Talk:CYP4F2/Archive 1

Archive 1

Drug metabolism

Section states a difference between anti-malarial drugs and anti-parasitic - malaria is caused by a parasite.--Iztwoz (talk) 14:29, 25 November 2023 (UTC)

Good point. Pafuramidine is a pro-drug of furamidine. Hence these are essentially the same medication. Both are anti-malarial and anti-parasitic. Boghog (talk) 14:52, 25 November 2023 (UTC)

Thank you, I fixed these inconsistencies. Maxim Masiutin (talk) 16:29, 26 November 2023 (UTC)

Crystallographic structure

The File:CYP4F2 protein structure.png graphic does not specify where is came from. As far as I can tell, there are no experimental structures of CYP4F2, but there is an AlphaFold structure (AF_AFP78329F1). Is the File:CYP4F2 protein structure.png based on AF_AFP78329F1 or some other structure? This should be specified. According to Swiss-model, the most closely related experimental structure is CYP4B1 (PDB: 6C94​).

I have a couple of requests for the graphic of the CYP4F2 structure:

1. The background should be transparent, not white.
2. It is not clear what the color scheme represents (AlphaFold reliability?) It would be more informative to color the structure in "chainbow" (N-terminus blue, C-terminal red).
3. It would also really help to include the heme/iron cofactor in the structure. 6C94 could be overlaid on the AF_AFP78329F1, and the heme structure from 6C94 could be copied into AF_AFP78329F1.

If you would like, I could do this using PyMOL. Boghog (talk) 15:18, 25 November 2023 (UTC)

Thank you very much for your graphics! Maxim Masiutin (talk) 16:30, 26 November 2023 (UTC)

Also, thank you very much for the schematic on the chemical reaction! Maxim Masiutin (talk) 16:54, 26 November 2023 (UTC)

There are some problems with the rendering of the reaction schematic. I have submitted a bug report. If I cannot get the svg to work, I my need to replace with a png. Boghog (talk) 17:03, 26 November 2023 (UTC)

This is a known old problem, we had to post-process an SVG manually to get it accepted by Wikipedia. I can try to download it from wikimedia and upload the processed version if you wish; don't upload PNG for now.

Can you please help with HNMT:

1. by making the same 3d model as you did for CYP4F2 and CYP21A2
2. by adding a schematic of reaction when HNMT catalyzes histamine conversion N-methilhystimane (probably showing the role of SAMe)?

Maxim Masiutin (talk) 17:24, 26 November 2023 (UTC)

Just convert text to curves and it should be OK. Maxim Masiutin (talk) 17:34, 26 November 2023 (UTC)

I uploaded the SVG where all characters are "traced" to curves, so there should be no rendering issue. Maxim Masiutin (talk) 17:44, 26 November 2023 (UTC)

According to WP:MCBMOS, there should be a "Protein" section with specific information about the protein (splice variants, post translational modifications, etc.) -- I didn't find that information. Still, I written a small section. Can you please review whether it is correct? Maxim Masiutin (talk) 00:33, 27 November 2023 (UTC)

WP:MOSLEAD and really - considering the audience.

I think this reads very well, the big concern I have is - who is it really written for? I think I am a little technical, but I'm just not sure who it was ever written for, a little scope creep or perhaps written from the get go like this.

The observation was made by other editors - and would go even further. "drop the details of each study. This is far too detailed for a Wikipedia article – the average reader doesn’t need to know the number of study participants. "has been confirmed by a study of 21 participants with different CYP4F2*3 variants enrolled (8 for *1/*1, 7 for *1/*3, and 6 for *3/*3).[57] The inhibitory effect of sesamin has been confirmed by a randomized, controlled crossover trial, where 33 overweight "

I think the lede is making assumptions - as to the knowledge of any 'even a technical reader' - it presumes a heck of a lot of knowledge in many scientific fields - the required organic chemistry knowledge is likely at grad/undergrad level - biochem/pre-med/chem/org. chem or even molecular biology - I think this is hard to debate.

In the lede I would consider removing the super techy lingo and then slowly introducing it in a thoughtful way - why are CYP enzymes so well studied and of such importance? Start there and then get fancy later. I likely have missed something as to the scope of WP.

I'd go for something in the lede with the vague tone of:

"Cytochrome P450 4F2, is an enzymatic protein that is made in the human body from information located in the CYP4F2 gene, is a crucial protein in humans with a significant role in metabolism. This enzyme is involved in metabolic processing of internal substances, such as fatty acids, and many external substances, it is important in metabolizing drugs. Cytochrome P450 4F2 plays a role in regulating inflammation levels in the body. This function is essential for maintaining a balanced and healthy immune response in the human body. It is a member of a large group of well-studied enzymes called the cytochrome P450 superfamily, this enzyme is encoded in a cluster of genes located on chromosome 19. Notably, it has the capability to bioactivate and chemically transform specific prodrugs, transforming them into their active therapeutic metabolites. For instance, it converts the prodrug pafuramidine into its active form, furamidine. This ability to chemically transform is important in a number of similar therapeutic applications by members of this enzyme class. Genetic variations in the CYP4F2 gene can impact enzymatic activity, carrying implications for drug dosing. Additionally, these variations can influence the bioavailability of fat-soluble vitamins like E and K. Particularly noteworthy is the impact on Vitamin K, which, in turn, affects the dosing of Vitamin K antagonists such as the blood thinner warfarin or coumarin. These medicines are important therapeutic agents used to treat conditions such as atrial fibrillation (aFib), a common cause of strokes, Understanding these genetic variations is crucial for optimizing drug therapy and ensuring proper vitamin intake for individuals."

More broadly:

If you read something like the Encyclopedia Britannica's take on these deeper technical subjects, they are terse, light weight and really focused on a more typical reader of encyclopedic materials - though I think WP has some better 'takes' on some technical subjects - though it is super variable.

So IS the target audience - a college level Biochem/Premed type - it is unlikely a pro., and I doubt many HS Biol/Science students are exposed to much more than 'what is an enzyme'.

I recall the theme of opening ledes as think of 'talking to a person without any real/deep super knowledge of the subject' initially and then building the article as one introduces new and more sophisticated ideas and terminology.

I do not see that here, it leaps deep into the discussion at a very high level - certainly undergraduate Biochem. Though lower down it does talk this way - but not really in the lede.

I worked in a number of biotech startups were CYP enzymes were largely the target of therapeutic agents - I think if you peruse this term "CYP and clinical targets of therapy" - it will provide a lot of hits - like:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657965/#:~:text=Human%20cytochrome%20P450%20(CYP)%20enzymes,%2C%20cellular%20metabolism%2C%20and%20homeostasis.

Perhaps disease states and CYP are another reason I might read it.

1. I'd argue this 'value as a therapeutic target' is at least ONE of the most important reasons a typical individual might want to read such an article.
2. Is the enzyme at present in any active clinical studies - as a therapeutic target obviously, I once worked for a renal therapeutic outfit called 'Cytochroma' - they are still around in some shape or form - this was back in the 2000s but 'CYP' modulation agents were a part of their portfolio - hence the company name.
3. I think I would offer the following input - I am a bit biased as I think most WP readers of these articles are not professional researchers and again per GA guidance - who really is the target audience:

a. Make the lede a super gentle introduction, moving materials of why these enzymes are important in a clinical/commercial/health context - into part of the lede - or at least higher in the article.

b. Build the article much more slowly, assuming the individual has a HS level education - so around 12 years of formal education. Perhaps even the first year of a decent University. In 2023 this is hard to gauge - but the thinking is sound.

c. I actually am not sure what GA guidance is for an article in this niche - I should read that before offering any deeper opinions.

d. The are many 'side' discussions that refer to chemical processes that this enzyme is involved in (mixed-function oxidation reactions, plus some reductions and rearrangements of oxygenated species) so it leaps into an organic chemistry dialog in numerous areas - I think that again is expecting the reader to be more knowledgeable than most are. I think maintaining a tighter scope about the subject, makes it an easier read.

Provided in good faith.

Dr. BeingObjective (talk) 19:41, 25 November 2023 (UTC)

Lede mods - they do change the tone and audience by the changes made.

@Maxim Masiutin

I really like the changes made to the lede - I added a little more - the thinking is - it starts as a specific discussion, the protein/enzyme - then talks to the role of the superfamily of enzymes - now the CYP sub-enzymes are better studied - and then goes back to the specific - enzyme-substrate and then the content makes more sense.

There is a LOT of data on the superfamily of CYPS - but I would check what I wrote makes sense - I added one citation - I would check I did not plagiarize it - so many similar sentence structures are used in these types ot journals.

I think the lede now sets the stage for a broader discussion - I think you made other changes - but the lede really expands the audience now - many folks should know the superfamily - it is taught in British HS at O and A level - so, now the audience should be 'a reasonably informed person.

Cheers Dr. BeingObjective (talk) 00:40, 26 November 2023 (UTC)

Thank you, I tried to further improve your edits to address the audience issues that you raised.

1) I copied the text (that you added to lead) to the main body and referenced it there to remove references from lead;

2) I tried to explain some notions, for instance, in the "Function" section, after "oxidative meabolism" I added "which generally makes the substrate more water-soluble and so more readily excreted by the kidneys". Maxim Masiutin (talk) 07:06, 26 November 2023 (UTC)

I think this is very good - there are two themes that are worth expanding on.

The specific - this is an article about one defined enzyme but it is a subset of the larger cytochrome family - I think what is common to all CYP enzymes and what is unique to CYP4F2 makes for a good discussion.

The broader class are known to anyone who has taken Biochem/Biology to even O level standard - now GCSE (16+ exam) in the UK - the more narrow specific functions these are new to me as they were likely not well defined when I was in University and even when I worked in this research business space.

I do see the article differently now - just small adds - enzyme/protein/catalyst in the lede - to me, add really big value - it is still an encyclopedia and not a peer reviewed journal - so all of the article that make assumptions of a knowledge base, likely could be treated this way - I need to understand the Wikiprojects and a lot of articles I think - can only be directed at graduate molecular biologists - I might be way off on what WP is thinking.

Making information as broadly accessible as possible has to be within the Wikipedia ethos and also makes it a GA candidate inherently - does this make sense?

That is why we are all here surely -

I could see many more similar articles. Or they might exist and could be refined.

The human genome encodes at least 57 CYPs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657965/#:~:text=Human%20CYPs&text=In%20looking%20at%20the%20fraction,43%20subfamilies%20(Table%201).

BeingObjective (talk) 11:07, 26 November 2023 (UTC)

I added some minor edits, such as sections or clarifications for the distinction.

I am concerned about the statement that CYPs reside in liver. There are some CYPs such as CYP11 and CYP21 that reside exclusively in the adrenal gland. Maxim Masiutin (talk) 15:28, 26 November 2023 (UTC)

I also added information to the clinical significance section and looking for information on what can we describe on the role of CYP4F2 as an enzyme that controls inflammation, as various inducers and inhibitors of CYP4F2 may affect inflammatory processes in the body; probable role of CYP4F2 in autoimmune disorders. Maxim Masiutin (talk) 08:09, 26 November 2023 (UTC)

I need to read a lot more - there whole field on inflammation is a massive area - cytokines and such - and it is well studied - as heart disease is an inflammatory process this fits into my core interests - so I am happy to take some effort to research the literature - I think there a numerous GA potential articles just sitting out there -

Tangential note - I think I mentioned the benzodiazepine article which has GA status - but I do not think it is GA worthy due to all of the little 'nugget adds' I'd ask you to work with me on that one - perhaps recruiting another objective editor - it has 'defenders of the faith' folks who watch it like a hawk - with three editors - it would be easier to change for the better - perhaps a project for next year - Benzodiazepine - I need to start a list and learn how to make sub-pages.

BeingObjective (talk) 11:18, 26 November 2023 (UTC)

I didn't notice anything bad in the article of Benzodiazepine, probably because I accustomed to Wikipedia and its style already :-( Maxim Masiutin (talk) 15:17, 26 November 2023 (UTC)

I might be biased - a lot of little adds seem to occur and some 'lingo' that is really not very clinical - in truth it might even be in a publication - but it is not always a credible clinical way of speaking and communicating - might be my personal bias.

BeingObjective (talk) 15:27, 26 November 2023 (UTC)

Yes, this is how it works in Wikipedia. No central editor-in-chief, and all people add small information here and there. Maxim Masiutin (talk) 15:56, 26 November 2023 (UTC)

Indeed - totally understood. I note at least three articles I have contributed to - seemed totally 'abandoned' - think I mentioned the only reason I looked at the DES and colonoscopy and stress test articles - they stalled out in 2009. I will get used to it - and I understand one can request an article can be 'locked down' to some degree to stop the wilder IP edits - BeingObjective (talk) 16:04, 26 November 2023 (UTC)

This CYP4F2 article also totally stalled. Probably, interest of people fades in Wikipedia, probably due to the fact that they think that the evironment is hostile/toxic. Maxim Masiutin (talk) 16:06, 26 November 2023 (UTC)

I apologize for asking this - I know I can research this on my own.

I want to create a few articles from scratch - I can start with the sandbox - I think - and then look for a template - can you give me a jump start - I think you gave me materials already - yes, I have a serious lazy streak - but your directives are FAR easier to follow than the WP directives - I tend to get very lost.

You had a few ideas - are these still things you want to work on?

I think I am not super interested in the HTML/ML part of WP - I will get onboard with things, but it takes time - should I select a template and drop it into the sandbox - any help is appreciated and I know this makes me seem super lazy - because I am - I like to help - but learning the tags - and the scripting stuff - others seem to be interested in this - BogHog and Wham2001.

Asking for a helping hand to jump start something unique - cheers Dr. BeingObjective (talk) 16:23, 26 November 2023 (UTC) -

Ermm - the toxic ref. Well, it began that way - but seems to have evaporated. Not sure if there is a correlation - but as soon as I created a detailed User Page - the nasty tone seems to have changed - not sure if there is a connection but I do not care - as long as folks are not being hostile - it has greatly improved, one does wonder why. BeingObjective (talk) 16:28, 26 November 2023 (UTC)

Let me reply on your user talk page. Maxim Masiutin (talk) 16:38, 26 November 2023 (UTC)

Citations/Refs - not sure what happened to the ref - https://www.frontiersin.org/articles/10.3389/fphar.2022.1043836/full#:~:text=CYP450s%20belonging%20to%20CYP%20families,safety%2C%20bioavailability%2C%20and%20toxicity.

I think this is where the 80 percent figure came from - I confess Cytochrome Oxidase as a CYP - I guess so, but it is fairly important in ATP synthesis etc. BeingObjective (talk) 13:01, 26 November 2023 (UTC)

It is better to put references via the PMID number (36353494) and the citation filler https://citation-template-filling.toolforge.org/cgi-bin/index.cgi Maxim Masiutin (talk) 15:20, 26 November 2023 (UTC)

Understood - the whole citation deal is still a bit hit and miss for me. BeingObjective (talk) 15:23, 26 November 2023 (UTC)

Key reference materials. Talking about the broader P450 family.

https://pubmed.ncbi.nlm.nih.gov/22680629/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093435/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093435/#:~:text=Cytochrome%20P450%20(CYP)%20is%20a,drug%20interactions%20can%20be%20profound. BeingObjective (talk) 12:48, 26 November 2023 (UTC)

Thank you! I split the text into subsestions to address broader families with "See also". Maxim Masiutin (talk) 15:14, 26 November 2023 (UTC)

Makes sense - really not a big change. I was not clear on why this was rejected initially as a GA - what was the actual reason ?- I did read the section, but cannot say I was clear on the issue.

BeingObjective (talk) 15:29, 26 November 2023 (UTC)

It was 2 years ago an the article was in bad state yet. Maxim Masiutin (talk) 15:59, 26 November 2023 (UTC)

I think it is now - to me - an article I would make an effort to peruse.

BeingObjective (talk) 16:32, 26 November 2023 (UTC)