How Is Vitamin C Synthesized

L-Gulonolactone Oxidase

GULOP is the human remnant of the gene that encodes L-gulonolactone oxidase in most other mammals.

From: Nutrigenetics , 2013

Nervous System Disorders of Nonhuman Primates and Research Models

MicheleA. Fahey , SusanV. Westmoreland , in Nonhuman Primates in Biomedical Research (Second Edition), Volume 2, 2012

Ascorbic Acid/Vitamin C Deficiency

Primates lack the ability to synthesize ascorbic acid/vitamin C due to absence of the enzyme L-gulono-γ-lactone oxidase. Ascorbic acid is a cofactor required for the function of several hydroxylases. The absence of ascorbic acid reduces the function of prolyl hydroxylase, which is required to form hydroxyproline, which stabilizes the collagen triple-helix. Collagen lacking hydroxyproline is more fragile and contributes to the clinical manifestations of scurvy, including vessel wall fragility. Diets deficient in vitamin C may lead to several conditions in nonhuman primates. One condition worth noting related to the CNS is the formation of cephalohematomas in squirrel monkeys, which is pathognomonic for vitamin C deficiency in this species. Grossly, the large subdural hematoma results in a distortion of the shape of the head. Nonhuman primates recognized with vitamin C deficiency respond to treatment with ascorbic acid at 250 mg i.m. twice a day or 30–100 mg/kg/day orally (Ratterree et al., 1990; Eisele et al., 1992); however, the cranial deformity will remain.

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Systems Toxicologic Pathology

Diane Gunson , ... Aurore Varela , in Haschek and Rousseaux's Handbook of Toxicologic Pathology (Third Edition), 2013

Collagen Synthesis Defects

Guinea pigs, humans, non-human primates, most bats, and some birds require a dietary source of Vitamin C as they do not have the gene for gulonolactone oxidase, the enzyme necessary for the formation of ascorbic acid. Without sufficient exogenous Vitamin C, tissue levels are depleted and defects of collagen synthesis and blood clotting will lead to lameness, swollen joints, and widespread hemorrhage at growth plates and beneath the periosteum as well as in connective tissue, skeletal muscle, and other tissues (Figure 63.23A). Clinical signs like painful locomotion, weakness, and lethargy in a susceptible species warrant an investigation into the possibility of Vitamin C deficiency (scurvy). Hemorrhage and swelling of the gums and loosening of the teeth also are frequent findings. Because of the defect in collagen synthesis, there is a dearth of osteoid production in the primary spongiosa so that below the growth plate there are spicules of calcified cartilage with no new bone forming on this scaffold (Figures 63.23B, C). This defect prevents the formation of secondary or tertiary spongiosa as well (Figure 63.23B).

Errors in the formulation of commercial feeds (omission of Vitamin C) or inappropriate storage (warm or damp conditions, which lead to the degradation of Vitamin C) have led to the recommendation to regularly supply secondary sources of Vitamin C to susceptible species (e.g., drinking water supplementation or daily feeding of fresh fruit or vegetables). Adequate Vitamin C also can be provided to omnivorous species (e.g., man) by regular supplies of fresh meat or fish.

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Micronutrients in Skin Immunity and Associated Diseases

Se K. Jeong , ... Kyungho Park , in Immunity and Inflammation in Health and Disease, 2018

21.4.2 Vitamin C

Vitamin C is an essential micronutrient for humans, although they are unable to synthesize vitamin C (or l-ascorbic acid) endogenously due to a lack of l-gulono-gamma-lactone oxidase, an enzyme that catalyzes the last step of vitamin C biosynthesis (Nishikimi et al., 1994). Since distribution of vitamin C is quite different in various human tissues/organs, it moves across cell membranes through sodium-vitamin C cotransporters to maintain optimal concentration (1–15 µg/mL in serum) (Tsukaguchi et al., 1999). Interestingly, vitamin C is detected in the stratum corneum, the outermost layer of the epidermis, forming a gradient with decreasing concentration from inner layers to the surface, contributing to the enhancement of epidermal barrier integrity (Weber et al., 1999).

Vitamin C is well known as an effective antioxidant that cooperates with other antioxidants, including vitamin E, to protect the skin against a UV irradiation-induced increase in oxidative stress (Fig. 21.3) (Chen et al., 2012). Dermal collagen is composed of specific amino acids, e.g., glycine, proline, arginine, and hydroxyproline, and is a key factor for maintaining the structural integrity of skin (Murakami et al., 2012). UV irradiation stimulates production of proinflammatory cytokines, e.g., TNF-α, IL-1, IL-6 and IL-8, and matrix metallopeptidases, the major enzymes responsible for degradation of dermal collagen by activating certain transcriptional factors, such as protein-1 and NF-κB (Chen et al., 2012). In addition, a UV irradiation-induced increase in reactive oxygen species (ROS) significantly suppresses expression of transforming growth factor-β, a signaling mediator that promotes collagen formation (Quan et al., 2001). Vitamin C has been proven to stimulate collagen biosynthesis through different mechanisms: (1) increased expression of intercellular enzymes of collagen synthesis (Pinnell, 1985; Tajima and Pinnell, 1996); (2) increased stabilization of procollagen mRNA (Geesin et al., 1988); (3) induction of hydroxylation of lysine and proline amino acids, a critical step in the formation of type I collagen in the lumen (Peterkofsky, 1991); (4) acting as a cofactor of lysyl hydroxylase (procollagen-lysine 5-dioxygenases) responsible for collagen stabilization and cross-linking (Myllyla et al., 1984); and (5) stimulated lipid peroxidation (Darr et al., 1993).

Vitamin C appears to inhibit the growth of nonmelanoma skin cancers, e.g., basal cell carcinoma (Fig. 21.5) and squamous cell carcinoma (Fig. 21.6), by suppressing overall RNA, DNA, and protein synthesis (Table 21.2) (Bronsnick et al., 2014; Lupulescu, 1991). Previous studies have largely focused on examining the protective role of vitamin C on UV irradiation-mediated skin damage and diseases (Table 21.2), e.g., oxidative stress, wrinkling, aging, wound healing, and dry skin. Further studies are needed to understand how vitamin C contributes to skin immunity.

Table 21.2. Roles of Vitamin C in Skin Diseases

Disease	Key molecular mechanisms of action
Aging & wound healing	• Suppresses photo-aging through removing free radicals (Chen et al., 2012) • Promotes collagen synthesis via following mechanisms: • Increased stabilization of procollagen mRNA (Geesin et al., 1988; Peterkofsky, 1991) • Induction of hydroxylation of lysine and proline (Peterkofsky, 1991) • Acting as a cofactor of lysyl hydroxylase (Myllyla et al., 1984) • Stimulated lipid peroxidation (Darr et al., 1993)
Nonmelanoma cancer	• Inhibits overall DNA, RNA and other protein synthesis (Lupulescu, 1991)

Disease

Key molecular mechanisms of action

Aging & wound healing

•

Suppresses photo-aging through removing free radicals (Chen et al., 2012)

•

Promotes collagen synthesis via following mechanisms:

•: Increased stabilization of procollagen mRNA (Geesin et al., 1988; Peterkofsky, 1991)
•: Induction of hydroxylation of lysine and proline (Peterkofsky, 1991)
•: Acting as a cofactor of lysyl hydroxylase (Myllyla et al., 1984)
•: Stimulated lipid peroxidation (Darr et al., 1993)

Nonmelanoma cancer

•: Inhibits overall DNA, RNA and other protein synthesis (Lupulescu, 1991)

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Volume 2

Hamid M. Said , Ebba Nexo , in Physiology of the Gastrointestinal Tract (Sixth Edition), 2018

54.10.2 Physiology of the Intestinal Vitamin C Absorption Process

Most mammals generate vitamin C from d-glucose through gulonic acid in their liver. Humans, other primates, and the guinea pigs cannot do so because they lack the enzyme l-gulonolactone oxidase. Thus, they must obtain the micronutrient from exogenous sources via intestinal absorption. Dietary sources of vitamin C represent the main supply to humans as limited amount of the vitamin is generated by the gut microbiota. ²⁸ The mechanism of uptake of dietary AA has been investigated using a variety of intestinal tissue preparations from a number of species including humans (reviewed in Refs. 404, 405). These investigations have shown that intestinal AA uptake involves a specific Na⁺-dependent carrier-mediated mechanism. Subsequent investigations with purified intestinal BBMV and BLMV preparations have shown that while transport across both membrane domains is carrier mediate, the mechanism at the BBM domain is Na⁺ dependent in nature. ^404,406 Little metabolic alterations occur in the absorbed AA during transport in enterocytes.

As to the absorption of DHAA, the enterocyte takes up this form of vitamin C and metabolizes it to the reduced form by the action of DHAA-reductase. ^407–409 It is through this mechanism that the intracellular level of DHAA is maintained at low nontoxic levels. Studies on the cellular uptake of DHAA have shown that the enterocyte takes up this compound across the BBM by a Na⁺-independent process. ⁴⁰⁷ Uptake of DHAA was competitively inhibited by sugars due to structural similarities between these compounds. ⁴¹⁰ Substantial uptake of DHAA from the serosal surface of the intestinal epithelial cells, that is, across the BLM, also occurs via an exchange with the reduced AA. ⁴¹¹

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Mechanisms and Regulation of Intestinal Absorption of Water-soluble Vitamins

Hamid M. Said , Ebba Nexo , in Physiology of the Gastrointestinal Tract (Fifth Edition), 2012

64.8.1 Physiological Aspects of the Intestinal Vitamin C Absorption Process

Most mammals generate vitamin C from d-glucose through gulonic acid in the liver. Humans, other primates, and guinea pigs cannot synthesize this vitamin because they lack the enzyme l-gulonolactone oxidase. Thus, they must obtain the vitamin from exogenous sources via intestinal absorption. Unlike a number of other water-soluble vitamins where two sources are available to the gut (a dietary source and a bacterial source in the large intestine), only the dietary source is available in the case of vitamin C as no net synthesis of the vitamin occurs by the normal microflora of the large intestine. ¹⁸ The mechanism of uptake of dietary AA has been investigated using a variety of intestinal tissue preparations from a number of species including humans (reviewed in ²⁶⁶ ). These investigations have concluded that intestinal AA uptake occurs via a concentrative, carrier-mediated, and Na⁺-dependent mechanism. These findings were confirmed in studies with purified intestinal BBMV preparations. ^266,268 The exit process of AA from the enterocyte across the BLM has been characterized using purified intestinal BLMV and shown to also occur by a carrier-mediated system. ²⁶⁶ The latter carrier system, however, was found to be Na⁺ independent in nature. Little metabolic alterations occur in the absorbed AA during transport in the enterocytes.

In the absorption of DHAA, the enterocyte takes up this form of vitamin C and metabolizes it to the reduced form by the action of DHAA-reductase. ^267,269,270 It is through this mechanism that the intracellular level of DHAA is maintained at low non-toxic levels. Studies on the cellular uptake of DHAA have shown that the enterocyte takes up this compound across the BBM by a Na⁺-independent process. ²⁶⁷ Uptake of DHAA was competitively inhibited by sugars due to structural similarities between these compounds. ²⁷¹ Substantial uptake of DHAA from the serosal surface of the intestinal epithelial cells, that is, across the BLM, also occurs via an exchange with the reduced AA. ²⁷²

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Nutrition and Nutritional Diseases

Lewis Sherry M. , ... Ullrey Duane E. , in The Laboratory Primate, 2005

Vitamin C

Ascorbic acid is a cofactor in many enzymatic reactions, including those involved in the hydroxylation of proline or lysine in the formation of collagen. Studied primate species (with the exception of some prosimians) lack the enzyme gulonolactone oxidase, which is needed to synthesize ascorbic acid, and therefore must receive vitamin C in the diet. Vitamin C deficiency causes scurvy. In young animals, clinical signs are related to failure in formation and cross-linking of the organic matrix of developing bone. Bone growth and bone strength are impaired, and affected primates exhibit weakness, depression, reluctance to move, diaphyseal swellings, and epiphyseal fractures (Eisele et al., 1992). At any age, defective collagen synthesis is associated with increased capillary permeability, resulting in bruising, bleeding gums, and subperiosteal hemorrhages (Machlin et al., 1979). Cephalohematomas have been seen in vitamin C-deficient squirrel monkeys and capuchin monkeys (Lehner et al., 1968; Demaray et al., 1978; Kessler, 1980; Ratterree et al., 1990; Borda et al., 1996). Anemia is common due both to blood loss and the role of vitamin C in iron and folic acid metabolism (Eisele et al., 1992); the anemia may be microcytic to macrocytic and hypochromic to normochromic. Periodontal ligaments are weakened, gums necrose, alveolar bone is destroyed, and teeth are lost in scorbutic animals (Anonymous, 1981). Young animals may require more ascorbate than mature monkeys, and stress increases requirements (Tillotson and O'Connor, 1980) by increasing the metabolism of ascorbic acid to CO₂, which is then exhaled (Flurer et al., 1990). Flurer and Zucker (1987) found that tamarins (Saguinus fuscicollis) had lower plasma ascorbate concentrations than marmosets (Callithrix jacchus). Whether this finding was a species difference or due to a failure of the tamarins to adapt to their housing conditions was unclear (Flurer et al., 1990). Certain experimental treatments, such as administration of oral contraceptives, may also increase dietary requirements for ascorbic acid (Weininger and King, 1982).

Despite the addition of vitamin C to commercial primate diets, spontaneous scurvy was common in the past (Ratterree et al., 1990; Eisele, 1992). Manufacturing errors, use of diets containing unstable vitamin C forms, improper storage, and soaking diets in water can result in inadequate dietary vitamin C (Demaray et al., 1978). The recent availability of ascorbyl-2-polyphosphate, a stable and biologically active form of vitamin C, has the potential to eliminate scurvy as a practical problem.

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Vitamin C

F.M. Steinberg , R.B. Rucker , in Encyclopedia of Biological Chemistry (Second Edition), 2013

Summary

Ascorbic acid usually carries out redox reactions by mechanisms dependent upon free-radical processes. Ascorbate metabolism is linked to the metabolism of glutathione. Ascorbic acid is required in animals that lack or have mutations in the gene for L-gulonolactone oxidase. Ascorbic deficiency results in reduced mono- and dioxygenase activities. The consequences of severe deficiency are profound, since growth, extracellular matrix, and hormonal regulation are impaired. Recent data suggest that optimal intakes of ascorbic acid, based on a range of criteria, should be 75–90 mg d⁻¹ for adult humans, and possibly higher in some circumstances.

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Management, Husbandry, and Colony Health

Vincent C. Gresham , Vicky L. Haines , in The Laboratory Rabbit, Guinea Pig, Hamster, and Other Rodents, 2012

Hypovitaminosis C (Scurvy)

The primary nutritional disease of concern in the guinea pig is hypovitaminosis C. Like primates and some species of birds, fish, and bats, scurvy in the guinea pig is the result of the inability to produce the hepatic enzyme L-gulonolactone oxidase which converts L-gulonolactone into the isomers L-ascorbate (AH) and 1-dehydroascorbic acid (DHA), thus preventing the conversion of glucose to ascorbic acid ( Marcus and Coulston, 1990). Deficiency is often subclinical, and may present as mild conjunctivitis, or non-specific respiratory or intestinal signs. More advanced cases present with weight loss, reluctance to move, and swollen joints (Clarke et al., 1980). The vitamin C deficiency leads to an impaired synthesis of collagen secondary to defective hydroxylase reactions in the formation of hydroxylysine and hydroxyproline amino acids. Treatment consists of supplementation of vitamin C up to 230 mg/kg daily. Recovery is short, often only taking 1–2 weeks (Harkness et al., 2002). Vitamin C deficiency in early postnatal life may result in impaired neuronal development and a functional decrease in spatial memory in the guinea pig (Tveden-Nyborg, 2009). Because current laboratory guinea pig diets are supplemented with vitamin C, scurvy has essentially been eliminated from the research setting.

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CORONARY HEART DISEASE | Antioxidant Status

D.S.P. Abdalla , in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003

Ascorbic acid

Ascorbic acid (vitamin C) is an essential micronutrient required for normal metabolic functions in the organism. Like other primates, humans lost the ability to synthesize ascorbic acid, as a result of a mutation in the gene coding for l-gulonolactone oxidase, required for the biosynthesis of ascorbic acid via the glucuronic acid pathway. A lack of ascorbic acid in the diet causes the disease scurvy, which can be prevented with 10 mg per day, an amount easily obtained by consumption of fruit and vegetables. Tissue saturation in healthy men occurs at ascorbic acid intakes of approximately 0.1 g per day. Thus, further increases over this intake may have minimal or no additional effect on tissue ascorbic acid concentration, and hence disease risk. Ascorbic acid is a cofactor for several enzymes involved in the biosynthesis of neurotransmitters, collagen, and carnitine. Ascorbic acid has also been implicated in the catabolism of cholesterol to bile acids by the enzyme cholesterol 7α-monooxygenase and in the steroid metabolism in the adrenals. The role of ascorbic acid in these metabolic pathways is basically to reduce the central metal ion of the mono- and dioxygenases, acting as a cosubstrate in these reactions. Ascorbic acid is an important water-soluble antioxidant in biological fluids. Ascorbic acid scavenges reactive oxygen and nitrogen species, such as superoxide, hydroxyl, nitroxide and aqueous peroxyl radicals, singlet oxygen, ozone, peroxynitrite, nitrogen dioxide, and hypochlorous acid. Two major properties of ascorbic acid make it a strong antioxidant: (1) the low one-electron reduction potentials of both ascorbate and its one-electron oxidation product, the ascorbyl radical, which allows both forms to react with and reduce basically all physiologically relevant oxidants; (2) stability and low reactivity of the ascorbyl radical. The latter readily dismutates to form ascorbate and dehydroascorbic acid, or is reduced back to ascorbate by an NADH-dependent semidehydroascorbate reductase. Ascorbic acid can also act as a co-antioxidant by regenerating α-tocopherol from α-TO•, although in vivo, this interaction is not clear.

The effect of ascorbic acid on hypercholesterolemia has been investigated in numerous studies, although results are still controversial. In one supplementation study, consumption of 1.0 g of ascorbic acid per day for 4 weeks resulted in a reduction in total cholesterol, whereas in another study, supplementation with (0.060–6.0) g per day for 2 weeks had no effect. The positive effect of ascorbate may be related to its role as a cofactor for cholesterol 7α-monooxygenase, or, its modulating effect on HMGR. Several observational studies have found a significant association between elevated plasma ascorbic acid and increased concentrations of HDL-cholesterol and reduced concentrations of LDL-cholesterol. In relation to thrombosis, two studies found an inverse association between serum ascorbate concentrations and coagulation factors, as well as a positive association between low serum ascorbate and elevated coagulation activation markers. However, these effects were not confirmed by further studies. In-vitro studies have shown that physiologic concentrations of ascorbic acid increase PGE₁ (protaglandin E₁) and PGI₁ (prostacyclin) production, reducing platelet aggregation and thrombus formation. Low concentrations of ascorbate have also been associated with increased concentration of plasminogen activator inhibitor 1, a protein that inhibits fibrinolysis. High doses of ascorbate, administered either orally or by intra-arterial infusion, have shown beneficial effects on vasodilation. Four studies investigated vasodilation in patients with CVD and found increases of 45–220% in vasodilation after administration of ascorbate (1.0–2.0 g oral or 0.025 g min⁻¹ infusion). A 100% reversal of epicardial artery vasoconstriction was observed in coronary spastic angina patients infused with 0.010 g of ascorbate per minute. In the studies reporting an inverse association between plasma ascorbate and angina pectoris and CHD, the association was reduced after adjusting for smoking, suggesting that smokers may need additional ascorbic acid intakes. The possible mechanisms to explain the positive effect of ascorbate on vasodilation are related to its antioxidant activity and are suggested as the following: (1) ascorbate may spare •NO by scavenging superoxide radicals or preventing the formation of oxLDL; (2) maintenance of intracellular concentrations of glutathione by a sparing effect or regeneration of thiols from thyil radicals, which may enhance the bioavailability of •NO or increase the stabilization of •NO through the formation of S-nitrosothiols.

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Biology and Diseases of Guinea Pigs

Nirah H. Shomer DVM, PhD, DACLAM , ... John E. Harkness DVM, MS, MEd, DACLAM , in Laboratory Animal Medicine (Third Edition), 2015

Etiology

Hypovitaminosis C, known also as scorbutus or scurvy, is a multisystemic disease occurring in the small number of species (notably humans, some other primates, guinea pigs, and bats) that lack the genetic code to produce the hepatic enzyme l-gulonolactone oxidase. This enzyme converts l-gulonolactone into the isomers l-ascorbate (AH) and l-dehydroascorbic acid (DHA) (Marcus and Coulston, 1990). Probable primary roles of vitamin C are acting as a cofactor in hydroxylation and amidation reactions by transferring electrons to enzymes that provide reducing equivalents (i.e., protons) and scavenging both intracellular and extracellular superoxide radicals and singlet oxygen, whose activity results in tissue damage (Chakrabarty et al., 1992). Lack of vitamin C results in defective cross-linking of collagen fibrils characterized by defective wound healing and fragile capillaries.

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How Is Vitamin C Synthesized

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How Is Vitamin C Synthesized