---
# System prepended metadata

title: Vitamins
tags: [vitamins, page]

---

---
breaks: True
title: Vitamins
disqus: hackmd
---
Vitamins
===
:::success
> Documentation [name=MrDr.Staffan]
###### tags: `page`, `vitamins`
:::

:::danger
Code snippet

    align, &nbsp;, <br/>
:::spoiler


<p style="text-align:left;">
    1EJI - Mouse
    <span style="float:right;">
        1BJ4 - Human
    </span>
</p>

a&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;b

<br/>
<br/>
:::

<br>

:::info
### Table of Contents
[TOC]
:::
[Top](#Table-of-Contents)

**Why this page?**

Vitamin A
Vitamin B
Vitamin C
Vitamin D
Vitamin E
Vitamin K

 your-text-here



---
# General
[Top](#Table-of-Contents)

##  Chemical names




 ![](https://i.imgur.com/RpdGZBH.png)
## Solubility & Stability
![](https://i.imgur.com/BpnACMB.png)

Fat soluble: A, D, E, K
Water soluble: C, B1, (B2), B3, B5, B6, (B7), B9, B12

## Maximum RDI set
A, D, E, B3, B6, B9


## Transport


# Vitamin A
[Top](#Table-of-Contents)

[See RA](https://hackmd.io/@sholmqvist/BJpKurTBB/%2F0PlaL5-7R3qAUZYVeGXbmg)

[See Intracellular signaling](https://hackmd.io/@sholmqvist/BJpKurTBB/https%3A%2F%2Fhackmd.io%2FHi_KrVDMS72extkwqJfUJw#Retinoid-signaling)

[See Aldh1a1,2,3](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FEw8b0ZyLQ3y-vlsYE6rWeQ#ALDH1A1)

[See Aldh8a1](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FEw8b0ZyLQ3y-vlsYE6rWeQ#ALDH8A1)


"all-trans-Retinol, Retinals, and
alternative provitamin A-functioning Carotenoids including all-trans-beta-carotene"

## Detecting retinols (methods)
 detection of retinoic acid synthesizing enzymes in the central nervous system

https://www.sciencedirect.com/science/article/pii/S0076687920301221

Chapter Six - Use of fixatives for immunohistochemistry and their application for


## Retinyl acetate (retinol acetate, vitamin A acetate)
B27 without vitamin A, neccesity in many differentiation protocols.
vitamin A (retinyl acetate)


## The Biological Effects of Retinoids on Cell Differentiation and Proliferation
https://sci-hub.se/10.1515/cclm.1988.26.8.479


## A-Deficiency
[Top](#Table-of-Contents
Night blindness, hyperkeratosis, and keratomalacia[9]

## A-Overdose?
[Top](#Table-of-Contents)
Hypervitaminosis A

## Genes

### RA metabolism
Rbp1 // CRBP1 // Cellular Retinol Binding Protein 1
LRAT Lecithin Retinol Acyltransferase
Bco1 // Cmo1 // Beta-Carotene Oxygenase 1

RetinOL dehydrogenase
(alcohol dehydrogenase = produce aldehydes)
RDH10
RDH11
RDH12
RDH13
RDH14
RDH16
RDH5
RDH8
RetinAL dehydrogenase RALDH genes Ald1a1 Aldh1a2 Aldh1a3
(aldehyde dehydrogenase = produce carboxy acids) 
[![](https://i.imgur.com/BHMgO4C.png)](https://pubmed.ncbi.nlm.nih.gov/21515404/)
Beta-carotene
![](https://i.imgur.com/vxC4uN5.png "Beta-carotene")

### RA inactivation
Cytochrome P450 proteins are monooxygenases
![](https://i.imgur.com/zzjVcCt.png =500x)

**Cyp26a1** Cytochrome P450 Retinoic Acid-Inactivating

- Catalyzes the hydroxylation of carbon hydrogen bonds of atRA primarily at C-4 and C-18. 
- **Substrate preference**: No activity toward 9-cis and 13-cis retinoic acid stereoisomers (PubMed:22020119, PubMed:9228017, PubMed:9716180).


**Cyp26b1** Cytochrome P450 Retinoic Acid-Inactivating
- Localized to the endoplasmic reticulum
- Germ cell development: acts by degrading RA in the developing testis, **preventing STRA8 expression** [see receptors below](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FVRxXizYGTSmR_hDbuSI8LQ#Retinoic-acid-receptors)
- Catalyzes the hydroxylation of carbon hydrogen bonds of atRA primarily at C-4 (PubMed:10823918, PubMed:22020119)
- Skeletal development, role both at the level of patterning and in the ossification of bone and the establishment of some synovial joints (PubMed:22019272)
- **Substrate preference**: all-trans-RA > 9-cis-RA > 13-cis-RA

**Cyp26c1** Cytochrome P450 Retinoic Acid-Inactivating
- Focal Facial Dermal Dysplasia
- **Substrate preference**: Acts on retinoids, including all-trans-retinoic acid (RA) and its stereoisomer 9-cis-RA (preferred substrate)


### **RBPs Retinol-binding protein**
"Cellular: RBP1, RBP2, RBP5, RBP7
Interstitial: RBP3
Plasma: RBP4"

Crabp1 // RBP5 Cellular Retinoic Acid Binding Protein 1
Crabp2 // RBP6 Cellular Retinoic Acid Binding Protein 2
Rbp7 // CRABP4

![](https://i.imgur.com/83HiRgi.png =500x)


||||
|-|-|-
|**Rbp1**<br> Nucleus Accumbens|[![Rbp1](https://i.imgur.com/5aYOM1C.jpg =200x)](http://mouse.brain-map.org/experiment/siv?id=68076899&imageId=68005433&initImage=ish&coordSystem=pixel&x=4996&y=5548&z=3)|![](https://i.imgur.com/H2ZnXsO.png =200x)
|**Rbp2**<br> Cortex|[![Rbp2](https://i.imgur.com/XNyxaIP.png =200x)](http://mouse.brain-map.org/experiment/siv?id=69818042&imageId=69785674&initImage=ish&coordSystem=pixel&x=7722&y=1202&z=4)|![](https://i.imgur.com/BlsIVZH.png =200x)
|Rbp3|[![(none?)](https://i.imgur.com/1GZTOLj.png =200x)](http://mouse.brain-map.org/experiment/siv?id=68342360&imageId=68021041&initImage=ish&coordSystem=pixel&x=6540&y=5940&z=3)| n/a
|**Rbp4**<br> Cortex|[![Rbp4](https://i.imgur.com/37xyA76.jpg =200x)](http://mouse.brain-map.org/experiment/siv?id=68632655&imageId=68212486&initImage=ish&coordSystem=pixel&x=4124&y=3204&z=3)|![](https://i.imgur.com/q1w6wBA.png =200x)
|**Rbp5** // **Crabp1** <br> Hypothalamus|[![Crabp1](https://i.imgur.com/4NSlOR9.jpg =200x)](http://mouse.brain-map.org/experiment/siv?id=1179&imageId=101358838&initImage=ish&coordSystem=pixel&x=2566&y=2418&z=2)|![](https://i.imgur.com/vSTiMsV.png =200x)<br> ![](https://i.imgur.com/UkA3QUG.png =200x) Htr3b (Serotonin) Tmem215
|Rbp6 // Crabp2|[![](https://i.imgur.com/IgoOkAE.png =200x)](http://mouse.brain-map.org/experiment/siv?id=68076913&imageId=68005844&initImage=ish&coordSystem=pixel&x=3372&y=3700&z=3)|![](https://i.imgur.com/WQomtNZ.png =200x)
|Rbp7 // Crabp4|[![](https://i.imgur.com/opjo6SM.jpg =200x)](http://mouse.brain-map.org/experiment/siv?id=68545057&imageId=68161734&initImage=ish&coordSystem=pixel&x=4112.5&y=2808.5&z=1)|![](https://i.imgur.com/HIEyVUo.png =200x)

 ***Bold** = peculiar expression pattern


### **Retinoic acid receptors**

Rara Retinoic Acid Receptor Alpha
Rarb Retinoic Acid Receptor Beta
Rxra Retinoid X Receptor Alpha


Stra6 Signaling Receptor And Transporter Of Retinol Stra 6
Stra8 Stimulated By Retinoic Acid 8

BHLHE41 // **Stra13** // Sharp1 - acts as retinoid receptor coexpressors - Astro & Oligo
BHLHE40 // Sharp2 - acts as retinoid receptor coexpressors

CENPX // **STRA13** - Stimulated By Retinoic Acid Gene 13 Protein Homolog

Nr1h3 / LXRA

Nr1h2 / LXRB

Rora	RAR Related Orphan Receptor A
**Rorb** 	RAR Related Orphan Receptor B
Rorc



![](https://i.imgur.com/GD41KtM.png =500x)
![](https://i.imgur.com/O6STJ1n.png =500x)
![STRA13 // Bhlhe41](https://i.imgur.com/IN4Buyh.png =150x)
STRA13 // CENPX? = Some oligo, Fibroblasts, (Tanycytes OPC/NG2)
BHLHE41 = not the same? See Campbell
![](https://i.imgur.com/w7zLp85.png)
BHLHE40 = Tany, ParsT, Ependyme

### **Retinol dehydrogenases**
 Rdh1 Rdh5 Rdh7 Rdh8 Rdh9 Rdh10 Rdh11 Rdh12 Rdh13 Rdh14
Dhrs9 // RDH15 Rdh16 Rdh19
![](https://i.imgur.com/vWnTxP3.png =500x)
![](https://i.imgur.com/WwE90jm.png =500x)


### Others
Lrat Cyp2w1 Rpe65 Bco1 Bco2 cd36


Lrat Lecithin retinol acetyl transferase

Rlbp1
Cyp2w1 involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein

RPE65 Retinoid Isomerohydrolase RPE65
Bco2 Beta-Carotene Oxygenase (see below)

Ttr Transthyretin involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein

[#TTR also marks a subtype of Pomc neurons in Hypothalamus]
[See Pomc](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FzYBouPLtQPCuuhgcVhhYtA#Pomc)

![](https://i.imgur.com/FvF6oeU.png =500x)



### Retinol GO terms
Accession: GO:0034632
Name: retinol transmembrane transporter activity
Members Mus: 2

Rbp4
Stra6

Accession: GO:0016918
Name: retinal binding
Members Mus: 21 (16 unique)

Cyp2w1 Rbp7 **Rlbp1** **Rho** Rbp3 Rbp2 **Rbp1** Opn3 Akr1b10 
Opn5 Adh4 Aldh1a2 Stra6 Crabp2 Crabp1 Opn4

![](https://i.imgur.com/OHyv97c.png =500x)
![](https://i.imgur.com/Xsc7SdS.png =500x)



Accession: GO:0019841
Name: retinol binding
Members Mus: 20 (14 unique)

Cyp2w1 Rbp7 Adh7 Rlbp1 Rbp3 Rbp2 Rbp1 Rbp4 Adh4 Stra6
 C8g Crabp2 Crabp1 Lrat

![](https://i.imgur.com/lxtU5PW.png =500x)
![](https://i.imgur.com/xQcna3l.png =500x)



## Retinol Beta-caroten Obesity and Oxygenase 
[# Should look up the phylogeny of oxygenases. Also a dioxygenase such as Bbox1]
https://www.mdpi.com/2072-6643/11/4/842/htm
![](https://i.imgur.com/B6TMKNS.jpg)
Bco1

![](https://i.imgur.com/T68qaeR.png =300x)![](https://i.imgur.com/RLBd0fn.png =300x)


NinaB  https://www.pnas.org/content/105/48/19000.full

    Evidence from cell culture systems has implicated that the retinal pigment epithelium protein of 65 kDa (RPE65) is the long-sought all-trans to 11-cis retinoid isomerase. RPE65 is structurally related to nonheme iron oxygenases that catalyze the conversion of carotenoids into retinoids

---

![](https://hackmd.io/_uploads/SysYYFOxp.png)


---

# Vitamin B~1~
[Top](#Table-of-Contents)
"Thiamine"
[**Also see co-factors**](https://hackmd.io/@sholmqvist/BJpKurTBB/%2Ff7Jt1byBR7-a4DdZjX8q2g#Thiamine-pyrophosphate-TPP-vitamin-B1)

## B~1~-Deficiency
Beriberi, Wernicke-Korsakoff syndrome
## B~1~-Overdose
Drowsiness and muscle relaxation

Thiamine diphosphate (**ThDP**), or cocarboxylase

**Slc19a2** (oldhs neuron?)
High-affinity transporter for the intake of thiamine (+Folate?) 
**Slc19a3** (oldhs astro?)
Mediates high affinity thiamine uptake, probably via a proton anti-port mechanism. Has no folate transport activity.

[Slc19a1 - Folate transporter] (oldhs astro?)

**Tpk1**

Slc25a19 - Mitochondrial Thiamine carrier



TPP works as a coenzyme in many enzymatic reactions, such as:

Pyruvate dehydrogenase complex[6]
Pyruvate decarboxylase in ethanol fermentation
Alpha-ketoglutarate dehydrogenase complex
Branched-chain amino acid dehydrogenase complex
2-hydroxyphytanoyl-CoA lyase
Transketolase

Thiamine pyrophosphate is synthesized in the cytosol and is required in the cytosol for the activity of transketolase and in the mitochondria for the activity of pyruvate-, oxoglutarate- and branched chain keto acid dehydrogenases


# Vitamin B~2~
[Top](#Table-of-Contents)
"Riboflavin"

## B~2~-Deficiency
Ariboflavinosis, glossitis, angular stomatitis



# Vitamin B~3~
[Top](#Table-of-Contents)
"Niacin, Niacinamide, Nicotinamide riboside"
Pyridine-3-carboxylic acid

[See Metabolic disease - Pellagra](https://hackmd.io/@sholmqvist/BJpKurTBB/https%3A%2F%2Fhackmd.io%2F8k_yTptWSpOPAjBttu6Ypg#Pellagra)

[See Co-factors**](https://hackmd.io/@sholmqvist/BJpKurTBB/%2Ff7Jt1byBR7-a4DdZjX8q2g#Vitamin-B3-NAD--NAD)

![](https://i.imgur.com/SPzojsE.png =100x)

[Do pi-orbitals/aromaticity make metabolites more difficult to handle?]


<iframe style="width: 500px; height: 300px;" frameborder="0" src="https://embed.molview.org/v1/?mode=balls&cid=938"></iframe>

## B~3~-Deficiency
Pellagra
## B~3~-Overdose
Liver damage (doses > 2g/day)[11] and other problems

Nicotinamide riboside was identified as a form of vitamin B3 in 2004

Loosely Vitamin b3 complex.

    Amounts far in excess of the recommended dietary intake for vitamin functions will lower blood triglycerides 
    and low density lipoprotein cholesterol (LDL-C), and raise blood high density lipoprotein cholesterol 
    (HDL-C, often referred to as "good" cholesterol)

[See Cholesterol](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FgRCfhM49T-yl7l8wFSN1sQ)

NAD+ (is used for catabolic processes as an oxidizing agent)
[See NAD+ in RedOx state](https://hackmd.io/@sholmqvist/BJpKurTBB/https%3A%2F%2Fhackmd.io%2FSfqcAU4uTK-tBuX41qqFrg#NADPH-amp-NADH)

## Niacin precursor for NAD
Niacin - precursor for nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), niacin is involved in DNA repair and calcium mobilization.

![](https://hackmd.io/_uploads/Hyw-m2EOn.png =200x) ![](https://hackmd.io/_uploads/S1MNQ3Nd3.png =200x)
NAD & NADP

![](https://hackmd.io/_uploads/r1lzLnEuh.png =400x)

NAD is adenine+phosphoribose dimerized with 
![](https://hackmd.io/_uploads/H1kkw2Vu3.png =200x)

Both NAD+ and NADH strongly absorb ultraviolet light because of the adenine. For example, peak absorption of NAD+ is at a wavelength of 259 nanometers (nm), with an extinction coefficient of 16,900 M−1cm−1.

Adenine forms several tautomer forms.

![](https://hackmd.io/_uploads/HJ0hwh4uh.png)

The structure of cyclic ADP-ribose
















# ???
![](https://i.imgur.com/e85QVFc.png)
Yu et al 2020   
**Genes**

    Nadk  Nadk2  Sarm1  Bst1  cd38  Nadsyn1   nmnat1 nmnat2   nmnat3  nampt  nmrk1  nmrk2  nampt naprt   naxe naxd  Nqo1 Nqo2  Parp1 Sirt1
    
![](https://i.imgur.com/SsllR6J.png)
![](https://i.imgur.com/QjWoP2P.png)
Naxe + naxd not found

Naprt
cd38
Nqo1

**Sirtuins**
"proteins that possess either mono-ADP-ribosyltransferase, or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity"


[**Also see Sirts in Histones**](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FFTG3zDLIRjOQtrWE2DD6gg#Histone-deacetylase-HDACs)

[**Also see Sirts in FA metabolism**](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FLviQI1LDRae6qatO08KKLQ#Sirts-Sirtuins)

![](https://i.imgur.com/txAgdEN.png)
![](https://i.imgur.com/wFXWrWm.png)
Hdac8 - astrocytes
Sirt2 - oligo

Hdac2 (HsBarres astro)
Hdac4 (HsBarres astro)

**Parps** Poly (ADP-ribose) polymerase

*PARP // COL11A2 is differen*t

![](https://i.imgur.com/Odnlr42.png)
![](https://i.imgur.com/92jK3ca.png)
parp1 parp2 parp3 parp4 parp6 parp8 parp9 parp10 parp11 parp12 

Parp11 (astro HsBarres)

Tiparp (Parp7) Zc3hav1 (Parp13) parp14  parp16

Tnks (Parp5a)
Tnks2 (Parp5b)


# Vitamin B~5~
[Top](#Table-of-Contents)
"Pantothenic acid"
![](https://i.imgur.com/C3rkLcY.png =150x)
<iframe style="width: 500px; height: 300px;" frameborder="0" src="https://embed.molview.org/v1/?mode=balls&cid=6613"></iframe>

All animals require pantothenic acid in order to synthesize coenzyme A


## B~5~-Deficiency
Paresthesia
## B~5~-Overdose
Diarrhea; possibly nausea and heartburn.[12]


# Vitamin B~6~
[Top](#Table-of-Contents)

[Also see co-factors](https://hackmd.io/@sholmqvist/BJpKurTBB/%2Ff7Jt1byBR7-a4DdZjX8q2g#Vitamin-B6-Pyridoxal-phosphate-PLP)

"Pyridoxine, Pyridoxamine, Pyridoxal,Pyridoxal phosphate"
<iframe style="width: 500px; height: 300px;" frameborder="1" src="https://embed.molview.org/v1/?mode=balls&cid=1054"></iframe>
## B~6~-Deficiency
Anemia,[13] Peripheral neuropathy
## B~6~-Overdose
Impairment of proprioception, nerve damage (doses > 100 mg/day)

# Vitamin B~7~ Biotin
[Top](#Table-of-Contents)
"Biotin"

[See TCA - Anaplerotic](https://hackmd.io/@sholmqvist/BJpKurTBB/%2F2wsa_kXnQQ2p8vUIrTj-_w#Anaplerotic)

![](https://hackmd.io/_uploads/rkWbQtKT3.png =200x)

Biotinylation of histone proteins in nuclear chromatin is a posttranslational modification that plays a role in chromatin stability and gene expression.[4][7]


The enzyme holocarboxylase synthetase (HLCS) covalently attaches biotin to five human carboxylase enzymes:[4]

Acetyl-CoA carboxylase alpha (ACC1)
Acetyl-CoA carboxylase beta (ACC2)
Pyruvate carboxylase (PC)
Methylcrotonyl-CoA carboxylase (MCC)
Propionyl-CoA carboxylase (PCC)

For the first two (**ACC1,2**), biotin serves as a cofactor responsible for transfer of bicarbonate (HCO3) to **acetyl-CoA**, converting it to malonyl-CoA for fatty acid synthesis.
[Acetyl-CoA "fuel" absorbs dissolved CO2, for FAs.]


PC participates in gluconeogenesis.
CO2
[Pyruvate absorbs CO2 and expands TCA forming Oxaloacetat.]

MCC catalyzes a step in leucine metabolism.

PCC catalyzes a step in the metabolism of propionyl-CoA.[1][3][4]

Metabolic degradation of the biotinylated carboxylases leads to the formation of biocytin. 

![](https://hackmd.io/_uploads/Hku6MtF6n.png)
ε-Biotinoyl-L-Lysine

![](https://hackmd.io/_uploads/Sy22tKFa2.png)




## B~7~-Deficiency
Dermatitis, enteritis



# Vitamin B~9~
[Top](#Table-of-Contents)
"Folates, Folic acid"
![](https://i.imgur.com/9DwmHv4.png =200x)

<iframe style="width: 500px; height: 300px;" frameborder="0" src="https://embed.molview.org/v1/?mode=balls&cid=135444742"></iframe>


Tetrahydrofolate is a soluble coenzyme (vitamin B9) that is synthesized de novo by plants and microorganisms, and absorbed from the diet by animals. It is composed of three distinct parts: a pterin ring, a p-ABA (p-aminobenzoic acid) and a polyglutamate chain with a number of residues varying between 1 and 8. Only the tetra-reduced form of the molecule serves as a coenzyme for C1 transfer reactions. In biological systems, the C1-units exist under various oxidation states and the different tetrahydrofolate derivatives constitute a family of related molecules.


## B~9~-Deficiency
Megaloblastic anemia and deficiency during pregnancy is associated with birth defects, such as neural tube defects
## B~9~-Overdose?
May mask symptoms of vitamin B12 deficiency; other effects.

## Biosynthesis
Synthesis by SHMT Serine hydroxymethyltransferase

<iframe style="width: 247px; height: 300px; float:left" frameborder="1" src="https://embed.molview.org/v1/?mode=balls&pdbid=1EJI&chainType=cylinders&chainColor=spectrum"></iframe> <iframe style="width: 247px; height: 300px; margin-left: 2px;" frameborder="1" src="https://embed.molview.org/v1/?mode=balls&pdbid=1BJ4&chainType=cylinders&chainColor=spectrum"></iframe>


<p style="text-align:left;">
    1EJI - Mouse
    <span style="float:right;">
        1BJ4 - Human
    </span>
</p>
a

<br/>
<br/>

a&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;b

# Vitamin B~12~
[Top](#Table-of-Contents)
"Cyanocobalamin, Hydroxocobalamin, Methylcobalamin, Adenosylcobalamin"

## B~12~-Deficiency
Vitamin B12 deficiency anemia[14]





# Vitamin C
[Top](#Table-of-Contents)
[See Evolution of Humans](https://hackmd.io/@sholmqvist/BJpKurTBB/%2F_nRvA-YUSomXntMLaaOJsw#65-Ma-Vitamin-C)



"Ascorbic acid // Ascorbate"

A six carbon almost fully hydroxylated.


:::info
[The loss of a gene can also be that the Product happens to become produced without the requirement of the enzyme. This would mean the enzymes synthesis is no longer needed.] 

[You cant look at cells using a purely abstract model composed of perfect pathways. You need to take into account, chaotic interactions and the flow of metabolites at any given time.]

[Hence in the cellar context a gene can perform a metabolic role, but it's presence in the genome doesn't mean it is always employed].

[If something remains, unused for a long period of time. It will likely mutate and be lost. If an enzyme for producing a specific scarce metabolite suddenly is no longer used, beacuse the animal found an unprescedented dietary source of this metabolite, then that gene if unused may disapear.]

[Metabolites naturally forming in one compartment of the cell, but requires an enzymatialLy lowered threshold in another setting.]
:::





[Also see Glut1](https://hackmd.io/@sholmqvist/BJpKurTBB/https%3A%2F%2Fhackmd.io%2FcB6TLk1tRfGw4PTQCKuhJg#Slc2a1-Glut1)

[Also see co-factors](https://hackmd.io/@sholmqvist/BJpKurTBB/%2Ff7Jt1byBR7-a4DdZjX8q2g#Vitamin-C)

![](https://i.imgur.com/xPpOlKz.png =300x) ![](https://hackmd.io/_uploads/H1De8CKZT.png)
Ascorbate & DHA dehydroascorbate

Many plants produce vitamin C. The interconversion of co2 by synligt into Sugars is near the formation of vitamin c.
Use in plants. Not as an antioxidant but as a natural product. Heavily oxygenate






## Transport

**Transport to mitochondria**

Vitamin C accumulates in mitochondria, where most of the free radicals are produced, by entering as DHA through the glucose transporter GLUT10. Ascorbic acid protects the mitochondrial genome and membrane.[3]

**Transport across BBB**

Vitamin C does not pass from the bloodstream into the brain, although the brain is one of the organs that have the greatest concentration of vitamin C. Instead, DHA is transported through the blood–brain barrier via GLUT1 transporters, and then converted back to ascorbate.[8]

Transport into cells

In a cell culture growth medium, dehydroascorbic acid has been used to assure the uptake of vitamin C into cell types that do not contain ascorbic acid transporters.[13]
Slc23a1 Slc23a2





semidehydroascorbic acid is a radical.

## Vitamin C Brain and CSF levels



[![](https://hackmd.io/_uploads/ryX6OEj-T.png)](https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/distribution-of-vitamin-c-is-tissue-specific-with-early-saturation-of-the-brain-and-adrenal-glands-following-differential-oral-dose-regimens-in-guinea-pigs/3612F04FFBDD3D7609D6F4E7BA1B5230)

500mg/Kg
at 176.124 MW
is 2.8389  millimolar

739
4.1959  millimolar

13
73.8116  micromolar

3.9
22.1435  micromolar


## In cell culture media
"It is generally accepted that the addition of vitamin C to cell culture medium improves cell growth. However, once added, the vitamin C concentration declines rapidly. This situation differs from the in vivo environment where the endothelium is constantly supplied with ascorbate from the blood."

"we simulated constant supply of ascorbate by the hourly addition of freshly prepared medium containing 75 μM ascorbate and subsequently compared it with more practical regimens using combinations of ascorbate and 2-phosphoascorbate. ==We found that a single supplement of ascorbate and 2-phosphoascorbate adequately maintains intracellular vitamin C at physiological levels for up to 72 h=="

[2010 Keeping the intracellular vitamin C at a physiologically relevant level in endothelial cell culture](https://www.sciencedirect.com/science/article/abs/pii/S0003269709006769)






## Vitamin C systemic level
![](https://i.imgur.com/dEkeevA.png)



## Genes
Vitamin C is transported across the BBB by Glut1 in the form of DHA

a sodium-dependent transporter for vitamin C exists, it is present mainly in specialized cells, whereas the glucose transporters, the most notable being GLUT1, transport Vitamin C (in its oxidized form, DHA)
[See Glut1 - Slc2a1](https://hackmd.io/@sholmqvist/BJpKurTBB/https%3A%2F%2Fhackmd.io%2FcB6TLk1tRfGw4PTQCKuhJg#Slc2a1-Glut1)

Ugdh
Ugp2


Akr1a1 Akr1b1 Rgn
Slc23a1 Slc23a2 Glut1 Glut3 Gulo (Hs GuloP)




## Synthesis in organisms
Vast majority of animals and plants are able to synthesize vitamin C, through a sequence of enzyme-driven steps, which convert monosaccharides to vitamin C

**Yeasts** do not make l-ascorbic acid but rather its stereoisomer, erythorbic acid

In **plants**, through the conversion of mannose or galactose to ascorbic acid

In **animals**, the starting material is glucose generated and dependent on glycogenolysis.

**Animals unable** to synthesise aa - the enzyme enzyme **l-gulonolactone oxidase** (**GULO**), that catalyses the last step in the biosynthesis, is highly mutated and non-functional

## Synthesis in able vertabrates

> UDP-glucose :arrow_right: UDP-glucuronic acid

**UGDH** UDP-glucose 6-dehydrogenase  (co-factor NAD+ // vitamin B3 as electron acceptor)
**UGP2** UDP-Glucose Pyrophosphorylase 2 (transferase), - removes a UMP
**glucuronokinase**, with the cofactor ADP, - removes the final phosphate 
->leading to d-glucuronic acid


> glucuronic acid + NADPH + H⁺ :left_right_arrow: L-gulonic acid

The aldehyde group of this compound is reduced to a primary alcohol using the enzyme **glucuronate reductase** // **AKR1A1** and the cofactor NADPH, yielding :arrow_right: l-gulonic acid + NADP⁺

gulonic acid :arrow_right: gluconolactonase
followed by lactone formation—utilizing the hydrolase gluconolactonase (**RGN, Regucalcin**).

    Rgn is a calcium-binding protein. Calcium efflux. Needed for vitamin c synthesis. Source: OMIM.  age-associated down-regulation. GeneCards

> l-Gulonolactone + 0~2~ +  FAD+ :arrow_right: 2-keto-gulonolactone. 

 l-Gulonolactone then reacts with oxygen, catalyzed by the enzyme **L-gulonolactone oxidase** // **GULO**
 (which is nonfunctional in humans and other Haplorrhini primates; see Unitary pseudogenes)

spontaneously undergoes enolization to form ascorbic acid

[# conclusion, with GULO mutated in humans there should be another pathway for Gulonolactone]

**GULOP **(Ms Gulo)
- Humans lack the enzyme for synthesis
non-functional in Haplorrhini (including humans), in some bats, and in guinea pigs

- It is likely that some level of adaptation occurred after the loss of the GULO gene by primates. Erythrocyte Glut1 and associated dehydroascorbic acid uptake modulated by stomatin switch are unique traits of humans and the few other mammals that have lost the ability to synthesize ascorbic acid from glucose.[11] As GLUT transporters and stomatin are ubiquitously distributed in different human cell types and tissues, similar interactions can be hypothesized to occur in human cells other than erythrocytes.

- Found in astrocytes to low levels (Linnarsson)

- Found in afferent nuclei of cranial nerves.
![](https://i.imgur.com/GuqB6RP.png)
http://mouse.brain-map.org/experiment/siv?id=68498427&imageId=68111077&initImage=ish&coordSystem=pixel&x=6980&y=3436&z=3



## C-Deficiency
Scurvy

Scurvy is characterized by a generalized tissue disintegration, dissolution of intercellular ECM, which induces an excessive proliferation of undifferentiated cells and a reversion to a primitive form of the tissue

That mental depression is an early symptom of scurvy ( Hodges et al ., 1971 ) indicates the importance of maintaining physiological levels of vitamin C in the brain. R & Wilson 1995





# Vitamin D
[Top](#Table-of-Contents)

[See Cholesterol](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FgRCfhM49T-yl7l8wFSN1sQ)

[See Carnitine heterocycles](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FU69Xd8D0TreBQ1qYozxh9A#Heterocycles-and-carnitine)

[See TCA - slides](https://docs.google.com/presentation/d/1OBWe0RZk7GlKqi6yrUXaou-iYRY9BSwG5OhjTSUT1u0/edit#slide=id.g288d2170ad6_0_13)

![image](https://hackmd.io/_uploads/BJhf52RFT.png)
Effect of vitamin D on the metabolic profile of HEK293T cells.

Vitamin D is a group of fat-soluble secosteroids ("Broken ring") responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and multiple other biological effects

![image](https://hackmd.io/_uploads/ryiC52CFp.png)



NaPi-IIa
Slc34a2
NaPi-IIb
Slc34a2

Claudin2 
Claudin12

Trpv6

Derived from steroids

- Vitamin D3 (cholecalciferol - Skin and some foods)
- Vitamin D2 (ergocalciferol - Foods and supplements)

Inactive Calciferol
Active: Calci**triol**

## D-Synthesis
[Top](#Table-of-Contents)

[See Cholesterol](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FgRCfhM49T-yl7l8wFSN1sQ)

- Photochemistry
    1. 7-dehydrocholesterol is photolyzed by ultraviolet light in a 6-electron conrotatory ring-opening electrocyclic reaction; the product is previtamin D3.
     
![](https://i.imgur.com/CNWCAa9.png)
    2. Second, previtamin D3 spontaneously isomerizes to vitamin D3 (cholecalciferol)
    
![](https://i.imgur.com/aFelRaz.png)




- Subsequent activation in liver  and kidneys liver. Hydroxylate  it (-OH) to convert it to the active form Calci**triol**
    - cholecalciferol :arrow_right: calcidiol (Liver - CYP2R1, CYP27A1)
     - calcidiol :arrow_right: calci**triol** (Kidney - CYP27B1)
    - Parathyroid hormone: CYP27B1 mediated synthesis :arrow_up:
    - Pi & Ca: inhibits CYP27B1 mediated synthesis :arrow_down:

![](https://hackmd.io/_uploads/BkvPdoLGp.png "CalciDiol - CYP2R1, CYP27A1 - Liver" =200x)![](https://hackmd.io/_uploads/HywddjLMT.png "CalciTriol - CYP27B1 - Kidney" =200x)
CalciDiol - CYP2R1, CYP27A1 - Liver
CalciTriol - CYP27B1 - Kidney
## Vitamin D3 Lactone 
[See Lactones](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FL9mCmUogRgmDf2T3ht93bQ)
[See TCA - slides](https://docs.google.com/presentation/d/1OBWe0RZk7GlKqi6yrUXaou-iYRY9BSwG5OhjTSUT1u0/edit#slide=id.g288d2170ad6_0_13)
[See Carnitine II](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FU69Xd8D0TreBQ1qYozxh9A#Lactones)

![](https://hackmd.io/_uploads/rk-PtjUGT.png "Calcitroic acid" =200x)
Calcitroic acid


![](https://hackmd.io/_uploads/HkvE6jIf6.png "23S,25-Dihydroxyvitamin D3")
23S,25-Dihydroxyvitamin D3

![](https://hackmd.io/_uploads/B1wR2s8Ga.png)

lactone-vitamin D3

## D-Catabolism
[Top](#Table-of-Contents)

- Degradation
    - calcidiol :arrow_right: Inactive 24,25-OH- vitamin D (CYP24A1)
    - Parathyroid hormone: CYP24A1 mediated degradation :arrow_up:
    - The **rate-limiting step** in catabolism is the degradation of
     25(OH)D3 and 1,25(OH)2D3 (Calcitriol) into 
     24,25(OH)D3 and 1,24,25(OH)2D3. By 24-OHase, encoded by the CYP24A1
    - levels of circulating inactive 24,25-Dihydroxyvitamin D is usually x1000 that of Calcitriol.
- However, through the past decades data have accumulated that 24R,25(OH)2D3 is not merely a degradation product but **has effects on its own**
    - Normal chicken egg hatchability and calcium and phosphorus homeostasis
    - Distinct effects on cartilage in particular the resting zone cells
    - stimulates Osteocalcin synthesis in human osteoblasts

Cyp27b1 hydroxylates 25-hydroxyvitamin D3 at the 1alpha position. This reaction synthesizes 1alpha,25-dihydroxyvitamin D3, the active form of vitamin D3, which binds to the vitamin D receptor and regulates calcium metabolism

[See Cyp27b1](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FPqRHnwoCQE2vfdv9-shjeA#Cyp27b1)

## Calcitriol - active secosteroid 1 ,25(OH)2D3
[Top](#Table-of-Contents)

- Calcitriol circulates as a hormone in the blood, having a major role regulating the concentration of calcium and phosphate, and promoting the healthy growth and remodeling of bone
- Calcitriol, which then produces effects via a nuclear receptor in multiple locations
- Calcitriol also has other effects, including some on cell growth, neuromuscular and immune functions, and reduction of inflammation

## D-Deficiency
[Top](#Table-of-Contents)

- Rickets & osteomalacia (softening of bones)

## D-Overdose
[Top](#Table-of-Contents)

- Hypervitaminosis D
    - causes abnormally high blood concentrations of calcium
    - overcalcification of the bones, soft tissues, heart and kidneys
    - Hypertension
    - mutation of the *CYP24A1* gene can lead to a reduction in the degradation of vitamin D and to hypercalcaemia
- vitamin D toxicity include mental retardation in young children
- abnormal bone growth and formation
- diarrhea, irritability, weight loss, and severe depression



## D-Cellular effects & Receptors
[Top](#Table-of-Contents)

- VDR = NR1I1 (nuclear receptor subfamily 1, group I, member 1)
    -  Forms a heterodimer with the retinoid-X receptor. RXRA RARB

    - Binding of calcitriol to the *VDR* allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as *TRPV6* and *calbindin*)

    - Vitamin D receptor expression decreases with age

    - VDR not only regulates transcriptional responses but also involved in microRNA-directed post transcriptional mechanisms

- In vitro, vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells, and affects the synthesis of neurotrophic factors, nitric oxide synthase, and glutathione.[10.1016/0169-328X(95)00314-I]

- Apart from VDR activation, various alternative mechanisms of action are under study, such as inhibition of signal transduction by **hedgehog**, a hormone involved in morphogenesis[10.1210/me.2014-1043]

![](https://i.imgur.com/RH4qvDQ.png)

## D-Extra
[Top](#Table-of-Contents)

![](https://i.imgur.com/d0mVq8Q.png =400x)




# Vitamin E
[Top](#Table-of-Contents)
"Tocopherols, Tocotrienols"
![](https://i.imgur.com/b84OOPD.png)
![](https://i.imgur.com/IUlA9nk.png)

four tocopherols and four tocotrienols

Vitamin E is a fat-soluble antioxidant which may help protect cell membranes from reactive oxygen species

Both the tocopherols and tocotrienols occur in α (alpha), β (beta), γ (gamma) and δ (delta) forms, as determined by the number and position of methyl groups on the chromanol ring

2,2,7,8-Tetramethyl-6-chromanol
![](https://i.imgur.com/O3NUO5R.png)


## E-Deficiency
Deficiency is very rare; mild hemolytic anemia in newborn infants[15]

## E-Overdose?
Possible increased incidence of congestive heart failure.[16][17]


# Vitamin K
[Top](#Table-of-Contents)
"Phylloquinone, Menaquinones"

The coagulation vitamin.

The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.[76]

The "precise" function of vitamin K was not discovered until 1974, when prothrombin, a blood coagulation protein, was confirmed to be vitamin K dependent




## K-Deficiency
Bleeding diathesis (susceptibility to bleed)
## K-Overdose
Decreased anticoagulation effect of warfarin.[18]





