Ascorbate is a Multifunctional Micronutrient Whose Synthesis is Lacking in Primates

Ascorbate (vitamin C) is an essential micronutrient in primates, and exhibits multiple physiological functions. In addition to antioxidative action, ascorbate provides reducing power to α-ketoglutarate-dependent non-heme iron dioxygenases, such as prolyl hydroxylases. Demethylation of histones and DNA with the aid of ascorbate results in the reactivation of epigenetically silenced genes. Ascorbate and its oxidized form, dehydroascorbate, have attracted interest in terms of their roles in cancer therapy. The last step in the biosynthesis of ascorbate is catalyzed by l-gulono-γ-lactone oxidase whose gene is commonly mutated in all animals that do not synthesize ascorbate. One common explanation for this deficiency is based on the increased availability of ascorbate from foods. In fact, pathways for ascorbate synthesis and the detoxification of xenobiotics by glucuronate conjugation share the metabolic processes up to UDP-glucuronate, which prompts another hypothesis, namely, that ascorbate-incompetent animals might have developed stronger detoxification systems in return for their lack of ability to produce ascorbate, which would allow them to cope with their situation. Here, we overview recent advances in ascorbate research and propose that an enhanced glucuronate conjugation reaction may have applied positive selection pressure on ascorbate-incompetent animals, thus allowing them to dominate the animal kingdom.