Review ArticleAscorbate Metabolism and Its Regulation in Animals
Introduction
Ascorbic acid participates in a variety of enzymatic reactions (e.g. collagen and catecholamine synthesis) as an electron donor and it is one of the most important water soluble antioxidants of mammalian tissues.1, 2, 3, 4, 5 Its role as a free radical scavanger and the redox interrelationships between ascorbate and other antioxidants are in the focus of continuous interest. Despite its eminent importance and early discovery, less attention has been paid to the metabolic basis of these reactions (i.e., to the biosynthesis and breakdown of ascorbate). The steps of these pathways are not fully known either in plants or animals. The fact that human beings are unable to synthesize this vitamin diverted the interest from the area. The exploration of ascorbate metabolism and its regulation may nevertheless contribute to the understanding of advantages and disadvantages of the evolutionary events leading to the loss of ascorbate synthesizing ability. The aim of this review is to survey this neglected field emphasizing its possible human relations.
Section snippets
Ascorbate Synthesis
Ascorbate can be synthesized de novo in the hexuronic acid pathway of the liver or the kidney of species having gulonolactone oxidase activity or it can be regenerated from its oxidized form (ascorbate recycling, see the next section) in any cells of any mammalian species. Hexuronic acid pathway can use glucose units theoretically originating from glycogenolysis, gluconeogenesis or glucose uptake, therefore, the hepatic (or renal) carbohydrate metabolism and the ascorbate synthesis should
Ascorbate Recycling
All of the ascorbate utilizing reactions are based on its property of being easily oxidized. Ascorbic acid is oxidized in animal cells to dehydroascorbic acid. The reaction occurs by one-electron oxidation of ascorbate to semidehydroascorbate radical followed by further oxidation to dehydroascorbate or by very rapid disproportionation to dehydroascorbate and ascorbate. From an economical point of view, it is more advantageous for the cell to reduce back the oxidized forms of ascorbate, than to
Ascorbate Breakdown
Dehydroascorbate, if not reduced back to ascorbate, decomposes with a half-life of a few minutes, since this compound is unstable at physiologic pH.3, 35 The product of the hydrolysis is 2,3-diketo-l-gulonate, which does not possess antiscorbutic effects any more. 2,3-diketo-l-gulonate is decarboxylated to l-xylonate and l-lyxonate.52, 53 These 5-carbon compounds can enter the pentose phosphate pathway and the l- to d-conversion is suggested to occur through xylitol. Another minor pathway of
Ascorbate/Dehydroascorbate Transport, Ascorbate Cycles
Even in ascorbate synthesizing species the majority of cells needs ascorbate from outside. Simple diffusion through the plasma membrane plays a minor role in ascorbate/dehydroascorbate uptake, being both compounds charged and water soluble. Therefore more or less specific proteins should be supposed for their transport. The uptake mechanism can be different in various cells, but some characteristic features seem to be constant.[54] The transports of dehydroascorbate and ascorbate are mediated
Regulation of Ascorbate Metabolism
The regulation of ascorbate metabolism should serve the adaptation to at least three different situations. First, in case of abundant exogenous ascorbate supply the endogenous synthesis is superfluous. Furthermore, during starvation the organism should switch over to the endogenous ascorbate production. Finally, when there is an increased demand of antioxidants, ascorbate generation should be accelerated. Indeed, we can find examples for all the three types of regulation.
High dietary ascorbic
Advantages and Disadvantages of the Lost Ascorbate Synthesizing Ability
The ancestors of primates had lost their ascorbate synthesizing ability during the evolution roughly 70 million years ago owing to mutations in the gulonolactone oxidase gene.[25] In a sense, this is the most frequent genetic disorder in humans, because all individuals carry this trait. One can regard the loss of this enzyme as an accident which was not realized in an environment abundant of ascorbate.77, 78 The tropical jungle supplied our ancestors with ascorbate, since “not only does the
Conclusion
Ascorbate metabolism in the organism involves a series of carbohydrate metabolizing pathways, not only in the liver and kidney but through interorgan cycles in the peripheral cells, as well. It is connected to the metabolism of the other water soluble antioxidant glutathione and the antioxidant status of hepatocytes. Glycogen metabolism is an essential part of this regulatory system. Humans lost their ability to synthesize ascorbate but they need it in a large quantity. It is tempting to
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