Antimetabolites

What are they? Antimetabolites are a class of drugs that interfere with compounds in the cell necessary for metabolism, usually enzymes. They work by tricking the cell into believing they are a different compound found in the cell. The cell will then try to use the antimetabolite for its chemical reactions, however, this gives the antimetabolite a chance to disrupt the cell’s function. The antimetabolite must be similar enough to bind to enzymes of another substrate. The similarity in structure allows the antimetabolite to replace another compound and the differences allow the antimetabolite to either block a reaction entirely, or change its outcome.

And introduction to antimetabolites is provided here.

One of the more common groups of antibacterial antimetabolites are sulfonamides, or sulfa drugs. All sulfa drugs have a sulfonamide functional group bonded to a carbon                                                                                                 ring  bonded to an amine group. This structure are designed to mimic para-aminobenzoic acid. When the process is working correctly, the enzyme dihydropteroate synthetase binds para aminobenzoic acid, or PABA, in a dehydration synthesis to produce an essential compound to bacteria, tetrahydrofolate. Since tetrahydrofolate has no use to humans, it’s an optimal target for an antimetabolite. PABA                                              has an amine group connected to a carbon ring that makes it compatible with dihydropteroate synthetase. The sulfonamide antimetabolite has the same structure, making it compatible with the enzyme. This is how sulfonamides are accepted by the dihydropteroate synthetase. This prevents PABA from binding with the dihydropteroate synthetase. This inhibits bacterial growth, because the bacteria can no longer synthesize a necessary compound, allowing the body’s defense mechanism to take care of the rest.

Sulfonamides consist of the sulfonamide functional group, which is essentially a sulfonyl group connected to an amine group (-S(=O)2-NH2). The actual compound of a sulfonamide will have a chemical formula similar to RSO2NH2, where R denotes some kind of an organic group (often times using a carbon ring).  Both primary and secondary amines (RNH2) can be combined with the sulfonyl chloride to create either an N-Substituted sulfonamide or an N,N-Disubstituted sulfonamide.  N-substitution stands for nucleophilic substitution, where an electron nucleophile selectively bonds with or attacks the positive charge of an atom. With a secondary amine, we would have two different instances of this. This difference in electron bonding gives the sulfonamides a wider range of bacteria which they can treat, which only increases the chances of winning the battle against the bacteria.

Antimetabolites, specifically switch antimetabolites, offer interesting insight regarding the metabolic pathways of an organism. When present in a system, antimetabolites can have a profound effect on that system’s chemical kinetics. When switch antimetabolites are ingested though antibiotics, the homeostasis of the body provides positive and negative feedback. The antimetabolite can provide inhibition for positive or negative feedback. The positive feedback of homeostasis refers to the enhancement and acceleration of the process or output which has already been activated whereas the negative feedback of homeostasis refers to the reduction of the process or output to prevent harm to the body.

The chemical kinetics at the site of positive feedback are more thoroughly addressed in this scientific journal. The journal included some surprising results about three different situations.

  1. The first and most common occurrence was when the path to synthesis was blocked off at substoichiometric concentration levels of the antimetabolite. In such a reaction with classical metabolites, inhibition would not occur unless a minimum stoichiometric concentration of antimetabolites was present.
  2. Second, inhibition was at an “all or nothing” point at specific concentrations of the antimetabolite ranging from substoichiometric to superstoichiometric values. This means the when the antimetabolite is present, the inhibition either occurs fully or not at all at random points whereas in classical metabolites, change in inhibition is continuous meaning that it partially inhibits relatively predictably at various values. However, as concentration of switch antimetabolite rose, the inhibition rate would rise and fall sharply.
  3. Finally, the inhibited system remained inhibited even after the antimetabolite was removed from the system. In a classical case, the rate of concentration change of the antimetabolite in a system should not be altered once the inhibitor has been removed.

This experiment exemplified the variations switch metabolites and classical metabolites have on the kinetics of an inhibiting reaction throughout the process of homeostasis.

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