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I have this question - Q. Competitive inhibitor which binds to the enzyme (a) has structural similarity with the product (b) is chemically similar to the substrate (c) has physical structure similar to the substrate (d) both option (b) and (c)

I'm confused between options (c) and (d). I looked up the answer and it said option (c). But say, for example, malonate [inhibitor] and succinate [substrate] for the enzyme succinic dehydrogenase, inhibitor and substrate are chemically similar as well :

enter image description here

Image source - https://www.toppr.com/ask/en-bh/question/the-activity-of-succinate-dehydrogenase-is-inhibited-by/

Kindly explain the answer to this question.

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    $\begingroup$ You've found an example where they are chemically similar; that doesn't mean this holds for all cases. A lemon is a sour fruit, that doesn't mean all fruit is sour. $\endgroup$
    – Bryan Krause
    Oct 19, 2023 at 14:38
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    $\begingroup$ MCQs are educational poison, as this example illustrates. Option (a) refers to “structural similarity with the product“, whereas (c) refers to “a physical structure similar to the substrate”. What is the difference between “structural similarity with” and “a physical structure similar to”? None that is apparent to me. So the question is designed to trick the student, not to see if he understands what a competitive inhibitor is. This is completely unforgivable. If I want to know if a student knows how a competitive inhibitor works, I ask him. If I’m employed to teach him I mark his answer. $\endgroup$
    – David
    Oct 19, 2023 at 15:33
  • $\begingroup$ @BryanKrause I've just been introduced to this topic so I guess my knowledge is pretty limited, I looked up the internet too but couldn't find anything. It would be a great help if you could give me an example where the substrate and competitive inhibitor are NOT chemically similar. Thanks:) $\endgroup$ Oct 19, 2023 at 18:29
  • $\begingroup$ @ApogeePoint Tubocurarine at nicotinic acetylcholine receptors? Bicuculline for GABA receptors? Though at some point it depends on what you mean by "chemically similar" since this is a very non-specific, qualitative description. I'd very much agree with David on this that it's better to understand what competitive inhibition is than to learn answers to MCQs like this one. $\endgroup$
    – Bryan Krause
    Oct 19, 2023 at 18:52
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    $\begingroup$ I also think the MCQ is simply wrong/misleading, as it's only necessary for competitive inhibitors to interfere directly with binding; it need not fit in exactly the same way as the normal substrate. But, for the concept it's trying to teach, it's only really important to recognize that concept. If you continue in biology education you'll learn that almost everything you learn has an exception. $\endgroup$
    – Bryan Krause
    Oct 19, 2023 at 18:54

1 Answer 1

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Like others commenting, I am not impressed with this question's answers even as multiple-choice questions go. Depending on how the question is interpreted, all 4 could be argued to be correct.

But only C is always true for a competitive inhibitor. The others are true for some competitive inhibitors, but not all.

What characterizes competitive inhibition (rather than non-competitive and uncompetitive inhibition) is binding at the active site of the enzyme. Nothing else need be true. An inhibitor that binds the active site regardless of how or why it binds there is considered a competitive inhibitor. The other two types of inhibition rely on binding to allosteric sites (binding sites other than the active site) that affect catalysis typically by altering the tertiary or quaternary structure of the enzyme.

An enzyme's active site is characterized by its shape (the space it occupies and does not occupy), and which amino acid functional groups project into that site in order to chemically interact with substrates as a part of the mechanism by which catalysis occurs.

In order to bind to the active site, the inhibitor may but does not have to interact with the amino acid site chains involved in catalysis. But they all must be capable of fitting into the site well enough to stick there, typically through multiple low strength interactions such as Van der Waals forces. Which means the molecule must have a shape that resembles the substrate enough to fit in its place. It must have "physical structure similar to the substrate" enough to do so. Occupancy of the site prevents the substrate from fitting into the site at all and/or interacting with mechanistically important amino acid side chains. Simple capacity to interact with mechanistically important amino acid side chains is not enough if it doesn't fit into the pocket of the active site as well.

And since the core definition of a competitive inhibitor is binding to the active site and nothing else, similar physical structure is the critical factor that must always be present. Thus, C is the answer.

But there are issues that can confuse making other answers seem correct even to someone who has a reasonably good understanding of competitive inhibition. First, for enzymes catalysing reactions reversibly (such as carbonic anhydrase which can either take CO2 and water and produce bicarbonate and hydrogen ions or take bicarbonate and hydrogen ions and produce CO2 and water), the products can be substrates so one could argue A is also correct. They probably discount it because the product of the forward reaction is the substrate of the reverse. Statement A about competitive inhibitors could only be considered true for reversible reactions, whereas statement C is always true for both reversible and nonreversible catalysts.

Second, as you observed, the primary way an inhibitor has "physical structure similar to the substrate" is because it is chemically similar to the substrate. But this is not the only way. In your example consider the case where one carboxyl group (COOH) of the succinate is replaced by a nitro group (NO2). The geometry and size of the nitro group is quite similar to the carboxyl group. Thus the physical structure is also quite similar despite the chemistry being dissimilar. 3-nitropropanoate inhibits this enzyme by binding at the active site and thus would be a competitive inhibitor of the enzyme. enter image description here So the reason C is the best answer is because it is the only statement that must always be true for an inhibitor to bind at an enzyme's active site.

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  • $\begingroup$ In point of fact, option "C" is not always true for a competitive inhibitor. A competitive inhibitor does not need to resemble the substrate at all in any respect, nor does an inhibitor need to bind to the active site for (reversible) inhibition to display a competitive pattern: an allosteric inhibitor (one that binds to a site other than the active site) can display competitive kinetics. This point is very well discussed in Segel (Model 5). $\endgroup$
    – user338907
    Oct 27, 2023 at 20:11
  • $\begingroup$ Segel's famous diagram (Segel, (not Segal), p102) is also reproduced here (where Model 5 of Segel is labelled Model e). As a corollary to the above comment: binding of an inhibitor at the active site does not necessarily mean that the kinetics are competitive. The binding of I to the active site may not prevent but only impair the binding of S to the active site: an inhibitory ESI complex may form with both E and I bound at the active site. $\endgroup$
    – user338907
    Oct 28, 2023 at 0:32
  • $\begingroup$ Model 5 was initially proposed by Changeux. See here: "Models proposed by myself in 1961 for the feedback inh of L‑Thr deaminase by L‑Ile. Model 1, named ‘overlapping’, describes the classic model of competitive inhib by mutual exclusion through steric hindrance of a common site. ... the substrate and inhibitor compete for the same site on the protein. In model 2, named ‘no-overlapping’, the binding-sites for the substrate and inhibitor are topographically distinct and the interaction between them is indirect or ‘allosteric’." $\endgroup$
    – user338907
    Oct 28, 2023 at 1:44
  • $\begingroup$ In addition, an Uncompetitive (or anti-competitive) inhibitor may bind at the active site. One model for UC inhibition is where I binds to the ES complex. For a two-substrate enzyme (where UC inhibition is common) this could be at the active site for the second substrate, in which case the inhibition pattern might be UC with respect to substrate 1 but competitive with respect to substrate 2, assuming (in the simplest case) an ordered addition of substrates to form a ternary complex $\endgroup$
    – user338907
    Oct 28, 2023 at 7:22
  • $\begingroup$ user338907, who I suspect to be a physical biochemist, further illustrates the original multiple choice problem's poor quality. His comments also illustrate the difference between understanding something on an intro to biology level and an expert in the field level. I freely admit that I am not at the field expert level, my undergrad degree is in biochem, but my graduate degree is in molecular biology... meaning I am neither a particularly good biochemist nor a particularly good geneticist (as the joke goes). The more one knows, the more one knows the exceptions from classical cases. $\endgroup$
    – DrRadium
    Oct 29, 2023 at 8:33

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