METABOLIC PATHWAYS

Metabolic Pathways

Cellular metabolism involves the chemical changes that occur within a cell, resulting in the breakdown and the synthesis of molecules which are usually catalysed by enzymes. Metabolic pathways are a series of enzyme catalysed reactions where the product from one reaction becomes the substrate for another. The process of a metabolic pathway allows for a more powerful change in a molecule than a single enzyme, as the process involves breaking several bonds.

Antimetabolites are antibiotics that disrupt essential metabolic pathways that occur within bacterial cells. They are competitive inhibitors in that their structure is similar enough to that of a bacterial metabolite to interfere with the process, however they do not provide metabolic functionality within the cell.

An example of a bacterial metabolic pathway is that used to synthesise tetrahydrofolic acid (THF), the active form of folic acid (Murima et al., 2014) (see Figure 1).

Figure 1. The tetrahydrofolic acid (THF) metabolic pathway.

One component in the pathway is Para aminobenzoic acid (PABA), which is outcompeted by sulphonamide, which is a structural analogue and antimetabolite (see Figure 2). The presence of sulphonamide block the dihydropteroate synthetase from reacting with PABA, thus disrupting the beginning of the THF metabolic pathway.

Similarly, another component in the pathway, dihydrofolic acid (DHF), is out-competed by trimethoprim, a structural analogue and antimetabolite. The presence of trimethoprim blocks the metabolic pathway by preventing the enzyme dihydrofolate (DHF) reductase from reacting with DHF.

Unlike animals, bacteria must synthesise folic acid themselves, therefore animal cells are not affected by these molecules, which gives these drugs selective toxicity for bacterial cells (Sköld, 2009).

Figure 2. The chemical structures of para-aminobenzoic acid (PABA) and analogue sulfanilamide.

References

Murima P, McKinney JD, Pethe K, (2014) Targeting Bacterial Central Metabolism for Drug Development. Chemistry & Biology. 21(11): 1423-1432.

Sköld O (2009) Sulfonamides and Trimethoprim. In: Mayers D.L. (eds) Antimicrobial Drug Resistance. Infectious Disease. Humana Press. Available at: https://doi.org/10.1007/978-1-59745-180-2_23.