Humans are unable to synthesise L-ascorbic acid (L-AA, ascorbate, vitamin C), and are thus entirely dependent upon dietary sources to meet needs. In both plant and animal metabolism, the biological functions of L-ascorbic acid are centred around the antioxidant properties of this molecule. Considerable evidence has been accruing in the last two decades of the importance of L-AA in protecting not only the plant from oxidative stress, but also mammals from various chronic diseases that have their origins in oxidative stress. Evidence suggests that the plasma levels of L-AA in large sections of the population are sub-optimal for the health protective effects of this vitamin. Until quite recently, little focus has been given to improving the L-AA content of plant foods, either in terms of the amounts present in commercial crop varieties, or in minimising losses prior to ingestion. Further, while L-AA biosynthesis in animals was elucidated in the 1960s, 1 it is only very recently that a distinct biosynthetic route for plants has been proposed. 2 The characterisation of this new pathway will undoubtedly provide the necessary focus and impetus to enable fundamental questions on plant L-AA metabolism to be resolved. This review focuses on the role of L-AA in metabolism and the latest studies regarding its bio- synthesis, tissue compartmentalisation, turnover and catabolism. These inter-relationships are considered in relation to the potential to improve the L-AA content of crops. Methodology for the reliable analysis of L-AA in plant foods is briefly reviewed. The concentrations found in common food sources and the effects of processing, or storage prior to consumption are discussed. Finally the factors that determine the bioavailability of L-AA and how it may be improved are considered, as well as the most important future research needs. # 2000 Society of Chemical Industry

Plant L‐ascorbic acid: chemistry, function, metabolism, bioavailability and effects of processing

Low literacy is termed ‘developmental dyslexia’ when reading is significantly behind that expected from the intelligence quotient (IQ) in the presence of other symptoms —incoordination, left ‐right confusions, poor sequencing —that characterize it as a neurological syndrome. 5‐10% of children, particularly boys, are found to be dyslexic. Reading requires the acquisition of good orthographic skills for recognising the visual form of words which allows one to access their meaning directly. It also requires the development of good phonological skills for sounding out unfamiliar words using knowledge of letter sound conversion rules. In the dyslexic brain, temporoparietal language areas on the two sides are symmetrical without the normal left-sided advantage. Also brain ‘warts’ (ectopias) are found, particularly clustered round the left temporoparietal language areas. The visual magnocellular system is responsible for timing visual events when reading. It therefore signals any visual motion that occurs if unintended movements lead to images moving off the fovea (‘retinal slip’). These signals are then used to bring the eyes back on target. Thus, sensitivity to visual motion seems to help determine how well orthographic skill can develop in both good and bad readers. In dyslexics, the development of the visual magnocellular system is impaired: development of the magnocellular layers of the dyslexic lateral geniculate nucleus (LGN) is abnormal; their motion sensitivity is reduced; many dyslexics show unsteady binocular fixation; hence poor visual localization, particularly on the left side (left neglect). Dyslexics’ binocular instability and visual perceptual instability, therefore, can cause the letters they are trying to read to appear to move around and cross over each other. Hence, blanking one eye (monocular occlusion) can improve reading. Thus, good magnocellular function is essential for high motion sensitivity and stable binocular fixation, hence proper development of orthographic skills. Many dyslexics also have auditory:phonological problems. Distinguishing letter sounds

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The magnocellular theory of developmental dyslexia.

ASCORBIC acid, originally called vitamin C, is required for human health.1 In human beings deprived of ascorbic acid, the deficiency disease scurvy develops and can be life threatening. Although a disease remarkably similar to scurvy was described by the ancient Egyptians,2 , 3 it was not until 1753 that a Scottish physician, James Lind, systematically described scurvy and its prevention by dietary means.4 Even then, the dietary requirements were controversial. For four decades the British navy refused to accept Lind's findings, and countless sailors continued to die unnecessarily from scurvy until lemon juice was finally included in sailors' rations. Research since Lind's . . .

New concepts in the biology and biochemistry of ascorbic acid.

Vitamin C, a reducing agent and antioxidant, is a cofactor in reactions catalyzed by Cu(+)-dependent monooxygenases and Fe(2+)-dependent dioxygenases. It is synthesized, in vertebrates having this capacity, from d-glucuronate. The latter is formed through direct hydrolysis of uridine diphosphate (UDP)-glucuronate by enzyme(s) bound to the endoplasmic reticulum membrane, sharing many properties with, and most likely identical to, UDP-glucuronosyltransferases. Non-glucuronidable xenobiotics (aminopyrine, metyrapone, chloretone and others) stimulate the enzymatic hydrolysis of UDP-glucuronate, accounting for their effect to increase vitamin C formation in vivo. Glucuronate is converted to l-gulonate by aldehyde reductase, an enzyme of the aldo-keto reductase superfamily. l-Gulonate is converted to l-gulonolactone by a lactonase identified as SMP30 or regucalcin, whose absence in mice leads to vitamin C deficiency. The last step in the pathway of vitamin C synthesis is the oxidation of l-gulonolactone to l-ascorbic acid by l-gulonolactone oxidase, an enzyme associated with the endoplasmic reticulum membrane and deficient in man, guinea pig and other species due to mutations in its gene. Another fate of glucuronate is its conversion to d-xylulose in a five-step pathway, the pentose pathway, involving identified oxidoreductases and an unknown decarboxylase. Semidehydroascorbate, a major oxidation product of vitamin C, is reconverted to ascorbate in the cytosol by cytochrome b(5) reductase and thioredoxin reductase in reactions involving NADH and NADPH, respectively. Transmembrane electron transfer systems using ascorbate or NADH as electron donors serve to reduce semidehydroascorbate present in neuroendocrine secretory vesicles and in the extracellular medium. Dehydroascorbate, the fully oxidized form of vitamin C, is reduced spontaneously by glutathione, as well as enzymatically in reactions using glutathione or NADPH. The degradation of vitamin C in mammals is initiated by the hydrolysis of dehydroascorbate to 2,3-diketo-l-gulonate, which is spontaneously degraded to oxalate, CO(2) and l-erythrulose. This is at variance with bacteria such as Escherichia coli, which have enzymatic degradation pathways for ascorbate and probably also dehydroascorbate.

Vitamin C. Biosynthesis, recycling and degradation in mammals.

The ability to synthesize ascorbic acid is absent in the insects, invertebrates, and fishes. The biosynthetic capacity started in the kidney of amphibians, resided in the kidney of reptiles, became transferred to the liver of mammals, and finally disappeared from the guinea pig, the flying mammals, monkey, and man. A similar transition in the biosynthetic ability was observed in the branched evolution of the birds.

https://science.sciencemag.org/content/sci/182/4118/1271.full.pdf

Evolution and the biosynthesis of ascorbic acid

IN previous reports1,2 from this laboratory, it has been shown that the liver tissue of mammals such as the cow, goat and rat (but not the guinea pig) could produce strikingly large amounts of ascorbic acid in vitro with D-glucuronolactone as substrate in presence of cyanide. This did not occur in the absence of cyanide, and no other substrate except L-gulonolactone was effective. It was, however, found1,2 that the liver tissue of birds such as the chicken and the pigeon, which are known to synthesize their own requirements of ascorbic acid, failed to synthesize ascorbic acid under these conditions. Grollman and Lehninger3 have meanwhile shown by their method that, as opposed to mammals, the capacity for synthesizing ascorbic acid in the birds and reptiles they studied, namely, the chicken, pigeon and tortoise, resides in the kidney tissues.

Species difference in regard to the biosynthesis of ascorbic acid.

The enzyme system concerned was present in the microsomes.6 The mitochondrial fraction also appeared to possess some activity; the activity diminished with washing but was recovered in the washings. The activity of the thrice-washed mitochondria was about one twelfth of that of the microsomes; electron microscopic studies revealed that the washed mitochondria1 fraction still contained some microsomes. Thus the observed activity of the mitochondria was very probably due to contamination by microsomes. It has been observed in amphibians and reptiles that the enzyme system is located in the kidney microsomes and not in the liver microsomes. However, in the different avian species examined (the species that are supposed to belong to the older natural orders in the evolutionary scale, namely, the chick and the pigeon), the kidney and not the liver microsomes synthesized ascorbic acid. In the majority of the avian species studied that belong to the more recent natural orders (the Passeriformes), however, the liver tissue and not the kidney tissue synthesized ascorbic acid. In two species (the house crow and the common myna) belonging to this natural order, both the liver and the kidney tissues could effect this synthesis, the liver being more active than the kidney. However, in one species (the red-vented bulbul) belonging to this natural order, neither the liver nor the kidney could bring about the ~ynthesis.'~ It was indeed possible to produce scurvy in this bird species by putting it on a scorbutic diet and to cure it by administering ascorbic acid.'* In the mammalian species that can synthesize L-ascorbic acid, the enzyme system concerned is present in the liver microsomes and not in the kidney microsomes. Again, neither the liver nor the kidney microsomes of man, monkey, the Indian fruit bat, or the guinea pig could synthesize this vitamin. These results indicate that in the evolutionary ascent the enzyme originally residing in the kidney gradually passes into the liver and finally disappears from the liver also. The microsomal enzymes, D-glucurono reductase and L-gulono oxidase, acted only on D-glucuronolactone and L-gulonolactone and not on the corresponding free acids.6 This was not due to the failure of penetration of the free acid through the microsomal lipid barrier since methyl glucuronate was not affected. Also a soluble enzyme system obtained from the microsomes still * The investigation reported in this paper was financed by the Indian Council of Medical Research, Calcutta, India.

Aspects of ascorbic acid biosynthesis in animals.

The enzyme system catalysing the conversion of D-glucuronolactone and L-gulonolactone into Lascorbic acid in animal tissues has been previously reported to be entirely located in the microsomal fractions ofratand goat-liver homogenates (Burns, Peyser & Moltz, 1956; Chatterjee, Ghosh, Ghosh & Guha, 1957a, b; 1958a, b). The kidney tissue has been found to be the site of this conversion in amphibian, reptilian and some of the avian species examined (Roy & Guha, 1958), and in chick kidney the enzyme system concerned has also been found to be located in the microsomes. Isherwood (1953) stated that mitochondria from rat liver catalyse the transformation of L-gulonolactone into L-ascorbic acid. However, our experiments indicate that the observed activity of mitochondria is probably due to their contamination by microsomes. Potassium cyanide greatly accelerates this synthesis from Dglucuronolactone but the synthesis from L-gulonolactone does not require cyanide or any other added factor (Chatterjee et al. 1958 b). Subsequently the conversion of L-gulonolactone into L-ascorbic acid by rat-liver microsomes has been found to be greatly accelerated by boiled rat-liver supernatant or a metal-binding agent such as sodium pyrophosphate, oco'-dipyridal and 8-hydroxyquinoline (Chatterjee, Chatterjee, Ghosh, Ghosh & Guha, 1958c). The microsomal enzyme concerned in the oxidation of L-gulonolactone to L-ascorbic acid is inhibited by heavy-metal ions (Hg2+, Cu2+ and Zn2+) and reversibly by p-chloromercuribenzoate, indicating the involvement of some essential thiol groups in the enzyme (Chatterjee et al. 1958c). It has already been reported that the microsomes can convert only the lactone forms of the precursors, namely D-glucuronolactone and Lgulonolactone. The sodium salts of the corresponding free acids are not acted on (Chatterjee et al. 1957b; 1958 a, b). The soluble supernatant has been found to inhibit the rate of conversion of L-gulQnolactone into L-ascorbic acid to a great extent and, though L-gulonate is not converted by the microsomes alone, it leads to the formation of L-ascorbic acid when soluble supernatant is added to the system. The factor in the supernatant which inhibits the rate of microsomal synthesis of ascorbic acid from L-gulonolactone but, curiously, helps in

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Biological synthesis of L-ascorbic acid in animal tissues: conversion of L-gulonolactone into L-ascorbic acid.

Simpson, S. A. & Tait, J. F. (1952). Endocrinology, 50, 150. Simpson, S. A. & Tait, J. F. (1953). Mem. Soc. Endocrin. 2,9. Southcott, C. M., Bandy, H. E., Newsom, S. E. & Darrach, M. (1956). Canad. J. Biochem. Phy8iol. 34, 913. Speirs, R. S. & Meyer, R. K. (1951). Endocrinology, 48, 316. Vogt, M. (1955). J. Physiol. 130, 601. Vogt, M. (1957). Ciba Foundation Colloq. Endocrin. 11, 193. Weichselbaum, T. E. & Margraf, H. W. (1955). J. clin. End,ocrin. Metab. 15, 970. Wilson, H. & Fairbanks, R. (1955). Arch. Biochem. Biophys. 54, 441. Zaffaroni, A. & Burton, R. B. (1951). J. biol. Chem. 193, 749.

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Biological synthesis of l-ascorbic acid in animal tissues: conversion of d-glucuronolactone and l-gulonolactone into l-ascorbic acid

IT has been reported1 that cyanide greatly stimulates the synthesis of L-ascorbic acid from D-glucuronolactone by the liver microsomes of the rat. By this method using cyanide it was found that either the liver or the kidney tissue of all the species examined which are known to be independent of an exogenous source of ascorbic acid was able to synthesize L-ascorbic acid, while the corresponding tissue of those which are dependent on such a source could not. Whether the enzyme system concerned was present in the liver or the kidney tissue depended on the position of the species in the phylogenetic scale of evolution2. This technique revealed further that, apart from man, monkey and the guinea pig, the India fruit bat (Pteropus medius) and the redvented bulbul (Pycnonotus cafer) were unable to synthesize L-ascorbic acid, and this was confirmed by the production of experimental scurvy in the bulbul and its cure by the administration of L-ascorbic acid3. This communication concerns the location of the genetic defect in all these species, which distinguishes them from those which can synthesize L-ascorbic acid.

B. C. Guha

Papers

Species difference in regard to the biosynthesis of ascorbic acid.

Aspects of ascorbic acid biosynthesis in animals.

Biological synthesis of L-ascorbic acid in animal tissues: conversion of L-gulonolactone into L-ascorbic acid.

Biological synthesis of l-ascorbic acid in animal tissues: conversion of d-glucuronolactone and l-gulonolactone into l-ascorbic acid

Biosynthesis of L -Ascorbic Acid: Missing Steps in Animals incapable of synthesizing the Vitamin