Talk:Histamine N-methyltransferase/GA1

GA Review

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Reviewer: Esculenta (talk · contribs) 15:29, 9 April 2021 (UTC)

@Esculenta - we had discussions in 2023 that, if you had time in 2024, you will be able to review the revised article, if no one reviews it by that time. Could you please do that? Thank you in advance. Maxim Masiutin (talk) 12:08, 19 January 2024 (UTC)

Hi, I'll review this article. I'll need a day (or few) to post a full review, but on first glance I notice that the article is missing historical background, i.e., who discovered the enzyme, when, why, etc. Also missing is any information about the enzyme structure. How big is it? Is it made of subunits? What is the nature of its active site, etc., etc. These aspects will have to be added to the article for it to meet WIAGA criteria 3a ("it addresses the main aspects of the topic"). There's 1000's of hits for this topic on Google Scholar, including several review articles published in the past years that haven't been used as sources, so it shouldn't be difficult to find this kind of information. I see the article is listed as A-class, but I can't find a link to an A-class review ... could you kindly point me to that? Esculenta (talk) 15:29, 9 April 2021 (UTC)

Thank you, I will address the issues that you have raised. There were no A-class review :-( Maxim Masiutin (talk) 19:02, 9 April 2021 (UTC)

Ok, I read through the article and it seems to me like it is quite a ways from GA-standard.

• the lead is too short and does not adequately summarize the article’s contents
• the lead should briefly explain what histamine is and why it is important, which would help give context for the reader about the importance of the enzyme
• the lead says MNMT is involved in histamine metabolism, which is of course true, but I get few hints from the article that it inactivates histamine - this should be more explicit
• should link gene, chromosome 2
• could we have a reaction equation somewhere in the article? see here for an example
• first paragraph of “Function” needs a citation
• ”In brain of mammals histamine neurotransmitter activity is controlled by Nτ-methylation” please explain how neurotransmission is “controlled” by methylation
• ”As about the biologic species” not sure what this phrase adds, can it be left out?
• ”Whereas DAO metabolizes extracellular free histamine, be it either exogenous came with food or mostly endogenous released from granules of mast cells and basophils[8] as a result of allergic reactions, in view of the fact that DAO is mainly expressed in the cells of intestinal epithelium, HNMT is involved in metabolism of the persistently present intracellular primarily endogenous histamine, mainly in kidneys and liver, but also in bronchi, large intestine, ovary, prostate, spinal cord, spleen, trachea[9] and peripheral tissues.” This is a really long sentence that’s hard to parse and would benefit by being broken up.
• ”The most studied genetic variant is T allele at rs11558538 (c.314C>T, p.Thr105Ile),” where in the two cited sources does it support the assertion that it is “the most studied genetic variant”? The first source says it “has been the matter of several case–control association studies”, while I cannot find any such assertion in the second cited article. The shorthand jargon (c.314C>T, p.Thr105Ile) is incomprehensible for the average reader and should be explained. Also, the frequency of this allele should be mentioned (“occurring in an estimated 5 to 10% of the healthy Caucasian population” according to PMC5058861)
• why is the website for the diagnostic testing company IMD Labor Berlin used as a source? Surely a neutral secondary source could be used to cite these basic facts.
• ”In a study of 48 adults, median enzyme activity was significantly lower in subjects with the CT or TT genotype than in those with the wild-type CC genotype (485 versus 631 U/mL of red blood cells).[13] In another study of 195 subjects, the C314T variant also showed an association with serum Interleukin-8 (IL-8) levels — individuals with the CT or TT genotype had lower levels of IL-8 (1.2 ± 0.7 versus 2.1) and higher levels of histamine (107.0 ± 53.9 versus 85.6 ± 45.7 ng/mL) in comparison with individuals with the CC genotype.” This is far too detailed for a Wikipedia article – the average reader doesn’t need to know the number of study participants, nor the experimentally determined concentrations (complete with standard deviations). Additionally, reference 13 is a pilot study (i.e. a primary study) from 2006, and shouldn’t even be used in an overview article like this (see WP:SCIRS)
• per WP:SEEALSO, links already in the article shouldn’t be repeated here, so this could just be removed
• any rationale for inclusion into the lengthy “Further reading” section? Some are older primary studies
• Missing stuff:

• basic info about HNMT’s enzymology: what’s its EC number? is it inhibited by its reaction product in a negative-feedback loop? Kinetic data comparing the standard form of the enzyme with the common Thr105 variant? (e.g. what is the difference in activities between standard and Thr105 variant?)
• mention of the association with defective HNMT (i.e. SNPs) and Parkinson’s disease, ADHD, mood disorders, or decreased intellectual ability
• mention of HNMT’s role in regulating the airway response (e.g. doi:10.1152/ajplung.1994.267.3.L342
• research into use of HNMT as treatment for meth overdose doi:10.4137/DTI.S38342
• there’s an image of HNMT’s structure in the infobox, so presumably this enzyme has been crystallized. When and by whom? Are there interesting aspects of its structure that have been revealed by this work? Does it have a structure consistent with other S-adenosyl-methionine-dependent methyltransferases (e.g. a standard AdoMet binding domain)?
• only human HNMT is discussed in the article. Any info on this enzyme from other animals? Is it highly conserved? % amino acid identities?
• has there been any work done with HMNT knockout mice?
• methylhistamine is one of the products of the enzyme reaction; perhaps a few words could be said about its resulting pharmacologic activity … is it active at histamine receptors?

For these reasons, I think the article needs quite a bit of work to meet the GA criteria, specifically criteria 1a, 3a, and 3b. I think this would be best worked on outside of the time contraints of the GA review, so I am closing this review, but hope to see it back at GAN after the issues above have been addressed. Esculenta (talk) 16:34, 15 April 2021 (UTC)

@Esculenta:Thank you very much! I will edit the page to address all the issues that you have described, and will then apply again. Thank you for your time and your carefully made, valuable observations! Maxim Masiutin (talk) 20:37, 15 April 2021 (UTC)

@Esculenta: thank you very much for your detailed feedback that I hope should contribute to the article improvement. I made updates and additions to the article based on your suggestions and observations. I hope that your contributions were not in vain. Thank you very much for your attention and you help.

the lead is too short and does not adequately summarize the article’s contents

Expanded the lead.

the lead should briefly explain what histamine is and why it is important, which would help give context for the reader about the importance of the enzyme

Done.

the lead says MNMT is involved in histamine metabolism, which is of course true, but I get few hints from the article that it inactivates histamine - this should be more explicit

Done.

should link gene, chromosome 2

Done.

could we have a reaction equation somewhere in the article? see here for an example

Thank you for this suggestion, I made a similar illustration, but an improved one: emphasized the transfer of the methyl group.

first paragraph of “Function” needs a citation

Now all the paragraphs have citations except the lead that does not contain claims on its own: all the claims made in the lead are repeated in the article, with appropriate references.

”In brain of mammals histamine neurotransmitter activity is controlled by Nτ-methylation” please explain how neurotransmission is “controlled” by methylation

Explained in the lead that HNMT controls histamine neurotransmitter activity "By degrading and regulating levels of intracellular histamine...."

Also explained in the body that "In the central nervous system, HNMT plays an essential role in degrading histamine, where it acts as a neurotransmitter, since HNMT is the only enzyme in the body that can metabolize histamine in CNS, ending its neurotransmitter activity."

”As about the biologic species” not sure what this phrase adds, can it be left out?

Thank you, clarified that.

”Whereas DAO metabolizes extracellular free histamine, be it either exogenous came with food or mostly endogenous released from granules of mast cells and basophils[8] as a result of allergic reactions, in view of the fact that DAO is mainly expressed in the cells of intestinal epithelium, HNMT is involved in metabolism of the persistently present intracellular primarily endogenous histamine, mainly in kidneys and liver, but also in bronchi, large intestine, ovary, prostate, spinal cord, spleen, trachea[9] and peripheral tissues.” This is a really long sentence that’s hard to parse and would benefit by being broken up.

Thanks, split that sentence.

”The most studied genetic variant is T allele at rs11558538 (c.314C>T, p.Thr105Ile),” where in the two cited sources does it support the assertion that it is “the most studied genetic variant”? The first source says it “has been the matter of several case–control association studies”, while I cannot find any such assertion in the second cited article.

I removed the claim about "most studied".

The shorthand jargon (c.314C>T, p.Thr105Ile) is incomprehensible for the average reader and should be explained.

Thank you! Explained that.

Also, the frequency of this allele should be mentioned (“occurring in an estimated 5 to 10% of the healthy Caucasian population” according to PMC5058861)

I rather mentioned it based on information from dbSNP, for global population, to avoid discrimination (Caucasian vs rest)

why is the website for the diagnostic testing company IMD Labor Berlin used as a source? Surely a neutral secondary source could be used to cite these basic facts.

Sorry, I removed reference to this testing company and instead put the references to reviews in journals that gave the same information. For example, from a study on "Two polymorphic forms of human histamine methyltransferase" I took the claim that "Methylated histamine metabolites are excreted with urine" because it is the easiest source for such a claim, however, the study itself is not related to metabolism of histamine or its excretion. It just gave this claim in the introduction, still, this claim was peer-reviewed, making this article a secondary source.

”In a study of 48 adults, median enzyme activity was significantly lower in subjects with the CT or TT genotype than in those with the wild-type CC genotype (485 versus 631 U/mL of red blood cells).[13] In another study of 195 subjects, the C314T variant also showed an association with serum Interleukin-8 (IL-8) levels — individuals with the CT or TT genotype had lower levels of IL-8 (1.2 ± 0.7 versus 2.1) and higher levels of histamine (107.0 ± 53.9 versus 85.6 ± 45.7 ng/mL) in comparison with individuals with the CC genotype.” This is far too detailed for a Wikipedia article – the average reader doesn’t need to know the number of study participants, nor the experimentally determined concentrations (complete with standard deviations). Additionally, reference 13 is a pilot study (i.e. a primary study) from 2006, and shouldn’t even be used in an overview article like this (see WP:SCIRS)

Sorry. I removed the description of studies.

There are some references to research articles, but these articles are used as secondary sources, i.e. I do not use research findings of these articles, but use commonly accepted claims not explicitly dependent on article reseach. Therefore, this research article becomes secondary source for those claims.

per WP:SEEALSO, links already in the article shouldn’t be repeated here, so this could just be removed

OK, thank you, removed that section.

any rationale for inclusion into the lengthy “Further reading” section? Some are older primary studies

It was a legacy section that existed before I started work on this article. I removed this section.

Missing stuff:

basic info about HNMT’s enzymology: what’s its EC number? is it inhibited by its reaction product in a negative-feedback loop?

Thank you, it is indeed inhibited in a negative feedback loop. I mentioned that in the article and gave a reference.

Kinetic data comparing the standard form of the enzyme with the common Thr105 variant? (e.g. what is the difference in activities between standard and Thr105 variant?)

I removed the jargon and explained in simpler way.

mention of the association with defective HNMT (i.e. SNPs) and Parkinson’s disease, ADHD, mood disorders, or decreased intellectual ability

OK, I mentioned that based on reviews.

mention of HNMT’s role in regulating the airway response (e.g. doi:10.1152/ajplung.1994.267.3.L342

I mentioned that mucosa of bronchus is affected based on reviews, however, those reviews did not explain the details, still, that study that you mentioned is a primary one, so I was afraid to mention it. There was a mention at https://www.uniprot.org/uniprotkb/P50135/entry but it relied on a case report, which, in turn refers to a review that describes the process.

research into use of HNMT as treatment for meth overdose doi:10.4137/DTI.S38342

Thank you for pointing that out, I mentioned it!

there’s an image of HNMT’s structure in the infobox, so presumably this enzyme has been crystallized. When and by whom? Are there interesting aspects of its structure that have been revealed by this work? Does it have a structure consistent with other S-adenosyl-methionine-dependent methyltransferases (e.g. a standard AdoMet binding domain)?

I mentioned that the crystallographic structure was first described in 2001 and gave the reference to the publication of the articles where the researchers described it (primary study), as well as to secondary study. I also mentioned that it has a classic fold found in many other methyltransferases. Thank you for bringing the attention!

only human HNMT is discussed in the article. Any info on this enzyme from other animals? Is it highly conserved? % amino acid identities?

I made a brief description on HNMT in other animals, but did not describe in detail, as research on animal HNMT was mainly focused on understanding human HNMT, not as a biological field of study per se.

has there been any work done with HMNT knockout mice?

Yes, I mentioned the findings on a few studies given in a review article (mice were aggressive, etc.).

methylhistamine is one of the products of the enzyme reaction; perhaps a few words could be said about its resulting pharmacologic activity … is it active at histamine receptors?

Thank you, I explained that.

Thank you very much for such valuable contributions to the article! Maxim Masiutin (talk) 01:07, 30 November 2023 (UTC)