Mutational 'hot-spots' in mammalian, bacterial and protozoal dihydrofolate reductases associated with antifolate resistance: sequence and structural comparison

Drug Resist Updat. 2009 Feb-Apr;12(1-2):28-41. doi: 10.1016/j.drup.2009.02.001. Epub 2009 Mar 9.

Abstract

Human dihydrofolate reductase (DHFR) is a primary target for antifolate drugs in cancer treatment, while DHFRs from Plasmodium falciparum, Plasmodium vivax and various bacterial species are primary targets in the treatment of malaria and bacterial infections. Mutations in each of these DHFRs can result in resistance towards clinically relevant antifolates. We review the structural and functional impact of active-site mutations with respect to enzyme activity and antifolate resistance of DHFRs from mammals, protozoa and bacteria. The high structural homology between DHFRs results in a number of cross-species, active-site 'hot-spots' for broad-based antifolate resistance. In addition, we identify mutations that confer species-specific resistance, or antifolate-specific resistance. This comparative review of antifolate binding in diverse species provides new insights into the relationship between antifolate design and the development of mutational resistance. It also presents avenues for designing antifolate-resistant mammalian DHFRs as chemoprotective agents.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Bacterial Agents / therapeutic use
  • Antimalarials / therapeutic use
  • Antineoplastic Agents / therapeutic use
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Drug Resistance / genetics*
  • Drug Resistance, Bacterial / genetics
  • Drug Resistance, Neoplasm / genetics
  • Folic Acid Antagonists / chemistry
  • Folic Acid Antagonists / therapeutic use*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Mutation*
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Protein Conformation
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*
  • Species Specificity
  • Structure-Activity Relationship
  • Tetrahydrofolate Dehydrogenase / chemistry
  • Tetrahydrofolate Dehydrogenase / genetics
  • Tetrahydrofolate Dehydrogenase / metabolism*

Substances

  • Anti-Bacterial Agents
  • Antimalarials
  • Antineoplastic Agents
  • Bacterial Proteins
  • Folic Acid Antagonists
  • Protozoan Proteins
  • Tetrahydrofolate Dehydrogenase