Vitamin C
Ascorbate
Stem Cells
Chromatin Remodeling
DNA/Histone Demethylation
Enzyme Cofactor

Ten-Eleven Translocation (TET)
Dioxygenase
Sodium Dependent Vitamin C Transporter (SVCT)
Jumonji Domain Containing Histone Demethylases (JHDMs)

Epigenetic Regulation
Somatic/Stem Cells
Embryonic Stem Cells
Pluripotent Stem Cells (iPSCs)

DNA
Sugar Phosphate Backbone
Phosphodiester Bond

https://en.m.wikipedia.org/wiki/Sugar_phosphates

https://en.m.wikipedia.org/wiki/Phosphodiester_bond

https://en.m.wikipedia.org/wiki/DNA_synthesis

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Neuron-Astrocyte Ascorbate Recycling System

Vitamin C Function in the Brain: Vital Role of the Ascorbate Transporter (SVCT2)

https://pmc.ncbi.nlm.nih.gov/articles/PMC2649700/

Reprogramming the Epigenome With Vitamin C

https://pmc.ncbi.nlm.nih.gov/articles/PMC6646595/

Role of vitamin C and SVCT2 in neurogenesis

https://pmc.ncbi.nlm.nih.gov/articles/PMC10324519/

Vitamin C in Stem Cell Biology: Impact on Extracellular Matrix Homeostasis and Epigenetics

https://onlinelibrary.wiley.com/doi/10.1155/2017/8936156

Vitamin C alleviates aging defects in a stem cell model for Werner syndrome

https://pmc.ncbi.nlm.nih.gov/articles/PMC4930768/

Antioxidants N-Acetylcysteine and Vitamin C Improve T Cell Commitment to Memory and Long-Term Maintenance of Immunological Memory in Old Mice

https://pmc.ncbi.nlm.nih.gov/articles/PMC7699597/

Induced pluripotent stem cell

https://en.m.wikipedia.org/wiki/Induced_pluripotent_stem_cell

SVCTs are responsible for bringing vitamin C into the cell, where it acts as a cofactor for JHDMs, the enzymes that modify chromatin by removing methyl groups from histones.

Stem cell reprogramming: Vitamin C significantly enhances the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). This effect is mediated by the activation of JHDM1a/1b, which drives the removal of repressive H3K36 methylation marks to promote a more open, embryonic-like chromatin state.

Vitamin C influences chromatin fibers through its role as a vital cofactor for several enzymes that modify DNA and histones, which are the fundamental components of chromatin. These enzymatic reactions ultimately regulate gene expression by making chromatin more or less accessible.
Key enzymes influenced by vitamin C
As a cofactor, vitamin C enhances the activity of specific iron(II)- and α-ketoglutarate-dependent dioxygenase enzymes. Its mechanism is thought to involve converting iron(III) to the catalytically active iron(II) state at the enzyme's active site. Two major classes of enzymes that depend on vitamin C are:
Ten-eleven translocation (TET) enzymes: TET proteins (TET1, TET2, and TET3) initiate DNA demethylation, a process that can lead to gene activation.
They catalyze the oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC).
This starts a chain of reactions that ultimately removes the methyl group and replaces it with an unmethylated cytosine via the base excision repair pathway.
Enhanced TET activity due to vitamin C promotes DNA demethylation, making the chromatin more open and transcriptionally active.
Jumonji-C (JmjC) domain-containing histone demethylases (JHDMs): These enzymes remove methyl groups from histone proteins, which can have diverse effects on gene expression.
Vitamin C promotes the activity of specific JHDMs, leading to histone demethylation. For example, it helps demethylate histone H3 at lysine 9 (H3K9me2), a repressive mark that typically keeps chromatin condensed.
By removing these repressive marks, vitamin C can facilitate the transition to a more open chromatin state that is conducive to transcription.

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controlling the accessibility of bone-specific genes. It also plays a role in neurodevelopment and myogenesis (muscle formation).
Prevention of disease: Chromatin dysregulation is a hallmark of many diseases, including cancer. Vitamin C's ability to modulate epigenetic enzymes is being explored for its potential therapeutic benefits, particularly in resetting the aberrant epigenetic patterns seen in some cancers.

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Ascorbic acid 2-sulfate (AAS) is a naturally occurring, more stable derivative of vitamin C where a sulfate group is attached to the second carbon of the ascorbic acid molecule. This modification enhances its stability, bioavailability, and ability to function as a long-lasting vitamin C source.

AAS is not directly biologically active but functions as a pro-vitamin. It is hydrolyzed by specific enzymes (like sulfatases) to release active L-ascorbic acid.

Direct conversion to a sulfate ester
In some organisms, vitamin C can be converted into a more stable compound called L-ascorbic acid 2-sulfate (AAS).
Production: This reaction involves the addition of a sulfate group to the second carbon of the ascorbic acid molecule. In mammals, this occurs through the action of a sulfotransferase enzyme, primarily in the liver.
Stability and role: Ascorbic acid 2-sulfate is more stable against oxidation than pure vitamin C. Its exact biological role is not fully established in humans. However, in some animals like fish, it serves as a long-term, stable source of vitamin C. An enzyme called L-ascorbic acid 2-sulfate sulfohydrolase (C2 sulfatase) can later remove the sulfate group to release active vitamin C.
Metabolic pathway: AAS is considered a phase II metabolite of vitamin C in humans, and it has been shown to donate its sulfate group in the body, such as in the formation of cholesterol sulfate.

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The transformation process Enolization: In an alkaline solution, a base removes a proton from the carbon atom adjacent to the carbonyl group (carbon) of the sugar.

Enediol intermediate: This proton abstraction leads to the formation of a negatively charged enolate intermediate. The rearrangement of electrons in this intermediate creates a double bond between the two central carbon atoms and two adjacent hydroxyl groups, forming an enediol.

Tautomerization: The unstable enediol intermediate can then rearrange to form a more stable keto or aldose form of the sugar. Since the enediol is a common intermediate, it can lead to different sugars.

Glucose to fructose: The enediol intermediate formed from glucose can revert to fructose (a ketose sugar) or revert back to glucose.

Glucose to mannose: The same enediol can also isomerize to mannose, an epimer of glucose. Role of the enediol structure in reducing sugars An enediol is a potent reducing agent because it is easily oxidized.

Oxidation reaction: The enediol intermediate readily donates electrons to an oxidizing agent, causing the sugar to be oxidized to a carboxylic acid.

Enediol functionality: Ascorbic acid is a lactone of 2-ketogluconic acid and features an adjacent enediol group.
Source of reducing power: This enediol structure is responsible for the potent antioxidant and reducing properties of Vitamin C. It readily donates two electrons to neutralize free radicals and reactive oxygen species.

The Reichstein process is the historical method for commercial Vitamin C synthesis, involves converting glucose to sorbitol, then L-sorbose, and finally oxidizing it to 2-oxo-L-gulonic acid, which is then enolized to form ascorbic acid.

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Histone acetylation (adding acetyl groups) generally promotes gene expression by loosening the chromatin structure, while deacetylation (removing acetyl groups) generally represses gene expression.

Histone acetylation generally leads to a looser chromatin structure and activated gene expression, whereas the removal of methyl groups (demethylation), often in the context of DNA demethylation, can also activate genes by relaxing chromatin to allow transcription factors access to the DNA.

Histone acetylation is a process where histone acetyltransferases (HATs), also known as Lysine Acetyltransferases (KATs), transfer an acetyl group from acetyl-CoA (Ac-CoA) to specific lysine residues on histone proteins. This post-translational modification reduces the positive charge of the histones, leading to chromatin relaxation and promoting gene transcription.

Acetylation pathways: Acetyl-CoA is the primary donor of acetyl groups for acetylation, another crucial epigenetic modification. While vitamin C does not directly interact with acetyl-CoA, its influence on the opposing process of methylation highlights the broad impact of epigenetic regulation on metabolism.

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Vitamin B3 (niacin) is involved in over 400 enzyme reactions, and magnesium is a cofactor for over 600 enzymatic reactions. This makes them two of the most critical elements in human metabolism, playing distinct but interconnected roles in cellular functions like energy production, DNA repair, and gene expression.

Vitamin B3 Niacin is involved in a vast number of enzyme-catalyzed reactions—totaling over 500, according to some estimates.

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High-dose intravenous (IV) vitamin C, or ascorbic acid, generates hydrogen peroxide ((H_{2}O_{2})) that can kill cancer cells in laboratory and animal studies. The (H_{2}O_{2}) selectively damages tumor cells, which have a reduced capacity to neutralize it compared to healthy cells.

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Vitamin C has a longer half-life of roughly 10-20 days in the body's total pool, but this is not a reflection of its presence in the brain, which maintains high concentrations for longer periods through recycling mechanisms like the one involving glutathione in astrocytes. The brain actively pumps and retains ascorbate, even when plasma levels are low, and the duration of vitamin C depletion significantly impacts brain concentrations.

Recycling and Retention:

The brain is particularly adept at retaining vitamin C. It does so by recycling ascorbate (the reduced form of vitamin C) using glutathione and the pentose phosphate pathway in astrocytes.

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Magnesium-Dependent Enzymes: Lithium's mood-stabilizing and toxic effects are thought to stem partly from its ability to interfere with various enzymes that rely on magnesium for their function, such as adenylate cyclase and ATP-magnesium.