The Evolution of Micronutrient Metabolism

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One of the great biological paradoxes is that although oxygen is vital for much planetary life, it can also cause great damage to our delicate cellular mechanisms. Antioxidant mechanisms therefore evolved to cope with the rise of an oxygen-rich atmosphere (Figure 5.1). A diet rich in plant antioxidants augments our inherent defense strategies for reactive oxygen species (ROS); i.e., our cellular biology interacts with the external environment to protect us against ROS. The composition of atmospheric oxygen reached its zenith at around 35% approximately 300 million years ago. By the late Paleozoic, it was 15%, and for the past 150 million years, it has leveled out at 21% (116). Biochemical evolution countered the oxygen threat by developing efficient aerobic catabolism (117). Despite this, the threat of a free radical attack still persists. A free radical is a highly reactive molecular species with an unpaired electron in its outer orbit. A reaction that involves a radical will generate another radical unless two radicals react together, which is actually unlikely because of low cellular concentrations of radicals and their extremely short half-life (nano-to picoseconds). As a result, free radical reactions form self-perpetuating chain reactions. It is worth noting that the major radicals that cause tissue damage are oxygen radicals. These are mainly the superoxide (*O2-), perhydroxyl (*O2H), and hydroxyl (*OH) radicals. As I mention below in discussing senescence, anionic *O2- is a particular problem, as it is constantly produced as part of mitochondrial respiration (Figure 5.1). It seems reasonable to view human antioxidant defences as an evolutionary adaptation to ROS. The mechanism for vitamin C quenching of ROS has been given earlier, but polyphenolic antioxidants like vitamin E work by delocalizing a single unpaired electron through a system of conjugated double bonds. The resultant radical is relatively stable and fairly unreactive. It persists long enough to be quenched and terminate the chain reaction of radical formation by interacting

Peroxinitrile Purine Metabolism

Figure 5.1. Scheme showing the built-in mechanism by which the cell deals with reactive oxygen species generated by cellular respiration. Although dietary antioxidants are a crucial defense mechanism against deleterious damage to DNA structure and membrane integrity, the superoxide dismutase system is considered to be the frontline built-in protection for the cell's delicate molecular organization.

Figure 5.1. Scheme showing the built-in mechanism by which the cell deals with reactive oxygen species generated by cellular respiration. Although dietary antioxidants are a crucial defense mechanism against deleterious damage to DNA structure and membrane integrity, the superoxide dismutase system is considered to be the frontline built-in protection for the cell's delicate molecular organization.

with another "stable" radical. However, there is no doubt that the fallibility inherent in our antioxidant defense system is responsible for senescence and its associated morbidities. Benzie (117) contends that this shortfall in antioxidant potential stems from the fact that adaptive changes are selected for on the basis of reproductive benefit in relation to metabolic cost. As a consequence, the evolution of our endogenous antioxidant potential has not yet progressed beyond the "break-even" point of cost effectiveness. The obvious corollary is that the oxidant:antioxidant equilibrium always favors deleterious oxidation.

Early man dined on a banquet of plant-derived antioxidants. The photosynthetic process generates high levels of ROS within the chloroplast, as a consequence of which, plants have evolved elaborate quenching systems to neutralize these damaging species. To give an example, sites within plants that are prone to oxidative stress can have levels of vitamin C up to 1000 x that found in human plasma. Levels of vitamin C also increase due to wounding, growth, fruit maturation, and environmental stress (117). The tocopherols and tocotrienols and carotenoids are equally important, as are compounds that are not dietary essentials for our species such as the colorful anthocyanidins and other polyphenolic antioxidant molecules.

This raises some interesting questions. Given the obvious importance of antioxidant vitamins, why do we simply not manufacture these molecules rather than have them as dietary essentials? It seems likely that it is easier to forage for the abundant types of food rich in such molecules rather than synthesize them de novo. Consider: If dietary antioxidants were widely available, selection pressures would not act on metabolism to produce them endogenously. This may be true for many antioxidants such as vitamin E, but it is not the case for vitamin C.

Vitamin C is a puzzling nutrient, particularly in the context of human evolution. The enigma is as follows: Almost all species apart from humans and our primate relatives, guinea pigs, and birds manufacture vitamin C de novo. We cannot synthesize vitamin C because the gene encoding the terminal step in vitamin C biosynthesis, L-gulono-lactone oxidase, is inactive in humans, creating the dilemma of "what kind of evolutionary advantage is conferred by a mutation that prevents biosynthesis of such an important biomolecule?"

Scientists have tried to explain this evolutionary dilemma (118-123), which has been comprehensively reviewed by Benzie (117). It could shift the average population age down to enhance fertility, protect against hemolytic glucose-6-phosphate dehydrogenase deficiency in areas where malaria is endemic, accelerate evolution via increased exposure of DNA to ROS, and enhance the efficacy of our early immune response. These hypotheses are unlikely, however, and the best explanation probably resides in positive selection for an inactivation of the L-gulono-lactone oxidase gene, perhaps in a staged downregulation. This would fit into a paradigm of optimizing metabolic efficiency by using dietary sources of vitamin C, which exist in abundance. The metabolic cost of manufacturing vitamin C de novo might then, over the course of time, be diverted to a more pressing biochemical process. This argument is strengthened by the fact that noxious hydrogen peroxide is produced as part of vitamin C biosynthesis (124). The evolutionary loss of the de novo pathway means that the implementation of further antioxidant processes to remove this hydrogen peroxide were rendered redundant. It is interesting to note that loss of the de novo ascorbic acid pathway may have represented an evolutionary chiasma where uric acid supplants ascorbic acid as one of the body's main antioxidants (125,126). Water-soluble uric acid is a ubiquitous product of purine catabolism, which humans cannot metabolize on to allantoin like other organisms, because we do not possess the enzyme uricase. Care is required: Theories such as this need to be counterbalanced: ROS are a necessary part of important cellular mechanisms such as signal transduction pathways and redox-controlled transcription (127-130), so evolutionary selection may well have encouraged equilibrium in favor of a more pro-oxidant intracellular milieu, and this is why de novo ascorbic acid synthesis was dropped. However, in either scenario, it is fair to assume that reducing de novo derived intra- and extracellular ascorbic acid levels may have improved our biological fitness.

The importance of essential micronutrients is well described in this text, and it is emphasized by the various vitamin deficiency diseases. However, two vitamins that exemplify the notion that ascorbic acid may have evolved to become a vitamin, i.e., a dietary essential, is given by panthothenic acid and biotin—two vitamins that we take for granted because they are simply so abundant that deficiency is largely unknown except under extraordinary circumstances. Indeed, panthothenic acid means literally, "available everywhere." Clearly, mechanisms for the synthesis of such ubiquitous dietary molecules by man would be unnecessary and a waste of valuable cellular resources (as may be the case with vitamin C). Because all other essential vitamins are less abundant in our contemporary diet, deficiency states involving these important micronutrients are more easily attained than with panthothenic acid and biotin. However, our ancestral diet may well have been sufficiently rich in these molecules for evolution to act upon cellular metabolism in the ways I have described, and forge the metabolome we have today.

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