Vitamin C: AA vs. DHA

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1		Francisco Nualart	+ 2142 word(s)	2142	2021-02-10 07:20:53	\|
2	format correct	Karina Chen	-4 word(s)	2138	2021-02-20 07:53:09	\|

This entry is adapted from the peer-reviewed paper 10.3390/antiox10020215

The reduced form of vitamin C (ascorbic acid, AA) is an essential micronutrient of small size; it is soluble in water and has two dissociable protons with pKa values of 4.2 and 11.8. At physiological pH, its reduced form predominates as the monovalent ascorbate anion (AA); when it loses the second proton, it is oxidized to dehydroascorbic acid (DHA). Most mammals can synthesize vitamin C from D-glucose in the liver, except guinea pigs, bats, and higher primates, including humans, due to the absence of the enzyme L-gulonolactone oxidase, which catalyzes the last step of the bio-synthesis of vitamin C . Therefore, to meet the body’s requirements, vitamin C must be incorporated into the diet. The best-known function of vitamin C is as an anti-oxidant agent that can act as a cofactor of enzymatic reactions involved in the synthe sis of catecholamines, carnitine, cholesterol, amino acids, and some hormonal peptides, as well as in the maintenance of brain function and the protection of central nervous system (CNS) structures .

AA uptake in different cells is performed by the sodium-ascorbate cotransporters SVCT1 and SVCT2, which stereospecifically transport the reduced form of vitamin C, L-ascorbate . Vitamin C can also be transported in its oxidized form, DHA, through the facilitative glucose transporters GLUT1, GLUT2, GLUT3, GLUT4, and GLUT8. However, for a long time, it has been postulated that the contribution of DHA to the accumulation of vitamin C in tissues is relatively low.

Vitamin C glucose transporters GLUTs dehydroascorbic acid

1. Molecular Pathways Regulated by Vitamin C

One of the first targets for vitamin C was discovered via its relationship to the NF‒κB pathway. In this pathway, vitamin C has an inhibitory function; in studies carried out in endothelial cells, millimolar doses of AA inhibited NF-κB and IL-8 activation in response to tumor necrosis factor (TNF) ^[1]. In this study, the authors also evaluated the toxicity generated by high doses of vitamin C supplementation and did not detect cell damage or lipid peroxidation ^[1]^[2]. Furthermore, they were able to determine that the inhibition of the NF-κB pathway was not due to the antioxidant activity of vitamin C, but rather to the direct inhibition of IκB kinase α/β (IKKα/β) ^[1]^[2]^[3]^[4]. In line with this notion, IKKα/β is a kinase responsible for the phosphorylation of IκBα protein that maintains NF-κB-p65 in the cytoplasm ^[5]. IκBα phosphorylation is a signal for proteasomal degradation of this protein, allowing NF-κB-p65 nuclear translocation, triggering the activation of specific genes ^[5]^[6]^[7]. In line with these findings, it was postulated that AA is a regulator of IKKα/β activity; however, subsequent studies determined that AA has no action on IKKα/β ^[3]^[8]. Interestingly, it was shown that DHA was a regulator of IKKα/β mediated by directly binding to this kinase, inhibiting it, and finally controlling the activity of NF-κB ^[8]. This function of DHA was determined through immunoprecipitation experiments using p-IκBα-GST where derivatives of vitamin C, AA, DHA, oxalic acid, and threonic acid were used. Only treatment with DHA inhibited IκBα-phosphorylation, and this inhibition was mediated by DHA directly blocking the activity of IKKα/β and p38, likely competing for the binding of ATP to the active site of IKKβ ^[3]^[8]. Given this evidence, it was concluded that vitamin C has a dual action against reactive oxygen species (ROS). Intracellularly, AA would fulfill its antioxidant function by neutralizing ROS, generating DHA. Thus, the intracellular accumulation of DHA would block the activation of NF-κB, involving vitamin C in signaling processes that control inflammatory responses and cell death among others.

Another kinase-dependent pathway that is regulated by vitamin C is that of the mitogen-activated protein kinases (MAPK), which involves three other MAPK-dependent pathways, extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 kinase, which are involved in proliferation, differentiation, and apoptosis, respectively ^[9]^[10]^[11]. The first studies examining the relationship between vitamin C and MAPK concluded that vitamin C was involved in in vitro cell death processes, but the mechanism of action was unknown. Thus, the possible regulation of MAPK-ERK mediated by vitamin C was analyzed. For this, leukemia cell lines were treated with AA (0-500 µM) for 1 to 3 h in order to analyze ERK activation by in vitro phosphorylation assays. In cells treated with concentrations as low as 100 μM AA, phosphorylation of ERK and therefore activation was induced ^[9]^[12]. Thus, it was proposed that the regulation of ERK mediated by vitamin C would be associated with eventual apoptotic processes that are observed in certain tumor lines when treated with vitamin C because ERK activation is associated with proliferative processes and cell death. However, to date, it has been shown that the use of pharmacological doses of AA induces tumor death from conventional necrosis due to the extracellular generation of H₂O₂ ^[13]^[14], as discussed in detail later. At the same time, it has also been shown that AA can antagonize apoptosis in cancer cells induced by classical mechanisms, such as treatment with doxorubidicin, TRAIL, or FAS ^[15]^[16]^[17]. In line with this notion, treatment with physiological doses of AA in neuronal cultures induces overexpression of antiapoptotic genes, such as Bcl-2, and decreases the expression of proapoptotic genes, such as Bax and caspase 8 ^[18]. Thus, the current evidence suggests that physiological doses of AA could inhibit apoptosis rather than activate this death pathway. Furthermore, AA-mediated ERK activation could be associated with neuronal arborization mechanisms, which would be an indicator of neuronal “good health” ^[9].

Subsequent studies have shown that vitamin C has a regulatory role on MAPK. Specifically, treatment with AA 60 μM for short periods of time (15‒20 min) induces epithelial cell proliferation that is dependent on the activation of ERK, but not p38 ^[19]. However, regulation of AA on MAPK seems to be dependent on its concentration and cell type; in melanoma cells treated with concentrations of 50‒500 μM AA, p38 phosphorylation increased, but no increase in ERK phosphorylation was observed ^[10]. Furthermore, treatment with 0.5‒1 mM AA could have an inhibitory effect on MAPK ^[20]^[21]. These data strongly suggest that there is a delicate balance between the dose of AA and the molecular target that is affected by the treatment. Given the accumulating evidence, it is tempting to speculate that, at low doses of AA, MAPK activation is favored, while at high doses, this pathway could be inhibited. Some of the main effects of vitamin C and the cell models used are summarized in Table 1. Thus, the role of vitamin C in the regulation of MAPK is unclear, because the literature has not been able to determine its specific role in this signaling pathway. This makes it difficult to propose a possible treatment against a pathology, where a therapy that includes pharmacological inhibitors or regulators of MAPK is used in conjunction with AA. What is clear, to date, is that AA is either a positive or negative regulator of MAPK not DHA, given that all experiments were carried out over short periods of time and under conditions where the oxidation of AA is not favored; thus, DHA apparently would not be involved in the regulation of MAPK/ERK.

2. Vitamin C as a Cell Cycle Regulator

The cell cycle is regulated by interactions between cyclins and cyclin-dependent kinases (cdk). The cyclin‒cdk complex is up- or downregulated by phosphorylation. When DNA damage occurs, cells can be arrested at the G1/S, S, or G2/M cell cycle checkpoints for DNA repair or to enter cell death processes ^[22]^[23]. In addition, AA has the ability to regulate the cell cycle directly. During periods of oxidative stress, AA can trigger cell cycle arrest at the S-phase checkpoint ^[24]. In line with this notion, a recent study in primary human fibroblasts showed that AA treatment decreased the expression of 31 genes ^[25]. Interestingly, of these 31 genes, 12 corresponded to tRNA synthetases and translation initiation factor subunits, which are required for cell cycle progression ^[25]. Strikingly, the effects on the cell cycle generated by vitamin C are frequently observed when it is used in combination with pro-oxidant molecules ^[26]^[27]^[28]^[29]. When AA was used in combination with agents that induce oxidative stress, growth was inhibited, and the cell cycle arrested at the G2/M checkpoint ^[30]. Co-incubation of AA together with pro-oxidant molecules triggered cell death, possibly due to necrosis ^[27]. This suggests that the effects observed and attributed to AA could possibly be triggered by DHA because, when AA is co-incubated with pro-oxidant molecules, it must neutralize ROS and oxidize to DHA. In addition, the treatments were generally for long periods of time and involved a single high-concentration supplementation, which would favor the oxidation of AA. Currently, there is evidence that supports the hypothesis that DHA could be the trigger for cell cycle arrest; when primary hepatocyte cultures were treated with AA, DNA synthesis and cell proliferation were observed ^[31]. However, when cells were treated with DHA, some proliferation was induced, but it was not sustained ^[31]. Thus, it is again unclear whether the impact of vitamin C on cell proliferation is due to AA or DHA. Thus, determining which form of vitamin C controls the regulatory functions of proliferation is essential before possible pharmacological use, such as its use as an antineoplastic.

Table 1. Molecular pathways regulated by vitamin C in different cell models.

Cell Type	Treatment	Effect	Ref.
ECV304, HUEVEC, HeLa.	AA/DHA	Inhibition translocation of NF-kB, inhibition phosphorylation of IkB	^[1]^[2]^[3]
MCF7, HL-60, HUVEC, HeLa.	DHA	Inhibition phosphorylation of IKKα/β and p38	^[3]^[8]
HL-60, NB4, NB4-R1, Neuro2a, HUVEC.	AA	Induction of ERK phosphorylation	^[9]^[12]
B16F10, HL-60.	AA/DHA	Activation of p38; suppression of p42/44	^[10]^[20]^[32]
MDA-MB-231.	AA	Arrest S-phase	^[24]
AS52 C8D1A.	AA/DHA	Arrest G₂/M	^[30]^[33]
Neuro2a, HT-1080.	AA	RIPK1 overexpression	^[18]^[34]

3. Vitamin C as an Enzymatic Cofactor

Epigenetic modifications are reversible changes that affect the genomic structure of DNA, which dictates the accessibility of transcriptional machinery to its sequence, thus regulating gene expression ^[35]. In particular, chromatin modifications include DNA methylation/demethylation and histone modification, which are introduced by the action of different enzymes. In this context, the influence of various metabolites on enzymatic activity has been widely described ^[36]. For example, different intermediaries of glycolysis and the citric acid cycle can introduce modifications, such as acetylation or methylation^[36]. In the same way, the action of various vitamins in the generation of epigenetic modifications has also been reported ^[37], indicating that these molecules would also play a role in enzymatic function. Particularly, vitamin C can act as a cofactor of the Fe²⁺ and 2-oxoglutarate (2-OG) family of dioxygenase enzymes ^[38], which includes important epigenetic regulators, such as Jumonji-C domain-containing histone demethylases (JHDMs) and TET hydroxylases, the latter associated with the conversion of 5-methylcytosine (5mC) into 5hydroxymethylcytosine (5hmC) in DNA ^[39].

Vitamin C deficiency generates scurvy, a condition in which collagen synthesis is mainly affected; it acts as a cofactor for proline hydroxylase and lysine hydroxylase ^[40], which are part of the Fe²⁺ and 2-OG-dependent dioxygenase family. Although they have various substrates, they share a conserved mechanism of action: a Fe²⁺ ion is coordinated at the enzyme's active site, which binds to 2-OG, permitting entry of the substrate and binding of an oxygen molecule ^[38]. Subsequently, the oxidative decarboxylation of 2-OG and the generation of ROS will oxidize the substrate and release secondary products ^[41]. In this context, vitamin C would be essential for maximum enzymatic activity, and it has been reported that the need for vitamin C in these reactions arises from its function as an electron donor to maintain an iron pool in its oxidation state +2 ^[42]^[43]. However, previous reports show that the effect of vitamin C is not reproduced in the presence of other antioxidant agents, and its direct interaction with the catalytic domain of TET enzymes has been described, which would indicate a specific role of vitamin C in the dioxygenase family ^[44]. Nonetheless, it should be noted that vitamin C has been associated with iron metabolism, increasing its uptake into the intracellular environment (and thus increasing the labile iron pool of Fe²⁺) ^[45]; therefore, vitamin C may be necessary for the maintenance of adequate levels of Fe²⁺.

Regarding the role of vitamin C in the action of epigenetic enzymes, one of the first analyses was performed on methylated oligonucleosomes in vitro, which were subjected to a histone demethylation reaction in the presence of a nuclear pellet obtained from HeLa cells. In these cells, the production of formaldehyde decreased by ~50% in the absence of vitamin C, indicating that it would be necessary for histone demethylase activity ^[46]. On the other hand, in vitro DNA demethylation assays in the presence of the catalytic domain of TET2 and different concentrations of vitamin C showed a progressive increase in 5hmC levels in relation to control conditions, an effect that was observed in a time-dependent manner, suggesting that vitamin C accelerates the hydroxymethylation reaction^[47]. Additionally, the incubation of vitamin C with the catalytic domain of TET2 showed a progressive extinction of the latter’s intrinsic fluorescence (determined by the presence of tyrosine residues that intrinsically fluoresce) in a concentration-dependent manner, thus suggesting a direct interaction between these two molecules^[47].

References

Bowie, A.G.; O’Neill, L.A. Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase. J. Immunol. 2000, 165, 7180–7188.
Bowie, A.; O’Neill, L.A. Vitamin C inhibits NF kappa B activation in endothelial cells. Biochem. Soc. Trans. 1997, 25, 131S.
Carcamo, J.M.; Pedraza, A.; Borquez-Ojeda, O.; Golde, D.W. Vitamin C suppresses TNF alpha-induced NF kappa B activation by inhibiting I kappa B alpha phosphorylation. Biochemistry 2002, 41, 12995–13002.
Abhilash, P.A.; Harikrishnan, R.; Indira, M. Ascorbic acid suppresses endotoxemia and NF-kappaB signaling cascade in alcoholic liver fibrosis in guinea pigs: A mechanistic approach. Toxicol. Appl. Pharmacol. 2014, 274, 215–224, doi:10.1016/j.taap.2013.11.005.
Yi, F.; Frazzette, N.; Cruz, A.C.; Klebanoff, C.A.; Siegel, R.M. Beyond Cell Death: New Functions for TNF Family Cytokines in Autoimmunity and Tumor Immunotherapy. Trends Mol. Med. 2018, 24, 642–653, doi:10.1016/j.molmed.2018.05.004.
Malek, R.; Borowicz, K.K.; Jargiello, M.; Czuczwar, S.J. Role of nuclear factor kappaB in the central nervous system. Pharma-col. Rep. 2007, 59, 25–33.
Engelmann, C.; Weih, F.; Haenold, R. Role of nuclear factor kappa B in central nervous system regeneration. Neural Regen. Res. 2014, 9, 707–711, doi:10.4103/1673-5374.131572.
Carcamo, J.M.; Pedraza, A.; Borquez-Ojeda, O.; Zhang, B.; Sanchez, R.; Golde, D.W. Vitamin C is a kinase inhibitor: Dehy-droascorbic acid inhibits IkappaBalpha kinase beta. Mol. Cell Biol. 2004, 24, 6645–6652, doi:10.1128/MCB.24.15.6645-6652.2004.
Salazar, K.; Martinez, M.; Ulloa, V.; Bertinat, R.; Martinez, F.; Jara, N.; Espinoza, F.; Bongarzone, E.R.; Nualart, F. SVCT2 Overexpression in Neuroblastoma Cells Induces Cellular Branching that is Associated with ERK Signaling. Mol. Neurobiol. 2016, 53, 6668–6679, doi:10.1007/s12035-015-9553-z.
Lee, S.A.; Son, Y.O.; Kook, S.H.; Choi, K.C.; Lee, J.C. Ascorbic acid increases the activity and synthesis of tyrosinase in B16F10 cells through activation of p38 mitogen-activated protein kinase. Arch. Dermatol. Res. 2011, 303, 669–678, doi:10.1007/s00403-011-1158-4.
Lei, F.X.; Jin, L.; Liu, X.Y.; Lai, F.; Yan, X.G.; Farrelly, M.; Guo, S.T.; Zhao, X.H.; Zhang, X.D. RIP1 protects melanoma cells from apoptosis induced by BRAF/MEK inhibitors. Cell Death Dis. 2018, 9, 679, doi:10.1038/s41419-018-0714-7.
Park, S.; Park, C.H.; Hahm, E.R.; Kim, K.; Kimler, B.F.; Lee, S.J.; Park, H.K.; Lee, S.H.; Kim, W.S.; Jung, C.W.; et al. Activation of Raf1 and the ERK pathway in response to l-ascorbic acid in acute myeloid leukemia cells. Cell Signal. 2005, 17, 111–119, doi:10.1016/j.cellsig.2004.06.006.
Chen, Q.; Espey, M.G.; Sun, A.Y.; Pooput, C.; Kirk, K.L.; Krishna, M.C.; Khosh, D.B.; Drisko, J.; Levine, M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. USA 2008, 105, 11105–11109, doi:10.1073/pnas.0804226105.
Chen, Q.; Espey, M.G.; Krishna, M.C.; Mitchell, J.B.; Corpe, C.P.; Buettner, G.R.; Shacter, E.; Levine, M. Pharmacologic ascor-bic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues. Proc. Natl. Acad. Sci. USA 2005, 102, 13604–13609, doi:10.1073/pnas.0506390102.
Heaney, M.L.; Gardner, J.R.; Karasavvas, N.; Golde, D.W.; Scheinberg, D.A.; Smith, E.A.; O’Connor, O.A. Vitamin C antago-nizes the cytotoxic effects of antineoplastic drugs. Cancer Res. 2008, 68, 8031–8038, doi:10.1158/0008-5472.CAN-08-1490.
Perez-Cruz, I.; Carcamo, J.M.; Golde, D.W. Vitamin C inhibits FAS-induced apoptosis in monocytes and U937 cells. Blood 2003, 102, 336–343, doi:10.1182/blood-2002-11-3559.
Perez-Cruz, I.; Carcamo, J.M.; Golde, D.W. Caspase-8 dependent TRAIL-induced apoptosis in cancer cell lines is inhibited by vitamin C and catalase. Apoptosis 2007, 12, 225–234, doi:10.1007/s10495-006-0475-0.
Ferrada, L.; Barahona, M.J.; Salazar, K.; Vandenabeele, P.; Nualart, F. Vitamin C controls neuronal necroptosis under oxida-tive stress. Redox Biol. 2020, 29, 101408, doi:10.1016/j.redox.2019.101408.
Ulrich-Merzenich, G.; Zeitler, H.; Panek, D.; Bokemeyer, D.; Vetter, H. Vitamin C promotes human endothelial cell growth via the ERK-signaling pathway. Eur. J. Nutr. 2007, 46, 87–94, doi:10.1007/s00394-006-0636-5.
Kim, H.N.; Kim, H.; Kong, J.M.; Bae, S.; Kim, Y.S.; Lee, N.; Cho, B.J.; Lee, S.K.; Kim, H.R.; Hwang, Y.I.; et al. Vitamin C down-regulates VEGF production in B16F10 murine melanoma cells via the suppression of p42/44 MAPK activation. J. Cell Biochem. 2011, 112, 894–901, doi:10.1002/jcb.22997.
Park, H.J.; Ock, S.M.; Kim, H.J.; Park, H.J.; Lee, Y.B.; Choi, J.M.; Cho, C.S.; Lee, J.Y.; Cho, B.K.; Cho, D.H. Vitamin C attenu-ates ERK signalling to inhibit the regulation of collagen production by LL-37 in human dermal fibroblasts. Exp. Dermatol. 2010, 19, e258-264, doi:10.1111/j.1600-0625.2010.01070.x.
Zinkel, S.; Gross, A.; Yang, E. BCL2 family in DNA damage and cell cycle control. Cell Death Differ. 2006, 13, 1351–1359, doi:10.1038/sj.cdd.4401987.
Nguyen, M.D.; Mushynski, W.E.; Julien, J.P. Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death Differ. 2002, 9, 1294–1306, doi:10.1038/sj.cdd.4401108.
El Banna, N.; Hatem, E.; Heneman-Masurel, A.; Leger, T.; Baille, D.; Vernis, L.; Garcia, C.; Martineau, S.; Dupuy, C.; Vagner, S.; et al. Redox modifications of cysteine-containing proteins, cell cycle arrest and translation inhibition: Involvement in vitamin C-induced breast cancer cell death. Redox. Biol. 2019, 26, 101290, doi:10.1016/j.redox.2019.101290.
Belin, S.; Kaya, F.; Duisit, G.; Giacometti, S.; Ciccolini, J.; Fontes, M. Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS ONE 2009, 4, e4409, doi:10.1371/journal.pone.0004409.
Martinotti, S.; Ranzato, E.; Parodi, M.; Vitale, M.; Burlando, B. Combination of ascor-bate/epigallocatechin-3-gallate/gemcitabine synergistically induces cell cycle deregulation and apoptosis in mesothelioma cells. Toxicol. Appl. Pharmacol. 2014, 274, 35–41, doi:10.1016/j.taap.2013.10.025.
Felipe, K.B.; Benites, J.; Glorieux, C.; Sid, B.; Valenzuela, M.; Kviecinski, M.R.; Pedrosa, R.C.; Valderrama, J.A.; Leveque, P.; Gallez, B.; et al. Antiproliferative effects of phenylaminonaphthoquinones are increased by ascorbate and associated with the appearance of a senescent phenotype in human bladder cancer cells. Biochem. Biophys. Res. Commun. 2013, 433, 573–578, doi:10.1016/j.bbrc.2013.03.028.
McConnell, M.J.; Herst, P.M. Ascorbate combination therapy: New tool in the anticancer toolbox? Sci. Transl. Med. 2014, 6, 222fs226, doi:10.1126/scitranslmed.3008488.
Alexander, B.; Fishman, A.I.; Eshghi, M.; Choudhury, M.; Konno, S. Induction of cell death in renal cell carcinoma with combination of D-fraction and vitamin C. Integr. Cancer Ther. 2013, 12, 442–448, doi:10.1177/1534735412473643.
Herst, P.M.; Broadley, K.W.; Harper, J.L.; McConnell, M.J. Pharmacological concentrations of ascorbate radiosensitize glio-blastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free. Radic. Biol. Med. 2012, 52, 1486–1493, doi:10.1016/j.freeradbiomed.2012.01.021.
Moteki, H.; Shimamura, Y.; Kimura, M.; Ogihara, M. Signal transduction pathway for L-ascorbic acid- and L-ascorbic acid 2-glucoside-induced DNA synthesis and cell proliferation in primary cultures of adult rat hepatocytes. Eur. J. Pharmacol. 2012, 683, 276–284, doi:10.1016/j.ejphar.2012.02.047.
Carcamo, J.M.; Borquez-Ojeda, O.; Golde, D.W. Vitamin C inhibits granulocyte macrophage-colony-stimulating fac-tor-induced signaling pathways. Blood 2002, 99, 3205–3212.
Bijur, G.N.; Briggs, B.; Hitchcock, C.L.; Williams, M.V. Ascorbic acid-dehydroascorbate induces cell cycle arrest at G2/M DNA damage checkpoint during oxidative stress. Environ. Mol. Mutagen. 1999, 33, 144–152.
Lorincz, T.; Holczer, M.; Kapuy, O.; Szarka, A. The Interrelationship of Pharmacologic Ascorbate Induced Cell Death and Ferroptosis. Pathol. Oncol. Res. 2019, 25, 669–679, doi:10.1007/s12253-018-0539-9.
Handy, D.E.; Castro, R.; Loscalzo, J. Epigenetic modifications: Basic mechanisms and role in cardiovascular disease. Circula-tion 2011, 123, 2145–2156, doi:10.1161/circulationaha.110.956839.
Lu, C.; Thompson, C.B. Metabolic regulation of epigenetics. Cell Metab. 2012, 16, 9–17, doi:10.1016/j.cmet.2012.06.001.
Huang, S.; Xu, YM.; Lau, A.T.Y. Epigenetic effects of the 13 vitamins. Curr. Pharmacol. Rep. 2018, 4, 453–467.
Kuiper, C.; Vissers, M.C. Ascorbate as a co-factor for fe- and 2-oxoglutarate dependent dioxygenases: Physiological activity in tumor growth and progression. Front. Oncol. 2014, 4, 359, doi:10.3389/fonc.2014.00359.
Melamed, P.; Yosefzon, Y.; David, C.; Tsukerman, A.; Pnueli, L. Tet Enzymes, Variants, and Differential Effects on Function. Front. Cell Dev. Biol. 2018, 6, 22, doi:10.3389/fcell.2018.00022.
Carr, A.C.; Frei, B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am. J. Clin. Nutr. 1999, 69, 1086–1107, doi:10.1093/ajcn/69.6.1086.
Farrow, S.C.; Facchini, P.J. Functional diversity of 2-oxoglutarate/Fe(II)-dependent dioxygenases in plant metabolism. Front. Plant. Sci. 2014, 5, 524, doi:10.3389/fpls.2014.00524.
Myllyla, R.; Majamaa, K.; Gunzler, V.; Hanauske-Abel, H.M.; Kivirikko, K.I. Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. J. Biol. Chem. 1984, 259, 5403–5405.
de Jong, L.; Albracht, S.P.; Kemp, A. Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron. The role of ascorbate in peptidyl proline hydroxylation. Biochim. Biophys. Acta 1982, 704, 326–332, doi:10.1016/0167-4838(82)90162-5.
Cimmino, L.; Neel, B.G.; Aifantis, I. Vitamin C in Stem Cell Reprogramming and Cancer. Trends Cell Biol. 2018, 28, 698–708, doi:10.1016/j.tcb.2018.04.001.
Lane, D.J.; Chikhani, S.; Richardson, V.; Richardson, D.R. Transferrin iron uptake is stimulated by ascorbate via an intracel-lular reductive mechanism. Biochim. Biophys. Acta 2013, 1833, 1527–1541, doi:10.1016/j.bbamcr.2013.02.010.
Tsukada, Y.; Fang, J.; Erdjument-Bromage, H.; Warren, M.E.; Borchers, C.H.; Tempst, P.; Zhang, Y. Histone demethylation by a family of JmjC domain-containing proteins. Nature 2006, 439, 811–816, doi:10.1038/nature04433.
Yin, R.; Mao, S.Q.; Zhao, B.; Chong, Z.; Yang, Y.; Zhao, C.; Zhang, D.; Huang, H.; Gao, J.; Li, Z.; et al. Ascorbic acid enhances Tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals. J. Am. Chem. Soc. 2013, 135, 10396–10403, doi:10.1021/ja4028346.

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1. Molecular Pathways Regulated by Vitamin C

2. Vitamin C as a Cell Cycle Regulator

3. Vitamin C as an Enzymatic Cofactor

References