B Vitamins and Their Role in Immune Regulation and Cancer

Abstract

B group vitamins represent essential micronutrients for myriad metabolic and regulatory processes required for human health, serving as cofactors used by hundreds of enzymes that carry out essential functions such as energy metabolism, DNA and protein synthesis and other critical functions. B vitamins and their corresponding vitamers are universally essential for all cellular life forms, from bacteria to humans. Humans are unable to synthesize most B vitamins and are therefore dependent on their diet for these essential micronutrients. More recently, another source of B vitamins has been identified which is derived from portions of the 10¹³ bacterial cells inhabiting the gastrointestinal tract. Here we review the expanding literature examining the relationship between B vitamins and the immune system and diverse cancers. Evidence of B vitamin's role in immune cell regulation has accumulated in recent years and may help to clarify the disparate findings of numerous studies attempting to link B vitamins to cancer development. Much work remains to be carried out to fully clarify these relationships as the complexity of B vitamins' essential functions complicates an unequivocal assessment of their beneficial or detrimental effects in inflammation and cancers.

Keywords: biotin; cancer; cobalamin; folate; gut microbiota; inflammation; niacin; oxidative stress; pantothenic acid; pyridoxine; riboflavin; thiamine.

Figure 1

Biochemical pathways for vitamin/cofactor biosynthesis in human gut microbiome. (A) thiamine pyrophosphate (TPP); (B) Flavin MonoNucleotide/Flavin Adenine Dinucleotide FMN/FAD; (C) Nicotinamide Adenine Dinucleotide (Phosphate) NAD/NADP; (D) coenzyme A (CoA); (E) pyridoxal-phosphate (PLP); (F) biotin; (G) tetrahydrofolate (THF); (H) adenosylcobalamine (AdoCbl). Enzymes are shown in white boxes. B-vitamins/cofactors are in blue/magenta text.

Figure 2

The central carbohydrate metabolism pathways involving thiamine pyrophosphate (TPP)-dependent enzymes. TPP serves as a cofactor for steps regulating the pentose phosphate cycle, fate of pyruvate and the tricarboxylic acid cycle. TKT; transketolase, PDH; pyruvate dehydrogenase, KGDH; α-ketoglutarate dehydrogenase.

Figure 3

The methionine and folate cycle pathways involving PLP-, FAD- and B12-dependent enzymes. The folate cycle begins with the conversion of dietary folate (B9) into dihydrofolate (DHF), which is then reduced to tetrahydrofolate (THF) by the enzyme dihydrofolate reductase (DHFR). THF is next converted to 5,10-methyleneTHF by serine hydroxymethyltransferase (SHMT), a reaction that is coupled with the hydroxylation of serine (Ser) to glycine (Gly) and requires PLP as a cofactor. Thymidylate synthase (TS) uses 5,10-methyleneTHF as a methyl donor to methylate deoxyuridine monophosphate (dUMP), creating deoxythymidine monophosphate (dTMP). This step regenerates DHF for continued cycling. Alternatively, 5,10-methyleneTHF can be reduced by methylenetetrahydrofolate reductase (MTHFR) to 5-methytetrahydrofolate (5-mTHF) using FAD as a cofactor. As part of the methionine cycle, 5-mTHF donates a methyl group to regenerate methionine from homocysteine (Hcy), which is catalyzed by methionine synthase (MS) that requires B12, in the form of methylcobalamin, as a cofactor. To generate the methyl donor S-adenosylmethionine (SAM) for use by multiple methyltransferases. SAM is demethylated during the methyltransferase reactions to form S-adenosylhomocysteine (SAH) which is then hydrolysed by S-adenosylhomocysteine hydrolase (AHCY) to form Hcy. Hcy can also enter the trans-sulfuration pathway catalyzed by cystathionine beta synthase (CBS) and cystathionine gamma lyase (CTH), both requiring PLP as a cofactor, to create cysteine.