Folate Biosynthesis Pathway Enzyme Inhibition

Folate coenzymes are pivotal for one-carbon transfers in nucleotide and amino acid metabolism. Microorganisms synthesise folate de novo, making the pathway an attractive target for antimicrobial and antiparasitic agents. Inhibition of enzymes such as dihydroneopterin aldolase, dihydropteroate synthase and dihydrofolate reductase disrupts essential folate production, arresting DNA synthesis and cellular proliferation. Structure-guided design has enabled the identification of active-site inhibitors that mimic pterin substrates or exploit unique conformations of catalytic loops. Recent advances in crystallography, molecular dynamics and medicinal chemistry have refined our understanding of enzyme–inhibitor interactions, facilitating the development of compounds with submicromolar potency and improved selectivity. These efforts underscore the global significance of targeting folate biosynthesis to combat drug resistance in pathogens such as Mycobacterium tuberculosis and Staphylococcus aureus, and to inform next-generation antifolate therapies.

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Folate Biosynthesis Pathway Enzyme Inhibition publication trend

The graph below shows the total number of articles in folate biosynthesis pathway enzyme inhibition across all publications each year (not limited to Nature Index journals).

Technical terms

Dihydroneopterin aldolase (DHNA): An enzyme that converts 7,8-dihydroneopterin to dihydropterin in the folate synthesis pathway.

Dihydropteroate synthase (DHPS): The enzyme that catalyses the condensation of p-aminobenzoic acid with dihydropterin pyrophosphate to form dihydropteroate.

8-Mercaptoguanine: A pterin-analogue inhibitor that targets catalytic sites in DHNA and HPPK enzymes.

IC50: The concentration of an inhibitor required to reduce enzyme activity by fifty per cent under defined conditions.

References

1. Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity. Journal of Enzyme Inhibition and Medicinal Chemistry (2024).
2. Crystallographic and molecular dynamics simulation analysis of Escherichia coli dihydroneopterin aldolase. Cell & Bioscience (2014).
3. The Structural and Functional Basis for Recurring Sulfa Drug Resistance Mutations in Staphylococcus aureus Dihydropteroate Synthase. Frontiers in Microbiology (2018).