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I've been looking through PDB — the Protein Data Bank — and I noticed that the protein with the most structures is human carbonic anhydrase II (UniProt: P00918), with over a thousand X-ray structures.

This seems surprising to me, as carbonic anhydrase is a zinc-containing enzyme which catalyses a really simple reaction, and doesn’t seem to be part of any key signalling pathways. In terms of relevance to disease or as a drug target, all I could find was on DrugBank was a few glaucoma drugs which have this as their target (diclofenamide, methazolamide, acetazolamide), and those are really old (60 years).

So, what is it about carbonic anhydrase that makes it so interesting? Is it that more or better drugs are needed to target it? (For what disease?) Is it that it’s a really interesting scientific model of a metalloenzyme? Or something else?

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  • $\begingroup$ Answering this question really needs some hard work, and we expect the poster to make a start looking through the PDB entries in terms of date/CA type/species/whether they have an associated paper/whether they relate to a complex with another molecule. Have you looked at some of the recent and older papers in which the work is reported to see how they justify their work and who funded it? Please do, and let us know what you find. $\endgroup$
    – David
    Sep 17 at 15:54

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It certainly is related to disease! There are tons of inhibitors (as David mentioned in the comments Aslam & Gupta 2022 ). The reaction is simple but maintaining the pH of your blood is essential (keep a perfect equilibrium between $CO_2$ and $CO_3^{2-}$). It's essential because pH determines if hemoglobin binds/releases $O_2$.

It's so famous because every beginner biochemistry course will talk about carboanhydrase at some point. The enzyme is very stable and can be purified relatively simply from blood, which was possible even 60 years ago. It helped early biochemists understand enzyme kinetics. Carboanhydrase in particular was interesting, since it has a ridiculously fast turnover rate ($10^6$ molecules per second). That makes it perfect to describe enzyme kinetics ($K_m$ and $k_{cat}$) and also chemical equilibria in general.

Bob1 pointed out that some courses even require you to crystallize, make an x-ray structure of carboanhydrase and submit the result. So carboanhydrase is like the absolute tutorial enzyme of biochemistry, which explains the inflated structure count.

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    $\begingroup$ It certainly is related to disease. I had a look at the hits on PDB, and a huge number are of inhibitors of CA. I searched for "Carbonic Hydrase Inhibitors" and found a short piece on this topic on NCBI Bookshelf that starts: "Carbonic anhydrase inhibitors are a medication used to manage and treat glaucoma, idiopathic intracranial hypertension, altitude sickness, congestive heart failure, and epilepsy, among other diseases." Why else would you determine the structure of protein that has already been done, and who would fund you? $\endgroup$
    – David
    Sep 15 at 21:58
  • $\begingroup$ @David True, I found a few links to diseases too but the number of structures still seems like way more than the disease relevance would suggest. Surely not enough to be the most studied enzyme - still somewhat puzzling $\endgroup$
    – Alex I
    Sep 16 at 0:03
  • $\begingroup$ @AlexI I think you will find that as per the second part of Markur's answer, a number of courses for biochem will have "purify, grow crystals, X-ray diffract and submit structure" as part of the course requirements. $\endgroup$
    – bob1
    Sep 16 at 0:55
  • $\begingroup$ @AlexI — This was a comment/criticism of the first sentence of this answer. It was not an answer to your question. I do not answer questions in comments. When/if I have considered the matter I will give you a balanced answer. $\endgroup$
    – David
    Sep 16 at 7:18
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Carbonic Anhydrase is heavily researched because of carbon dioxide capture.

It’s hoped to be used in getting $CO_2$ from combustion exhaust to hydrogen carbonate, and thence to other capture reactions in industrial settings.

Also for possible more efficient plant $CO_2$ capture, so plants can grow better with less water loss.

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  • $\begingroup$ This is very interesting, but would mainly make sense if those were (eg) extreme thermostable or pH-stable versions; rcsb.org has 1000 structures of plain old human CA2, so I feel this can't be the whole answer $\endgroup$
    – Alex I
    Sep 16 at 0:33

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