Chapter 38: Tetrahydrofolate, Vitamin B12, and S-Adenosylmethionine

Tetrahydrofolate, the active form of dietary folate, functions as the body's primary one-carbon carrier, accepting single-carbon units from amino acids including serine, glycine, and histidine, as well as from formate and formaldehyde. These donated carbons enter the one-carbon pool and become available for biosynthetic pathways that include thymidylate synthesis for DNA replication, purine ring formation for nucleotide assembly, and the reversible conversion between serine and glycine. When tetrahydrofolate becomes reduced to its N5-methyl form, the one-carbon unit becomes irreversibly trapped, a phenomenon known as the methyl-trap effect that prevents carbon reentry into biosynthetic pathways when vitamin B12 levels are inadequate. Vitamin B12, obtained principally from animal-derived foods, serves two indispensable enzymatic functions: it enables methionine synthase to convert homocysteine back to methionine, thereby recycling this critical amino acid, and it catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in the citric acid cycle pathway. B12 deficiency arises from multiple etiologies including pernicious anemia from intrinsic factor loss, malabsorption disorders, or adherence to strictly vegan diets, culminating in megaloblastic anemia, peripheral neuropathy, and cognitive dysfunction. S-adenosylmethionine, synthesized from methionine and ATP, serves as the universal methyl donor across hundreds of reactions that generate creatine, phosphatidylcholine, epinephrine, melatonin, and methylated chromatin proteins. Disruption of methionine metabolism leads to elevated plasma homocysteine concentrations, an independent risk factor for thrombosis, atherosclerosis, and neurologic disease, while folate insufficiency during pregnancy increases neural tube defect risk. The chapter incorporates clinical cases demonstrating methotrexate chemotherapy for malignancy, B12 malabsorption with neuropathic complications, and alcohol-induced folate depletion causing anemia, alongside diagnostic approaches such as the Schilling test and discussion of methylated adenosine as a potential therapeutic intervention for mood disorders.