---
title: Cytochrome P450
disqus: hackmd
---
:::success
> Documentation [name=MrDr.Staffan]
###### tags: `Cyp`

### Table of Contents
[TOC]
:::

[Top](#Table-of-Contents)

[The question is less, and more why are the compounds that form proteins around in the first place? Why do not the entire organic fire collapse and burn out. Why is the 'ash' kept? and what regulates, decided what is not furthter metabolised?
UGP controlling secretion. Cyps controlling breakdown of small complex molecules. E.g. aminoacids etc. As an essential amino acid, methionine is not synthesized de novo in humans and other animals. Cysteine and methionine, these are key players in the self-regulation of metabolic flow. Methionine triggers protein formation].

[See oxygenases](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FLLM5drPYRpaHsNk6M11lqw)

[Video Substrate promiscuity](https://www.youtube.com/watch?v=aqWvo-jGeSE)

[See Redundancy](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FEODEn7OuSn2d0Icb4XYz1A)

[[==There should be something called "CYP:Load"
The pressure of metabolites on the flow through this system. Basic oxygenation of small but complex carbon-molecules. Incl. n.t:s, (amino acids cyclic? i.e. [Histidine, proline, Phenylalanine, Tyrosine, Tryptophan](https://hackmd.io/@sholmqvist/BJpKurTBB/%2F6boDt7fZRfmxzsr9k2HIgg#Amines))==]]

[This image shows That CPR acts as an electron donor for CYP:s Immediately remind me of the electron transport chain. I can see how this would evolve into ETC.]

**CPR // POR** Cytochrome P450 Oxidoreductase

Cytochrome P450 monooxygenases (CYPs/P450s), heme thiolate proteins, have been under the spotlight due to their **regio**- and **stereo**-**selective** **oxidation** **activities**, which has led to the exploration of their applications in almost all known areas of biology.

[Togheter they constitute the machinery oxidizing those leftovers that cannot be handled by the TCA, peroxisomes, cant be used as proteins (~that does not end up as proteins i.e. those that cannot be or are not degraded.))]. [They are located on membranes.]

[I see it as a flow of masses. They see it as instructions and specific isolated mechanisms.]

Mutations in this gene cause a complex set of disorders, including apparent combined P450C17 and P450C21 deficiency, amenorrhea and disordered steroidogenesis, congenital adrenal hyperplasia and Antley-Bixler syndrome, that resemble those caused by defects in steroid metabolizing enzymes such as aromatase (Cyp19a1), 21-hydroxylase, and 17 alpha-hydroxylase.

**Cytochrome b5**
Cytochromes b5 are ubiquitous electron transport hemoproteins found in animals, plants, fungi and purple phototrophic bacteria.

# Families of CYPs
[CYP4A11](https://metabolomips.org/si/locus.php?id=4)
tetradecanedioate

10-undecenoate (11:1n1)
Dicarboxu C10,C11,C14, C16

# cytochrome P450 family
A distinct family of cytochromes is the cytochrome P450 family, so named for the characteristic Soret peak formed by absorbance of light at wavelengths near 450 nm when the heme iron is reduced (with sodium dithionite) and complexed to carbon monoxide.

# optimal activity for cyps?
How does temp change ptotei activity.

# Ligands of Cyp
[Structural basis for ligand promiscuity in cytochrome P450 3A4](https://www.pnas.org/doi/full/10.1073/pnas.0603236103)

The aim of this work was to obtain structural information on CYP3A4 in complex with larger ligands and, thus, probe conformational changes. We hypothesized that ligand-induced conformational changes must occur also in CYP3A4 and, therefore, great effort was made to characterize the protein–ligand complex **before crystallization**

# Cyp substrate specificity

[Lewis 2002](https://www.sciencedirect.com/science/article/pii/S1359644602024121)

CR= flatness of the molecule.

Area/depth = CR.
High: Large area to depth - flat
Low: Small area to depth - round.

[](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093435/)
[](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093435/)

# Evolution of Cyp genes
Cytochrome P450 (CYP) constitutes a large gene superfamily descended from a single common ancestor. CYP genes are widely distributed in all domains of life from bacteria, archaea, and viruses to higher plants and animals. Because of their monophyletic nature, all CYP genes may be hierarchically classified at several distinct levels based on similarity of the protein amino acid sequences. A five-level classification (class, group, clan, family, and subfamily) is reasonably stable and useful for conceptual categorization of CYP genes.

[2016. Review. Scientific Reports. Molecular evolutionary dynamics of cytochrome P450 monooxygenases across kingdoms: Special focus on mycobacterial P450s](https://www.nature.com/articles/srep33099)

"we analyzed 17 598 P450s belonging to 113 P450 families (bacteria −42; fungi −19; plant −28; animal −22; plant and animal −1 and common P450 family −1)"


[2013. Nelson.. Stegeman. The cytochrome P450 genesis locus: the origin and evolution of animal cytochrome P450s](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538424/pdf/rstb20120474.pdf)

# Localization - inside membranes
Most seem to locate to ER, and potentially m.t.

This suggest they are oxidising lipids not merely for catabolism. Put Perhaps for intracellular.

[cyps role in er? make insoluble soluble? Or pack into exosomes?]
Good article
Cyp:s vacuum the membranes.

[Membrane-attached mammalian cytochromes P450: An overview of the membrane's effects on structure, drug binding, and interactions with redox partners](https://www.sciencedirect.com/science/article/pii/S0162013417308413)

The products of CYP biotransformation generally have lower affinities for membranes [71] so their preferred positions are closer to the membrane/water interface and **they mostly ++leave to++ the bulk solvent**.

Mammalian CYPs are membrane-associated enzymes in contrast to prokaryotic CYPs, which are soluble.

Current knowledge converged to a model, where the CYP catalytic domain lies on the cytosolic side of the ER

# Substrate binding
[Interactions of cytochrome P450s with their ligands](https://www.sciencedirect.com/science/article/pii/S0003986110004340)
Water plays a role in binding

[](https://www.sciencedirect.com/science/article/pii/S0162013417308413#:~:text=full%2Dsize%20image-,Fig.%208,-.%20Localization%20of)[![](https://hackmd.io/_uploads/Sk4y0NTso.png "Cyp2d22" =200x)](https://alphafold.ebi.ac.uk/entry/Q9JKY7)

substrates enter the CYP active site from the membrane interior via a family 2 channel (shown in green)

active site housing the heme cofactor (violet)

products leave the CYP via, e.g., the solvent channel (shown in red).

[Interpreted: Cyps run as machines along cytosolic side of membranes. Sucking substrate from inside the membane, solubilizing the substrate and extruding the soluble product. This is done by introducing oxygen into hydrocarbon rings or such. These "clean" the membrane from hydrocarbon thick structures, by removal of complex hydrocarbons. This ensures there is not too much ~~lipid. protein~~. Cholesterol content, which makes the membrane brittle.

CYP51 is involved in cholesterol biosynthesis, whereas CYP 7A1, 27A1, 46A1, 7B1, 39A1, and 8B1 are the key enzymes in cholesterol catabolism to bile acids

If one measure the solubilization of different compounds you can look at the effect of a single or multiple KO Cyps.] [Which ones accept n.t. as substrates? Are these hydrophobic? Are they after?]

Because amphiphilic compounds may accumulate in membranes or at the membrane/water interface, there was presumably a strong evolutionary pressure driving the colocation of biotransformation enzymes (i.e., CYPs) and their potential substrates.
**amphiphilic = both hydrophilic and lipophilic **

Membranes also house CYPs' redox partners and other enzymes that contribute to the consecutive steps of xenobiotic biotransformation (UDP-glucuronosyltransferases), which makes membranes' active playgrounds responsible for the colocation

## Substrate specificity
[1999 ](https://sci-hub.hkvisa.net/10.1515/DMDI.1999.15.1.1)

[CYP2A6 and CYP1A2 have the least malleable active sites while CYP2D6, CYP2C9 and CYP3A4 exhibit considerably greater degrees of flexibility or malleability.](https://www.sciencedirect.com/science/article/pii/S1570963910002116)

Phenobarbital and other barbiturates induce P450s of subsfamilies CYP2A, CYP2B, CYP2C and CYP3A, whereas dexamethasone induce both CYP3A and CYP2A. Moreover, TCDD and other polyaromatics induce both CYP1A and CYP2A subfamilies. However, CYP2E is induced by acetone, ethanol and benzene, indicating that there are both similarities and differences in the regulatory mechanisms of mammalian P450s.

https://pubs.acs.org/doi/pdf/10.1021/tx0002583
Common and Uncommon Cytochrome P450 Reactions
Related to Metabolism and Chemical Toxicity

# Membrane anchoring
Usually a long helix. But It was also shown that another sequence contributes to CYP anchoring by Cullin.

However, the mitochondrial CYPs do not need an N-terminal transmembrane anchor because they have a so-called topogenic sequence [87] localized at the beginning of the enzyme sequence that initially serves as a signal peptide but is sequestered once the recognition process is complete [88,89].
https://www.sciencedirect.com/science/article/pii/S0162013417308413#bi0005

Cpr // Por

# Indole

Good paper with basics of the mechanism of how cyps introduce O2 into various substrates
https://pubs.acs.org/doi/pdf/10.1021/tx0002583

# Neuroglobin NGB
[Dehaloperoxidase: An enzymatic Swiss army knife](https://www.sciencedirect.com/science/article/pii/S0010854521002502#f0005)

Expressed by hypothalamic neurons (ChAT,Pmch,Trh)
Thyrotropin Releasing Hormone (thyroid axis)

[ ]( https://mouse.brain-map.org/experiment/show?id=79556712)

inhibiting cellular respiration via NO-binding to cytochrome c oxidase. Involved in neuroprotection during oxidative stress

Sets a threshold for the level of oxygen, before cellular respiration is inhbitied.
[I.e. if you dont have this or at low levels then the cells are not restricted by acess to oxygen.]

# CYPs and melatonin
Our results strongly suggest that 6-hydroxylation, the main metabolic pathway of melatonin, is mediated mainly, but not exclusively, by CYP1A2, the high-affinity enzyme involved in melatonin metabolism, confirming the observation that a single oral dose of fluvoxamine (SSRI) increases nocturnal serum melatonin levels in healthy subjects.

Furthermore, the results indicate that there is a potential for interaction with drugs metabolised by CYP1A2 both at physiological levels and after oral administration of melatonin, while CYP2C19 and CYP2C9 are assumed to be less important.

https://link.springer.com/article/10.1007/s002280000245

# Reviews etc
Cytochrome P450 enzymes: understanding the biochemical hieroglyphs
https://f1000research.com/articles/4-178
<br><br><br><br>

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease
https://pharmrev.aspetjournals.org/content/66/4/1106

"The role of 20-HETE in the regulation of microvascular function and angiogenesis was extensively reviewed by others (Harris and Hammock, 2013; Imig, 2013)"

Cytochrome P450 Metabolism of Polyunsaturated Fatty Acids and Neurodegeneration
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696575/

Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances
https://www.frontiersin.org/articles/10.3389/fphar.2021.650027/fulL

"both CYPs and UGTs also mediate metabolism of endogenous substances including dopamine and serotonin as well as some drugs such as morphine in brain, demonstrating their important roles in maintenance of brain homeostasis or pharmacological activity of drugs."

**Dopamine**
It was reported that inhibition of CYP2E1 increased the extracellular DA in the substantia nigra (Nissbrandt et al., 2001) and significantly altered metabolite pattern of L-dopa (Niazi Shahabi et al., 2003), indicating that CYP2E1 might participate in DA metabolism or release

glucuronidation also serves as a pathway of DA metabolism in brain (

**SeroTonin**
Data from recombinase and transgenic mice confirmed that the human CYP2D6 subtype catalyzed 5-methoxytryptamine (5-MT) to 5-HT in liver (Yu et al., 2003), which was also confirmed by rat brain CYP2D in vitro and in vivo (Haduch et al., 2013, 2015)

decreased activity of cerebellar CYP2D by quinine resulted in a behavioral deficit related to spatial learning and memory, as well as increased anxiety-related behavior (Zhang et al., 2018)

Thereby, we hypothesize that elevation of brain CYP2D under depressive disorder (Haduch et al., 2018) may increase melatonin consumption, **causing sleep disorders in patients with depressive disorder**.

[while inhibition of a cyp that catabolize serotonin would reduce melatonin use, reset sleep patterns and counteract anxiety.]

glucuronidation in human brain may be an important phase Ⅱ metabolism pathway of 5-HT (Figure 1B). 5-HT is the specific probe substrate of UGT1A6. The mRNA expression of Ugt1a6 was detected in brain of rats (Sakakibara et al., 2016).
[check expression Looks like astro]

**Bilirubin**

**AA**
...
Glutamate also induced the expressions and functions of CYP1B1 and CYP2U1 in astrocytes via mGlu5 receptor, suggesting that the neuron-astrocyte reciprocal signaling may affect the CYPs-mediated metabolism of AA (Yu et al., 2019).

**Cholesterol**
Since cholesterol can hardly pass BBB, most of the brain cholesterol is synthesized in brain rather than obtained from plasma. Brain CYPs are essential for the biosynthesis and excretion of cholesterol

Cyp51
CYP51 is the only CYP participating in cholesterol biosynthesis by removal of the 14α-methyl group of lanosterol, and it is ubiquitously expressed, including brain microsomes (Aoyama et al., 1996)

Cyp46a1
Cholesterol 24-hydroxylase is a type of CYPs (CYP46A1), which is selectively expressed in brain, including hippocampus, cortex and cerebellum (Lund et al., 1999). CYP46A1 is mainly involved in the catabolism of most cholesterol, and generated 24-S- hydroxycholesterol diffuses across BBB easily

It is the dominating pathway for cholesterol elimination from brain (Björkhem et al., 1998). Interestingly, CYP46A1 seems to regulate new cholesterol synthesis in brain. In Cyp46a1−/− mice, the synthesis of new cholesterol in brain was reduced by about 40% of wild type mice (Lund et al., 2003),

In addition, CYP11A1, CYP27A1 and CYP7A1 metabolize cholesterol to pregnenolone, 27-hydroxycholesterol and 7α-hydroxycholesterol in brain, respectively (Dutheil et al., 2008).

**Allopregnanolone**
Some antidepressants such as fluoxetine inhibited CYP2D-mediated 21-hydroxylation of allopregnanolone (Niwa et al., 2008)
[showiNg that Antidepressants changes cyp activity and might in part act through this inhibition]

**Also** cyp2f2 is up by NAdr and ACh treated astrocytes. See astro+neurotransmitters.

This gene is pseudo in humans. But enriched in the pituitary. [Suggesting a secretion association]

] (https://www.frontiersin.org/articles/10.3389/fphar.2021.650027/full#B76)

<br>

# General description
CYPs are, in general, the **terminal oxidase enzymes in electron transfer chains**, broadly categorized as P450-containing systems

(wiki)
Human CYPs are primarily membrane-associated proteins[20] located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells

CYPs are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism.

Most drugs undergo deactivation by CYPs, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYPs to form their active compounds like the antiplatelet drug clopidogrel and the opiate codeine.

Proportion of antifungal drugs metabolized by different families of CYPs

Hs CYP2D6 = Mm Cyp2d22 (astro)
Hs CYP3A4/5 = Cyp3a25, Cyp3a13, Cyp3a16, Cyp3a44, Cyp3a11, Cyp3a59, Cyp3a57, Cyp3a41a, Cyp3a41b

**Cyp2 families have 9 exons. Except Cyp2u1 & Cyp2r1 that have five exon**

[![](https://i.imgur.com/3jVcbZT.png "Cyp2d22" =150x)](https://alphafold.ebi.ac.uk/entry/Q9JKY7) &nbsp;&nbsp;&nbsp;[![](https://i.imgur.com/LDda2Zr.png "Cyp2u1" =200x)](https://alphafold.ebi.ac.uk/entry/Q9CX98) [![](https://i.imgur.com/Vo4q9H0.png "Cyp2r1" =150x)](https://alphafold.ebi.ac.uk/entry/Q32MW0)

Cyp2d22 (Mm of Hs CYP2D6) &nbsp;&nbsp;&nbsp;&nbsp; Cyp2u1 (CYP2U1) &nbsp;&nbsp;&nbsp;&nbsp; Cyp2r1
[Might this tail whip away too big substrates?]

Hs CYP2J2 (Cyp2j9, Cyp2j13)

[![](https://i.imgur.com/SrvOdjk.png "CYP2J2 Hs" =200x)](https://alphafold.ebi.ac.uk/entry/A0A2D1BTF8) [![](https://i.imgur.com/p13DOyi.png "Cyp2j13 Mm" =200x)](https://alphafold.ebi.ac.uk/entry/Q8K1C5) [![](https://i.imgur.com/rcDIvBu.png "Cyp2j9 Mm" =150x)](https://alphafold.ebi.ac.uk/entry/Q924D1)
CYP2J2 &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Cyp2j9 &nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Cyp2j13

<br><br><br><br>
# Drug metabolism
Phases I and II of the metabolism of a lipophilic xenobiotic.

## Phase I modification - **add polar group**.
"modification (**oxidation -O or reduction -OH**)"
In phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the cytochrome P-450-dependent mixed-function oxidase system.

|Oxidation|Reduction|
|-|-|
|Cytochrome P450 monooxygenase system | NADPH-cytochrome P450 reductase|
|Flavin-containing monooxygenase system |Reduced (ferrous) cytochrome P450
|Alcohol dehydrogenase and aldehyde dehydrogenase |**Hydrolysis**
|Monoamine oxidase | Esterases and amidase
|Co-oxidation by peroxidases | Epoxide hydrolase

E.g. Proline hydroxylase, - small circular. "Gamma oxidation"

## Phase II conjugation - **Solubilize with sugars**.
"conjugation".
activated xenobiotic metabolites are conjugated with
**charged species** such as glutathione (GSH), sulfate, glycine, or glucuronic acid.
**Sites** on drugs where conjugation reactions occur include carboxy (-COOH), hydroxy (-OH), amino (NH2), and thiol (-SH) groups.

![image](https://hackmd.io/_uploads/Syjy_tYOT.png "sulfate" =75x) ![image](https://hackmd.io/_uploads/rJdr_tF_6.png "Glycine" =75x) ![image](https://hackmd.io/_uploads/r175uKtO6.png "Glutathione" =200x)
![image](https://hackmd.io/_uploads/BJIRwYKd6.png "Glucuronic acid" =300x)

|Mechanism| Enzyme| Co-factor|Location|Example
|-|-|-|-|-
|methylation | [methyltransferase](https://en.wikipedia.org/wiki/Methyltransferase)| S-adenosyl-L-methionine| liver, kidney, lung, CNS| GAMT, COMT, DMNT1
|sulphation | [sulfotransferases](https://en.wikipedia.org/wiki/Sulfotransferase)| 3'-phosphoadenosine-5'-phosphosulfate| liver, kidney, intestine| CHST1, GAL3ST1, HS2ST1, SULT1A1 ...
|acetylation | N-[acetyltransferases](https://en.wikipedia.org/wiki/Acetyltransferase) <br> bile acid-CoA:amino acid N-acyltransferases| acetyl coenzyme A |liver, lung, spleen, gastric mucosa, RBCs, lymphocytes| HATs HDACs, CHAT, CRAT, AANAT//Sert
|glucuronidation | UDP-[glucuronosyltransferases](https://en.wikipedia.org/wiki/Glucuronosyltransferase) |UDP-glucuronic acid |liver, kidney, intestine, lung, skin, prostate, brain| UGT1A6, B3GAT1
|glutathione conjugation| [glutathione S-transferases](https://en.wikipedia.org/wiki/Glutathione_S-transferase) |glutathione| liver, kidney| GSTA1, GSTM1, MGST1
|glycine conjugation | Two step process: <br> 1. [XM-ligase](https://en.wikipedia.org/wiki/Butyrate%E2%80%94CoA_ligase) (forms a xenobiotic acyl-CoA) <br> 2. [Glycine N-acyltransferase](https://en.wikipedia.org/wiki/Glycine_N-acyltransferase) (forms the glycine conjugate) | glycine | liver, kidney | ACSM1 & GLYAT ,respectively

## Phase III further modification and excretion

A common example is the processing of glutathione conjugates to acetylcysteine (mercapturic acid) conjugates.[11] Here, the γ-glutamate and glycine residues in the glutathione molecule are removed by Gamma-glutamyl transpeptidase and dipeptidases.

In the final step, the cysteine residue in the conjugate is acetylated.

Conjugates and their metabolites can be excreted in phase III of their metabolism.
The conjugated anionic groups act as affinity tags for a variety of membrane transporters of the multidrug resistance protein (MRP) family

The human ABCB (MDR/TAP) family is responsible for multiple drug resistance (MDR) against a variety of structurally unrelated drugs. Expressed primarily in the blood brain barrier and liver.

ABCB family
ABCB1 ABCB2 ABCB3 ABCB4 ABCB5 ABCB6 ABCB7 ABCB8 ABCB9 ABCB10 ABCB11
MDR1, PGP1 (ABCB1)
TAP1 (ABCB2)
TAP2 (ABCB3)
PGY3 (ABCB4)
ABCB5
MTABC3 (ABCB6)
ABC7 (ABCB7)
MABC1 (ABCB8)
TAPL (ABCB9)
MTABC2 (ABCB10)
ABC16 (ABCB11)

ABCC4 ABCC5 ABCC11 ABCC12

ABCC1 ABCC2 ABCC3 ABCC6 ABCC10

<br><br><br><br>

# Activity


Cytochrome P450 hydroxylation mechanism

https://www.mdpi.com/1422-0067/22/23/12808/htm
Cytochrome P450 Enzymes and Drug Metabolism in Humans

https://pubmed.ncbi.nlm.nih.gov/33356626/
Cytochrome P450 expression and regulation in the brain

# Specific
Linnarsson Cyps
Cyp11a1
Cyp11b1
Cyp11b2
Cyp17a1
Cyp19a1
Cyp1a1
Cyp1a2
Cyp1b1
Cyp20a1
Cyp21a1
Cyp24a1
Cyp26a1
Cyp26b1
Cyp26c1
Cyp27a1
Cyp27b1
Cyp2a12
Cyp2a22
Cyp2a4
Cyp2a5

Cyp2ab1
Cyp2b10
Cyp2b13
Cyp2b19
Cyp2b23
Cyp2b9
Cyp2c29
Cyp2c37
Cyp2c38
Cyp2c39
Cyp2c40
Cyp2c44
Cyp2c50
Cyp2c54
Cyp2c55
Cyp2c65
Cyp2c66
Cyp2c67
Cyp2c68
Cyp2c69

Cyp2c70
Cyp2d10
Cyp2d11
Cyp2d12
Cyp2d22
Cyp2d26
Cyp2d34
Cyp2d37-ps
Cyp2d40
Cyp2d9
Cyp2e1
Cyp2f2
Cyp2g1
Cyp2j11
Cyp2j12
Cyp2j13
Cyp2j5
Cyp2j6
Cyp2j8
Cyp2j9

Cyp2r1
Cyp2s1
Cyp2t4
Cyp2u1
Cyp2w1
Cyp39a1
Cyp3a11
Cyp3a13
Cyp3a16
Cyp3a25
Cyp3a41b
Cyp3a44
Cyp3a57
Cyp3a59
Cyp46a1
Cyp4a10
Cyp4a12a
Cyp4a12b
Cyp4a14
Cyp4a29

Cyp4a30b
Cyp4a31
Cyp4a32
Cyp4b1
Cyp4f13
Cyp4f14
Cyp4f15
Cyp4f16
Cyp4f17
Cyp4f18
Cyp4f37
Cyp4f39
Cyp4f40
Cyp4v3
Cyp4x1
Cyp4x1os
Cyp51
Cyp7a1
Cyp7b1
Cyp8b1

Por

# Cyp1a1 Cyp1a2
Bilirubin. See https://www.frontiersin.org/articles/10.3389/fphar.2021.650027/full#B76

AHR encodes the aromatic hydrocarbon receptor, a transcription factor which activates CYP1A1 and CYP1A2 [10605936]. These enzymes metabolize **caffeine** [8095225]

# Cyp51
Up in coldKO vs CtrlWT

Cyp51a1P2
Shared enhancer: HSALNG0096032SLC46A3

# Cyp46a1
Up in coldKO vs ctrl WT

24S-HC binds to apolipoproteins such as apoE, apoJ, and apoA1 to form HDL-like complexes[5] which can cross the blood–brain barrier more easily than free cholesterol.


P450 monooxygenase that plays a major role in cholesterol homeostasis in the brain. Primarily catalyzes the hydroxylation (with S stereochemistry) at C-24 of cholesterol side chain, triggering cholesterol diffusion out of neurons and its further degradation (PubMed:10377398, 14640697, 18621681, 25017465). By promoting constant cholesterol elimination in neurons, may activate the mevalonate pathway and coordinate the synthesis of new cholesterol and nonsterol isoprenoids involved in synaptic activity and learning (By similarity).

# Cyp2


CYP2A7P
CYP2B7P
ENSG00000291083
CYP2B6
ZNF780B
ENSG00000205041
SNRPA
HNRNPUL1
ENSG00000269843
CCDC97
ZNF780
ACOQ8B
CYP2G1P
ENSG00000269069
AKT2

## CYP2B7P

**Shared promoter:**
ENSG00000291083
CYP2B6
ZNF780B
ENSG00000205041
SNRPA
HNRNPUL1
ENSG00000269843
CCDC97
ZNF780
ACOQ8B
CYP2G1PENSG00000269069
AKT2

## Cyp2d22
[See Anandamide](https://hackmd.io/@sholmqvist/BJpKurTBB/%2F3oIPrIVKRwSOOcH1TyOLpQ#Anandamide)

[See Cholesterol](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FgRCfhM49T-yl7l8wFSN1sQ#25-hydroxycholesterol)

CYP2D6 ortholog

Astro
Up in coldKo vs ctrlWT

Cyp2d22 // Cyp2d6
a) Metabolizes endocannabinoid arachidonoylethanolamide ([anandamide](https://hackmd.io/@sholmqvist/BJpKurTBB/%2F3oIPrIVKRwSOOcH1TyOLpQ#Anandamide)) (PubMed:18698000, 21289075)
[This Stops the endocannabinoid signaling, that is induced by FA metabolism in lack of oxygen.]
[rbm3 ko Result in Excess in response to cold and maintained high levels of Cyp2d22 following cold]
[high/maintained levels Cyp2d22 When rbm3 is mIssing Keep breakdown of endocannabinoids.
[Missing rbm3 also Keep conversion of cholesterol into 25HC high. This inhibits cholesterol synthesis.]
[therefore tha lack of rbm3 in cold result in low cholesterol synthesis and low endocannabinoid signaling.]

b) Metabolizes cholesterol toward [25-hydroxycholesterol](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FgRCfhM49T-yl7l8wFSN1sQ#25-hydroxycholesterol), a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599)
[This inhibit il1b synthesis/activation. Repress cholesterol biosynthetic enzymes]

25-Hydroxycholesterol acts as an amplifier of inflammatory signaling

anandamide converts into (20-HETE-EA & EpETrE-EAs)
**20-HETE-EA**

**EpETrE-EA = (±)8(9)-EET Ethanolamide**
(The physiological actions of (±)8(9)-EET ethanolamide have not been examined.)

![](https://hackmd.io/_uploads/BJFFCCB9s.png "EpETrE-EAs" =300x)
**EpETrE-EA = (±)11(12)-EET Ethanolamide**
(Evidence for the formation of 11(12)-EET ethanolamide in vivo has not been documented)
Changed with psy.

## cyp2d6 & melatonin

See melatonin
https://hackmd.io/@sholmqvist/BJpKurTBB/%2FGM9BEBVTQLmcV6ha-pQO8w#Melatoni

Cyp2d22 // cyp2d6 converts melatonin back into serotonin via 5-mythoxytryptamine (&Ache)

## Cyp2f1
naphthalene

## Cyp2f2
Cyp2f2p
pseudo

Shares promoter with:
EGLN2 (-AS1)

**Also** cyp2f2 is up by NAdr and ACh treated astrocytes. See astro+neurotransmitters.

This gene is pseudo in humans. But enriched in the pituitary. [Support secretion association]

Increased when astrocytes exposed to ACh

Zdhhc:s transfer lipid in recycling of proteins (membrane shuttle).
Zdhhc1
Zdhhc2
Zdhhc3
Zdhhc4
Zdhhc5
Zdhhc7
Zdhhc8
Zdhhc13
Zdhhc24

## Cyp2r1
## Cyp2r9
## Cyp2s1
All-trans-retinoic acid
retinoid substrates

peroxidase and isomerase activities toward various oxygenated eicosanoids such as prostaglandin H2 (PGH2) and hydroperoxyeicosatetraenoates (HPETEs)

## Cyp2t1P
Shared promoter
CYP2T1P
piR-57430-001
lnc-CYP2A6-3ENSG00000293405

CYP2T1P
ENSG00000269843
SNRPA
HNRNPUL1
ZNF780B
ENSG00000205041
AKT2
CCDC97
ITPKC
# Cyp1b1
[I suspect that this is handling something glutamate related] Downregulated upon psy.

# CYP2J2
Shared enchancer:
piR-33422-006
lnc-C1orf87-1

Hs CYP2J2 (601258), an arachidonic acid (AA) epoxygenase
Mm Cyp2j9 (astro) Cyp2j13

epoxidation of double bonds of PUFA (PubMed:19965576, 8631948)

Cyp2j9
Cyp2j13

## Cyp2r1
5 exons like Cyp2u1, not like other Cyp2:s which have 9. [Specialized to a small molecule?]
CYP2R1 (608713), a microsomal vitamin D-25 hydrolase

### Hydroxylation-induced activation
performs the first step in the activation of vitamin D by catalyzing the formation of 25-hydroxyvitamin D

Vitamin D 25-hydroxylase activity is also possessed by some other cytochrome P450 enzymes, in particular CYP27A1, which is found in mitochondria.

## Cyp2u1
CYP2U1
5 exons like Cyp2r1, not like other Cyp2:s which have 9. [Specialized to a small molecule? Are these perhaps not membrane bound?]

Three patients had cognitive impairment and 5 had a subclinical axonal neuropathy. In the same study, Tesson et al. (2012) identified pathogenic mutations in the DDHD1 gene (614603) as a cause of SPG28 (609340). Both the **DDHD1** and CYP2U1 gene products were expressed concomitantly in the developing mouse brain (omim)

[2020 - Cytochrome P450 2U1 Is a Novel Independent Prognostic Biomarker in Breast Cancer Patients](https://www.frontiersin.org/articles/10.3389/fonc.2020.01379/full)

[2017 Review - Cytochrome P450 2U1, a very peculiar member of the human P450s family](https://pubmed.ncbi.nlm.nih.gov/28083596/)

[2014 - Oxidation of Endogenous N-Arachidonoylserotonin by Human Cytochrome P450 2U1*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036169/)

The product (2-oxo) was 4-fold less active than N-arachidonoylserotonin in inhibiting fatty acid amide hydrolase.

Arachidonoyl serotonin is an endogenous lipid signaling molecule. It was first described in 1998 as being an inhibitor of fatty acid amide hydrolase (FAAH = Fatty Acid Amide Hydrolase // Anandamide Amidohydrolase 1)

**FAAH & FAAH2- dismantel amide lipids.**
Catalyzes hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide),
the endocannabinoid anandamide


Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates

### Hydroxylation-induced inactivation
ω-hydroxylate

CYPU21 along with members of the CYP4A and CYP4F sub-families also ω-hydroxylate and thereby reduce the activity of various fatty acid metabolites of arachidonic acid including LTB4, 5-HETE, 5-oxo-eicosatetraenoic acid, 12-HETE, and several prostaglandins that are involved in regulating various inflammatory, vascular, and other responses in animals and humans.

# Cyp2a7p1
CYP2A7P1

Enhancer/promoter
CYP2B7P
ENSG00000291083
CYP2B6
ZNF780B (Hs)
ENSG00000205041
SNRPA
HNRNPUL1
ENSG00000269843
CCDC97
ZNF780
ACOQ8B
CYP2G1P
ENSG00000269069AKT2

# DDHD1
Phosphatidic Acid-Preferring Phospholipase A1 Homolog
gene cutting off phosphatidic acid.

![](https://i.imgur.com/EZnHxha.png "Phospatidic acid" =100x) 

PA important to cell signaling and direct activation of [**lipid-gated ion channels**](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FPqRHnwoCQE2vfdv9-shjeA#lipid-gated-ion-channel)

# CYP3A7
CYP3A7-CYP3A51P (readthrough)

Cyp3a51
pseudogene is located between the CYP3A7 and CYP3A5 family members

# Cyp4

## Cyp4Z2P
Predicted to enable several functions, including heme binding activity; iron ion binding activity

# Cyp7a1

# Cyp11a
Cholesterol Side-Chain Cleavage Enzyme, Mitochondrial

# CYP11B2
[See Aldosterone](https://hackmd.io/@sholmqvist/BJpKurTBB/https%3A%2F%2Fhackmd.io%2FFOjKsFP4SYymP2GLRCIE2A#Mineralocorticoids)

Corticosterone is converted to aldosterone by aldosterone synthase (CYP11B2)

Aldosterone synthase is a protein which is only expressed in the zona glomerulosa[5] of the adrenal cortex and is primarily regulated by the renin–angiotensin system

It is the sole enzyme capable of synthesizing aldosterone in humans and plays an important role in electrolyte balance and blood pressure.[7]

Adrenocorticotropic hormone (ACTH // POMC) is assumed to play a role in the regulation of aldosterone synthase likely through stimulating the synthesis of 11-deoxycorticosterone which is the initial substrate of the enzymatic action in aldosterone synthase.[11]

# CYP21A1P
Promoter/enhancer
C4A-AS1
CYP21A1P
NONHSAG045970.2
NONHSAG045781.2-001
CYP21A2

# CYP21A2
Steroid 21-Hydroxylase
A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis. Catalyzes the hydroxylation at C-21 of progesterone and 17alpha-hydroxyprogesterone to respectively form 11-deoxycorticosterone and 11-deoxycortisol, intermediate metabolites in the biosynthetic pathway of mineralocorticoids and glucocorticoids (PubMed:10602386, 16984992, 22014889, 25855791, 27721825).

TF:
Zic2

The ZIC proteins are defined by the presence of a zinc finger domain that consists of five Cys2His2-type zinc fingers and which is most closely related to the zinc finger domain of the GLI, GLIS, and NKL families.

Zic2 was necessary and sufficient to regulate RGC axon repulsion by cues at the optic chiasm midline. Moreover, expression of Zic2 correlated with the extent of binocularity in pigmented mouse, albino mouse, ferret, frog, and chicken. Herrera et al. (2003) concluded that ZIC2 is an evolutionarily conserved determinant of RGCs that project ipsilaterally.

Zic3
ZIC3 is a nucleocytoplasmic shuttling protein that uses CRM1 for nuclear export.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11113920/#:~:text=The%20ZIC%20proteins%20are%20defined%20by%20the

# Cyp24a1
Needed for breakdown of excess vitamin D.

People with variant get sick from too much vitamin D. (giving kidney issues)

HyPercalcemia. That is mineralization of calcium is high.

# Cyp27a1
Linnarsson - oligos.
Cytochrome P450 monooxygenase that catalyzes regio- and stereospecific hydroxylation of cholesterol and its derivatives. Hydroxylates (with R stereochemistry) the terminal methyl group of cholesterol side-chain in a three step reaction to yield at first a C26 alcohol, then a C26 aldehyde and finally a C26 acid (PubMed:12077124, 21411718, 28190002, 9660774). Regulates cholesterol homeostasis by catalyzing the conversion of excess cholesterol to bile acids via both the 'neutral' (classic) and the 'acid' (alternative) pathways (PubMed:11412116, 1708392, 2019602, 7915755, 9186905, 9660774, 9790667). May also regulate cholesterol homeostasis via generation of active oxysterols, which act as ligands for NR1H2 and NR1H3 nuclear receptors, modulating the transcription of genes involved in lipid metabolism (PubMed:12077124, 9660774).

# Cyp27b1
[See Vitamin D](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FVRxXizYGTSmR_hDbuSI8LQ#Vitamin-D)
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

# PA
Phosphatididic acid

They constitute about 0.25% of phospholipids in the bilayer.

# lipid-gated ion channel
[Should be moved]
lots of (wiki) here...

## PIP2-gated channels
Kir Channels are lipid gated.

Phosphatidylinositol 4,5-bisphosphate (PIP2) was the first and remains the best studied lipid to gate ion channels. PIP2 is a cell membrane lipid, and its role in gating ion channels represents a novel role for the molecule.[1][2]

Kir channels: PIP2 binds to and directly activates inwardly rectifying potassium channels (Kir).[3] The lipid binds in a well-defined ligand binding site in the transmembrane domain and causes the helices to splay opening the channel. All members of the Kir super-family of potassium channels are thought to be directly gated by PIP.[1]

Kv7 channels: PIP2 binds to and directly activates Kv7.1.[4] In the same study PIP2 was shown to function as a ligand. When the channel was reconstituted into lipid vesicles with PIP2 the channel opened, when PIP2 was omitted the channel was closed.[4]

TRP channels: TRP channels were perhaps the first class of channels recognized as lipid-gated.[5] PIP2 regulates the conductance of most TRP channels either positively or negatively. For TRPV5, binding of PIP2 to a site in the transmembrane domain caused a conformational change that appeared to open the conduction pathway,[6] suggesting the channel is classically lipid-gated. A PIP2 compatible site was found in TRPV1 but whether the lipid alone can gate the channels has not been shown.[2] Other TRP channels that directly bind PIP2 are TRPM8 and TRPML.[7][8] Direct binding does not exclude PIP2 from affecting the channel by indirect mechanisms.

[See TRP channels]

## PA-gated channels
Phosphatidic acid (PA) recently emerged as an activator of ion channels.[9]

K2p: PA directly activates TREK-1 potassium channels
nAChR: PA also activates the nAChR in artificial membranes
Kv: PA binding can also influence the midpoint of voltage activation (Vmid) for voltage-activated potassium channels.

## PG-gated channels
Phosphatidylglycerol(PG) is an anionic lipid that activates many channels including most of the PA activated channels. The physiological signaling pathway is not well studied, but PLD can produce PG in the presence of glycerol[15] suggesting the same mechanism that is thought to generate local PA gradients could be generating high local PG gradients as well.

## Mechano sensitive channels
A specialized set of mechanosensitive ion channels is gated by lipid deformation in the membrane in response to mechanical force

[A theory involving the lipid membrane, called "force from lipid", is thought to directly open ion channels.[16] (Wiki)](https://en.wikipedia.org/wiki/Lipid-gated_ion_channels#:~:text=Lipid%2Dgated%20ion%20channels%20are,properties%20of%20a%20classic%20ligand.)

PIP2

# UGTs
Uridine diphosphate
Uridine = Pyrimidine (not purine as ATP )
 

UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. (Omics PG).

[ 2014 The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication (Front. Cell. Neurosci.)](https://www.frontiersin.org/articles/10.3389/fncel.2014.00349/full)

:::spoiler
FIGURE 1. MECHANISM OF THE GLUCURONIDATION REACTION CATALYZED BY UDP-GLUCURONOSYLTRANSFERASES (UGT). Glucuronidation is a bi-substrate reaction which requires an aglycone (for example, a phenol) and a high energy glucuronic acid donor, UDP-α-D-glucuronic acid, which is the common substrate to all UGT isoforms. The reaction leads to the release of UDP and formation of a β-D-glucuronide. UGT belongs to the inverting glycosyltransferase family which utilizes a direct SN2-like mechanism involving a base (B) catalyst. Structurally unrelated substances, brain transmitters and drugs against brain disorders that are UGT substrates are shown: 1, **serotonin**; 2, **dopamine**; 3, morphine; 4, **valproic acid**; 5, oxazepam; 6, lamotrigine; 7, apomorphine; 8, **ethanol**.
:::

<br>

Arachidonic acid C20:4w6

Alox# // Lox = Leukotrienes

Cox // PTGS1 = PGH2 -> Prostaglandins.
Cyclooxygenase

[2021 Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. (Nature.Signal Transduction and Targeted Therapy)](https://www.nature.com/articles/s41392-020-00443-w)


**Hs**
B3GAT1 B3GAT2 B3GAT3 UGT1A1 UGT1A3 UGT1A3 UGT1A4 UGT1A4 UGT1A5 UGT1A5 UGT1A6 UGT1A6 UGT1A6 UGT1A7 UGT1A7 UGT1A7 UGT1A8 UGT1A8 UGT1A8 UGT1A9 UGT1A9 UGT1A9 UGT1A10 UGT1A10 UGT1A10 UGT2A1 UGT2A2 UGT2A3 UGT2B4 UGT2B7 UGT2B10 UGT2B11 UGT2B15 UGT2B17 UGT2B28

**Mm**
B3gat1 B3gat2 B3gat3 Ugt1a1 Ugt1a5 Ugt1a2 Ugt1a5 Ugt1a2 Ugt1a5 Ugt1a2 Ugt1a6a Ugt1a7c Ugt1a6b Ugt1a8 Ugt1a10 Ugt1a9 Ugt1a8 Ugt1a10 Ugt1a9 Ugt1a8 Ugt1a10 Ugt1a9 Ugt1a8 Ugt1a10 Ugt1a9 Ugt2a1 Ugt2a2 Ugt2a3

## UGP2
[See Magnesium in Ions](https://hackmd.io/@sholmqvist/BJpKurTBB/https%3A%2F%2Fhackmd.io%2FmkCWgpLJQWWBSjCGd1yDtA#Magnesium)

"Conversion of carbohydrates"
UDP-Glucose Pyrophosphorylase 1

It transfers a glucose moiety from glucose-1-phosphate to MgUTP and forms UDP-glucose and MgPPi.