either synthesized in insufficient quantities in the organism, or not synthesized at all, they must be acquired by ingestion with the diet or by other means. The history of awareness about the importance of vitamins in human nutrition dates already from many centuries ago, when ancient Greeks, Romans, and Arabs realized that empirical healing of some diseases can be achieved by administration of certain foods. Furtherly, experiments such as intentionally inducing and curing dietary diseases in animals or administrating synthetic diets to discover essential nutrition factors were conducted. This sustained the fact that animals require small amounts of additional dietary factors, an idea widely accepted as early as the beginning of the 20th century. Vitamin deficiencies used to be a leading cause of illness and death (e.g., Pellagra, scurvy, beriberi), but thanks to the thorough mechanistic investigation and the present wide availability, these illnesses have become rare in many countries (Friedrich, 1988).

Vitamin B12: Unique Element of Human Nutrition

Among all known vitamins, vitamin B12 is unique, containing not only a complex organic structure, but being the only molecule involved in higher organisms that contains cobalt. The discovery of this molecule began with the documentation of pernicious anemia, described in 1855 by Thomas Addison as “a very remarkable form of general anemia, occurring without any discoverable cause whatsoever”. After 70 years and many fatalities, the medical world discovered that this disease could be cured by feeding a half-pound of lightly cooked liver to the patients, and with the further contributions from diverse fields such as chemistry, biochemistry, microbiology, x-ray crystallography and lastly molecular biology, nowadays we have a clear picture of what Vitamin B12 looks like on a structural level, what function it accomplishes in the human body and why the lack of it is such a threat to our lives (Janos et al., 2013).

Structure and Function of Vitamin B12

As previously mentioned, vitamin B12 has a complex structure, centered around a corrin ring system, to which cobalt is coordinated as Co3+. The corrin ring system is chemically related to the porphyrin ring system of heme, a group that is present in myoglobin, hemoglobin, and many other proteins (i.e., heme proteins) (Nelson & Cox, 2013). Upon metabolization, vitamin B12 can be turned into two cofactor forms, termed coenzyme B12 and cobalamin. Cofactors are molecules that are essential for the activity of an enzyme, and in the case of coenzyme B12 and cobalamin, these enzymes are methylmalonyl-CoA mutase and methionine synthase respectively (Feiters, 2020).

Figure 1: (left) The chemical structures of corrin in Vitamin B12 (Feiters, 2020) and (right) porphyrin in heme (Nelson & Cox, 2013). Compared to the Co-containing ring system of corrin, porphyrin has an additional carbon and an Fe ion coordinated in the center.

Methylmalonyl-CoA mutase is involved in the metabolization of unsaturated fatty acids and odd-number fatty acids (Nelson & Cox, 2013), the latter being unusual fatty acids that in large amounts can influence membrane functions and particularly the nervous system functions (Tagliamonte & Tomassi, 1976).

The most important role of methionine synthase is as part of the S-adenosylmethionine (SAM) biosynthesis and regeneration cycle (Banerjee & Matthews, 1990), molecule that regulates various processes in eukaryotic cells, including DNA, tRNA, and rRNA methylation, the immune response, or amino acid metabolism (Ding et. Al, 2015).

Sources and absorption

Animal cells cannot produce vitamin B12 on their own, and due to the extreme sensitivity of this molecule, it also cannot be made by plants (Nelson & Cox, 2013), but only by bacteria and algae, and it is therefore an essential component of human nutrition (Feiters, 2020). Gastrointestinal fermentation supports the growth of vitamin B12, which is subsequently incorporated into tissues, especially into the liver. This makes liver, beef, and chicken the richest sources for this vitamin, together with other products from herbivorous animals that are also part of vegetarian diet, such as milk and eggs (World Health Organization and Food and Agriculture Organization of the United Nations, 2004). Pescatarians can also acquire vitamin B12 from fish (Damayanti, 2014).

After ingestion, vitamin B12 is released from the proteins in food that it is bound to by the action of hydrochloric acid in the stomach, and immediately bound to a mixture of glycoproteins that protect it from denaturation. After binding to the intrinsic factor secreted by the stomach, it can be actively absorbed in the body (World Health Organization and Food and Agriculture Organization of the United Nations, 2004).

Lack of Vitamin B12: Veganism and Pernicious Anemia

Lacto-ovo vegetarians can still take up vitamin B12 by consuming eggs, milk, and other dietary products. However, individuals that follow completely animal-free diets (vegans) are at risk of vitamin B12 deficiency. The most serious disease that this can lead to is pernicious anemia, which cannot be abolished by iron supplements. Neurological symptoms can occur mostly due to the impairment of methylmalonyl-CoA mutase, that in the absence of coenzyme B12, cannot metabolize odd-number fatty acids anymore, which ultimately accumulate in neuronal membranes. Moreover, halting the activity of methionine synthase leads to poor regulation of, for example, DNA methylation, which is particularly a problem for cells that are renewed continuously, such as red blood cells (Feiters, 2020).

Figure 2: Symptoms of pernicious anemia (What Is Pernicious Anemia?, 2021).

Conclusions

Vitamins are an indispensable component of human nutrition. With a structure unique in composition and complexity, vitamin B12 accounts for an important function in the human body, acting as cofactor for methylmalonyl-CoA mutase and methionine synthase. The absence of vitamin B12 imposes serious risks on human health, being the main cause of developing pernicious anemia. This disease was thoroughly documented throughout several decades, and the knowledge we gathered until today highlights the need of a balanced nutrition and of vitamin B12 supplements for the individuals that choose animal-free diets.

References:

Banerjee, R. V., & Matthews, R. G. (1990). Cobalamin-dependent methionine synthase. The Faseb Journal, 4(5), 1450–1459.

https://doi.org/10.1096/fasebj.4.5.2407589

Damayanti, D. (2014). Foods and nutrients associated with vitamin b12 biomarkers among vegetarian and non-vegetarian participants of the adventist health study-2 calibration study [Doctoral dissertation, Loma Linda University].

Ding, W., Smulan, L. J., Hou, N. S., Taubert, S., Watts, J. L., & Walker, A. K. (2015). S-adenosylmethionine levels govern innate immunity through distinct methylation-dependent pathways. Cell Metabolism, 22(4), 633–45. https://doi.org/10.1016/j.cmet.2015.07.013

Feiters, M. C. (2020). NWI-MOL105 Study Guide/ Course Manual. Molecular Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen.

Friedrich, W. (1988). Vitamins. Walter de Gruyter, Berlin, New York.

Janos, Z., Suttie, J. W., Gregory III, J. F., & Stover, P. J. (2013). Handbook of Vitamins (pp. 448-478). CRC Press. https://doi.org/10.1201/b15413

Nelson, D. L., & Cox, M. M. (2013). Lehninger Principles of Biochemistry (6th ed.). W.H. Freeman and Company.

Tagliamonte, B., & Tomassi, G. (1976). Fatty acids with an odd number of carbon atoms: metabolic and nutritional aspects. S&TA&NU. Rivista di scienza e tecnolohia degli alimenti e di nutrizione umana, 6(1), 7-12.

World Health Organization and Food and Agriculture Organization of the United Nations (2004). Vitamin and mineral requirements in human nutrition (2nd ed., pp. 279-288). World Health Organization.

Visual references:

Cover image: Vitamin B12: Here's why your Body Needs it (2021). Wellbeing Nutrition. https://wellbeingnutrition.com/blogs/listing/vitamin-here-s-why-your-body-needs-it

Figure 1 (left): Adaptation of Feiters, M. C. (2020). NWI-MOL105 Study Guide/ Course Manual. Molecular Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen.

Figure 1 (right): Adaptation of Nelson, D. L., & Cox, M. M. (2013). Lehninger Principles of Biochemistry (6th ed.). W.H. Freeman and Company.

Figure 2: Jessen Hickman, R. (2021). What Is Pernicious Anemia?. Verywell Health. https://www.verywellhealth.com/pernicious-anemia-5085455