“A vitamin is a substance you get sick from if you don’t eat it” – Albert Szent-Gyorgyi

It’s interesting to think that most of us are content with eating our meals without paying too much, if any, attention to what food is made of and how all its little constituents work inside our bodies to keep us alive. This also implies that most of us are unaware of how incredibly complex the biochemistry of the human body is and how there are thousands upon thousands of biochemical reactions happening within our cells at any given moment. Thankfully, due to our innate intelligence, we don’t have to spend time thinking about our complicated system but with a little added awareness, any of us can take some handy steps to optimize our health and prevent disease. Most micronutrients get frequently overlooked by us because we only tend to superficially hear about a select few of them, like vitamin C and D, whenever they become relevant, such as when cold and flu season strike or when people are told they’re not getting enough sunlight. 

With that being said, I’d like to highlight the importance of a specific group of vitamins, the B vitamins, and how they influence many vital functions of our physiology. Essentially, B vitamins are the crux of our metabolism, playing integral roles in both anabolic and catabolic metabolism, which yield energy and/or form bioactive compounds. They are also critical in processes pertaining to neurotransmitter synthesis, axonal transport (nerve communication) and many other metabolic pathways (Hanna et al, 2022). The 8 water-soluble vitamins that make up the B vitamins all interplay to support every aspect of cellular functioning but each one plays distinct roles in our biochemistry.  

B1 (thiamine)

Thiamine’s core biochemical roles are to; 

• serve as a cofactor for enzymes involved in energy metabolism (mostly within mitochondria)
• aid the synthesis of nucleic acids (genetic material)
• assist antioxidant production 

Thiamine pyrophosphate, the bioactive form of thiamine, is a cofactor of transketolase, and enzyme involved in the pentose phosphate pathway. This pathway produces compounds that are essential for fatty acid and nucleotide synthesis, as well as antioxidant defence. Thiamine is a key factor in the metabolism of glucose, implying that an increased intake of carbohydrates will consequently increase the body’s demands for thiamine. This also explains why most deficiency signs associated with thiamine deficiency are neurological (ataxia, mood disturbances, altered level of consciousness), because glucose is the primary source of fuel for the brain some enzymes associated with glucose utilization are thiamine dependent (Lonsdale, 2006). 

As previously mentioned, thiamine plays an integral role in the metabolism of fatty acids. Long fatty acids are metabolised by enzymes dependent on thiamine and under situations of thiamine deficiency, improper catabolism of fatty acids can lead to accumulation of triglycerides, causing deleterious effects, including vison/hearing impairment, neuropathy, cerebellar ataxia, in in some cases, cardiac dysfunction. If thiamine is involved in nucleic acid, antioxidant, and fatty acid synthesis, then an increase in oxidative stress and a decrease in cell proliferation and fatty acids (including myelin) can result in neuronal damage and the aforementioned symptoms are the clinical signs of the insidious effects of thiamine deficiency on the nervous system (Dhir et al, 2019). 

Food sources of thiamine include whole grains, pork, fish, poultry, meat (organ meats), and nutritional yeast. Recommended daily intake of thiamine sits at 1.2 mg and 1.1 mg for men and women but pregnant women should increase their thiamine intake to 1.4 mg per day (Hanna et al, 2022). 

B2 (riboflavin)

Riboflavin is part of two key cofactors, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), for many important enzymes. The flavoproteins have the following roles in cellular function;

• Lipid and protein metabolism 
  • cofactor for 10 enzymes that catabolise lipids and several enzymes that breakdown amino acids and choline  
• Mitochondrial electron transport chain function (energy production)
  • Proteins that shuttle electrons and Coenzyme Q10 harbour FMN and FAD
• Cellular stress response (antioxidant production)
  • A flavin-dependent enzyme is necessary for the conversion of glutathione disulfide to glutathione, the body’s chief antioxidant
• Support drug metabolism
  • Cytochrome P450 enzymes receive electrons from flavoenzymes 
• Homocysteine and folate metabolism 
  • Re-methylation of homocysteine depends on the enzyme MTHFR, which is FAD-dependent and is also required to metabolize folate (Mosegaard et al, 2020)
• Red blood cell formation
  • Riboflavin is involved in heme protein production, improves iron absorption and supports the mobilization of ferritin (storage form of iron) from tissues

Symptoms of riboflavin deficiency include; 

• sore throat 
• hyperaemia
• oedema of oral and mucous membranes 
• cheilosis (cracking/inflammation of mouth) and glossitis (tongue inflammation) 
• inflammation of the skin 
• cataract development 
• decrease in haemoglobin status. 

To prevent deficiency, recommended daily intake of riboflavin sits at 1.4 mg/day for adult males even though the microbiota also produce endogenous riboflavin (Thakur et al, 2017).  Additionally, eggs, dairy products, mushrooms, green vegetables, and meat are valuable sources of riboflavin (Hanna et al, 2022).  

B3 (niacin)

Niacin is a generic term for nicotinic acid and nicotinamide, which is converted to NAD (nicotinamide adenine dinucleotide). NAD is phosphorylated into NADP and NADPH, which are cofactors for energy metabolism and antioxidant mechanisms. Nicotinic acid is unique in the sense that it acts directly on a set of cell receptor sites that influence cardiovascular outcomes and is therefore used as an adjunct in managing cardiovascular disease. The mechanisms that underlie these therapeutic benefits are;

• Increasing PPAR- and ABCA1 (proteins that influence lipid metabolism), which increases cholesterol efflux (mobilization of cholesterol to the liver by HDL) 
• Influencing lipolysis and free fatty acid secretion in adipocytes (fat cells) to decrease triglyceride synthesis
• Promoting cholesterol ester transfer to HDL and reducing the breakdown of proteins that mitigate clotting and inflammation
• Reducing vascular inflammation by inhibiting LDL oxidation (bad cholesterol) and increasing redox potential (balancing oxidants by influencing electron transport to promote energy production) (MacKay et al, 2012) 

The recommended dietary intake of niacin sits at 15-18 mg per day, however, supplemental dosages can go over 3 grams per day to manage dyslipidaemia but dosages as little as 50 milligrams can produce a “flushing” effect where the skin becomes red and itchy. Instant-release form of niacin tends to work superior to slow-releases forms and carries less risk of toxicity (Al-Mohaisen et al, 2010). Niacin is found in most animal-sources of food, as well as legumes, nuts and seeds. The same food sources of niacin, poultry in particular, also tend to contain tryptophan, which is metabolized into niacin (Hanna et al, 2022).  

B5 (pantothenic acid)

Vitamin B5 plays its most significant role by being a component of Coenzyme A, a cofactor involved in many metabolic reactions, including;

• Synthesis of fatty acids and lipids
• Oxidation of pyruvate in the citric acid cycle from 
  Acetyl-CoA (generation of energy in the form of ATP) 
• Acetyl-CoA is an intermediary in all of energy metabolism (fatty acid, carbohydrate, amino acid, and ketone body metabolism) (Dansie et al, 2014) 
• Forms acyl carrier protein (ACP), which is involved in acetylation reactions (acetyl and acyl group transfers), transferring fatty acyl group to enzyme CoA
• The production of many secondary metabolites (cholesterol, CoQ10, steroid hormones, vitamin D, bile acids, acetylcholine, prostaglandins) 

Food sources of pantothenic acid include; 

• chicken, beef, cheese, and lobster
• potatoes, broccoli, and tomato products 
• oats, 
• liver and kidney 
• peanuts and almonds 
• yeast, egg yolk, and whole grains (Vandamme & Revuelta, 2016, p.5-10)

Even though vitamin B5 deficiency is rare in developed countries, deficiency symptoms may include fatigue, irritability, headaches, gastrointestinal issues and increased arthritic pain. Recommended daily intake of vitamin B5 is 5 mg per day for both men and women and 6 mg for during pregnancy (Hanna et al, 2022).

B6 (pyridoxine)

Vitamin B6 has been implicated in more than 140 biochemical reactions and as all the other B vitamins, it has central roles in cellular metabolism which include;

• Aid the synthesis of amino acids, fatty acids, and neurotransmitters (epinephrine, dopamine, and serotonin)
• Antioxidant support (neutralizing reactive oxygen species which drive inflammation and oxidative stress
• Degrading storage compounds for cellular usage (glycogen can be broken down by phosphorylase, a B6 dependent enzyme, to glucose-1-phosphate, a precursor necessary for energy-production pathways)
• Aid the production of heme (protein that transport oxygen within red blood cells and cobalamins (vitamin B12)) (Parra et al, 2018) 

Deficiency of pyridoxine is normally associated with other B vitamin deficiencies, such as folate and B12 because it is rare in isolation. This is partly because certain risk factors that deplete pyridoxine, such as alcohol dependence, inflammatory bowel disease, obesity, and renal failure, also deplete other B vitamins. To get the recommended daily intake of pyridoxine, 1-1.7 mg per day for both men and women is sufficient and can be found in beef, poultry, starchy vegetables and non-citrus fruits (Hanna et al, 2022). 

B7 (biotin)

Biotin plays its role in controlling energy metabolism by acting as a cofactor for five carboxylase enzymes that are crucial for the synthesis of fatty acids, amino acid metabolism, and gluconeogenesis (producing glucose from amino acids and fats). The enzymes perform the following functions;

• Acetyl-CoA carboxylase generates malonyl-CoA, a building block for fatty acids, which are essential components of myelin sheath
• Pyruvate carboxylase (PC), 3‐methylcrotonyl‐CoA carboxylase (MCC), and propionyl‐CoA carboxylase (PCC) generate intermediates of the tricarboxylic acid cycle (citric acid cycle)
  • Generates one molecule of ATP per one molecule of acetyl-CoA used by the TCA cycle (Fourcade et al, 2020) 

Symptoms of biotin deficiency are mostly dermal and neurological, and include;

• Hair loss and/or a scaly, red rash around orifices (eyes, nose, and mouth)
• Numbness and tingling of extremities
• Hypotonia and/or ataxia (loss of muscle tone and coordination)  
• Mental retardation and developmental delay in children 

Biotin deficiency is rare but can occur in those with the inborn errors of biotinidase deficiency, or those with alcohol dependence, long-term use of anticonvulsant medication, and pregnancy. (Saleem & Soos, 2019). It is easy to prevent as the recommended daily intake of biotin is 30 micrograms per day and can be readily found in organ meats, eggs, fish, nuts, and soybean (Hanna et al, 2022).

B9 (folate)

Folate shares some of the same physiological roles as other B vitamins as well as some unique ones, including;

• Purine and thymidine synthesis
  • The bioactive forms of folate, produced in the folate cycle, are involved in epigenetic regulation and cell growth and proliferation 
• Mitochondrial protein translation
  • Promotes mitochondrial respiration as folate pathways contribute to the production of ATP, NAD, and NADP
• Methionine regeneration
  • Homocysteine, through 5-methyl-tetrahydrofolate and vitamin B12, gets converted to methionine, a precursor to S-adenosyl-methionine, the main methyl donor for DNA methylation reactions, RNA, phospholipids, proteins, and neurotransmitters (Lintas, 2019)
• Red blood cell production
  • As previously mentioned, substrates from the folate cycle are essential for DNA synthesis and deficiency in either folate or vitamin B12 causes megaloblastic anaemia due to defective DNA synthesis (Zheng & Cantley, 2019)

Folate deficiency, as previously mentioned, can cause megaloblastic anaemia, which can cause weakness, irritability, headaches and heart palpitations. Folate deficiency during pregnancy increases the risk of foetal neural tube defects, such as spina bifida, as well as congenital heart defects. Recommended daily intake of folate is 400 micrograms for men and women and 600 micrograms during pregnancy and unlike other B vitamins which are found readily in animal foods, folate is found in green leafy vegetables, citrus fruits, legumes, seeds and nuts (Hanna et al, 2022). 

B12 (cobalamin) 

Vitamin B12, colloquially known as cobalamin, was discovered for its role in red blood cell formation when a pernicious anaemia became attribute to a deficiency in it. Furthermore, cobalamin functions as a coenzyme (methylcobalamin/adenosylcobalamin) that is implicated in many biochemical roles, including;

• Nerve cell formation and regeneration
  • DNA synthesis of myelin-producing oligodendrocytes and myelin synthesis
• Homocysteine/energy metabolism
  • Methylcobalamin is required as a cofactor to methylate homocysteine to methionine, influencing protein, DNA, and neurotransmitter synthesis 
  • Supports methylmalonyl CoA mutase enzyme, which catalyses the formation of succinyl CoA, an important intermediate in the Krebs cycle
• Fatty acid and nucleic acid synthesis
• Antioxidant support
  • Cobalamin influences the amount of reduced glutathione in the liver and erythrocytes (Calderon-Ospina & Nava-Mesa, 2019) 

Recommended daily intake of cobalamin B12 is 2.4 micrograms for men and women and 2.6 micrograms during pregnancy and is readily found in beef, seafood, eggs, dairy and organ meats (Hanna et al, 2022). Given that cobalamin absorption requires intact intestinal mucosa and adequate intrinsic factor, gastrointestinal conditions that can damage the intestines, such as inflammatory bowel disease or celiac disease, are a risk factor for cobalamin deficiency. The clinical presentation of cobalamin deficiency varies upon severity of deficiency but can include;

• Megaloblastic/pernicious anemia
  • weakness, irritability, headaches and heart palpitations 
• Glossitis
• Neuropathy
• Impaired cognitive function (due to demyelination of nerves and neurotoxic homocysteine accumulation) (Briani et al, 2013)

References

Al-Mohaissen, M.A., Pun, S.C., Frohlich, J.J. (2010). Niacin: from mechanisms of action to therapeutic uses. Mini reviews in medicinal chemistry, 10(3), 204-17. https://doi.org/10.2174/138955710791185046

Briani, C, Dalla Torre, C., Citton, V., Manara, R., et al. (2013). Cobalamin deficiency: clinical picture and radiological findings. Nutrients, 5(11), 4521-4539. https://doi.org/10.3390/nu5114521

Calderon-Ospina, C.A. & Nava-Mesa, M.O. (2019). B vitamins in the nervous system: current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin. Neuroscience & therapeutics, 26(1), 5-13.  https://doi.org/10.1111/cns.13207

Dansie, L.E., Reeves, S., Miller, K., Zano, S.P., et al. (2014). Physiological roles of the pantothenate kinases. Biochemical society transactions, 42(4),1033-1036. https://doi.org/10.1042%2FBST20140096

Dhir, S., Tarasenko, M., Napol,i E. & Giulivi, C. (2019). Neurological, psychiatric, and biochemical aspects of thiamine deficiency in children and adults. Frontiers in psychiatry, 10, 207. https://doi.org/10.3389%2Ffpsyt.2019.00207

Fourcade, S., Goicoechea, L., Parameswaran, J., Schlüter A, et al. (2020). High-dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy. Brain Pathology, 30(5), 945-963. https://doi.org/10.1111%2Fbpa.12869

MacKay, D., Hathcock, J. & Guarneri, E. (2012). Niacin: chemical forms, bioavailability, and health effects, Nutrition Reviews, 70(6), 357–366. https://doi.org/10.1111/j.1753-4887.2012.00479.x

Hanna, M., Jaqua, E., Nguyen, V. & Clay, J. (2022). B vitamins: functions and uses in medicine. The permanente journal, 26(2), 89-97. https://doi.org/10.7812%2FTPP%2F21.204

Lintas, C. (2019). Linking genetics to epigenetics: The role of folate and folate-related pathways in neurodevelopmental disorders. Clinical genetics, 95(2), 241-252. https://doi.org/10.1111/cge.13421

Lonsdale, D. (2006). A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives. Evidence-based complementary and alternative medicine, 3(1), 49-59. https://doi.org/10.1093%2Fecam%2Fnek009

Mosegaard, S., Dipace, G., Bross, P., Carlsen, J, et al. (2020). Riboflavin deficiency—implications for general human health and inborn errors of metabolism. International journal of molecular sciences, 21(11), 3847. https://doi.org/10.3390/ijms21113847

Parra, M., Stahl, S. & Hellmann, H. (2018). Vitamin B₆ and its role in cell metabolism and physiology. Cells. 7(7), 84. https://doi.org/10.3390/cells7070084

Saleem, F. & Soos, M.P. (2016). Biotin deficiency. StatsPearl Publishing.  https://europepmc.org/article/nbk/nbk547751#free-full-text

Thakur K, Tomar SK, Singh AK, Mandal S, et al. (2017). Riboflavin and health: a review of recent human research. Critical reviews in food science and nutrition, 57(17), 3650-3660. http://dx.doi.org/10.1080/10408398.2016.1145104

Vandamme, E.J. & Revuelta J.L. (Eds.). (2016). Industrial biotechnology of vitamins, biopigments, and antioxidants. Wiley-VCH Verlag GmbH & Co.  https://doi.org/10.1002/9783527681754.ch4

Zheng, Y. & Cantley, L. (2019). Toward a better understanding of folate metabolism in health and disease. Journal of experimental medicine, 216(2), 253-266. https://doi.org/10.1084/jem.20181965