Antimalarial drugs capable of targeting multiple parasite stages, particularly the transmissible can be valuable tools for advancing malaria elimination agenda. Current antifolate such as pyrimethamine inhibit replicative stages in both humans and mosquitoes, but resistance remains a challenge. The lack reliable gametocyte-producing, antifolate-resistant Plasmodium falciparum laboratory strain ...

Objective Synthetic folic acid is widely used, amongst others in the prevention of neural tube defects and reducing homocysteine, a risk factor for cardiovascular disease. Its effect on intracellular folate and the activity of essential cellular folate-converting enzymes is poorly understood. Methods Six lymphoblast cell lines were cultured for 15 days with medium containing either FA, 5-methyl...

The role of protein motions in promoting the chemical step of enzyme catalysed reactions remains a subject of considerable debate. Here, a unified view of the role of protein dynamics in dihydrofolate reductase catalysis is described. Recently the role of such motions has been investigated by characterising the biophysical properties of isotopically substituted enzymes through a combination of ...

MDM2 is a ubiquitin ligase that is best known for its essential function in the negative regulation of p53. In addition, MDM2 expression is associated with tumor progression in a number of common cancers, and in some cases, this has been shown to be independent of p53 status. MDM2 has been shown to promote the degradation of a number of other proteins involved in the regulation of normal cell g...

The mouse dihydrofolate reductase (dhfr) gene possesses a bidirectional promoter that produces functional transcripts in the opposite direction. These opposite strand transcripts encode the Rep-3 gene product, a protein that has homology to DNA mismatch repair enzymes. The core of the bidirectional promoter consists of four consensus binding sites for the transcription factor Sp1. These binding...

Dihydrofolate reductase (DHFR) is the subject of intensive investigation since it appears to be the primary target enzyme for antifolate drugs. Fluorescence quenching experiments show that the ester bond-containing tea polyphenols (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) are potent inhibitors of DHFR with dissociation constants (K(D))of 0.9 and 1.8 microM, respectiv...

Methods to accurately predict potential drug target mutations in response to early-stage leads could drive the design of more resilient first generation drug candidates. In this study, a structure-based protein design algorithm (K* in the OSPREY suite) was used to prospectively identify single-nucleotide polymorphisms that confer resistance to an experimental inhibitor effective against dihydro...

An index which corresponds to charge transfer interaction is presented as a tool to study the correlation of molecular orbital (MO) distributions. The MO distribution correlation (MODIC) index was applied to Diels-Alder reaction systems (1-methoxy-1,3-butadiene—acrolein system and cyclopentadiene—maleic acid anhydride system), and the dihydrofolate reductase (DHFR) system. In the Diels-Alder re...

Over recent years many antimalarial drugs have been rendered useless by the development of resistance by the malaria parasite. New antimalarials are rapidly suffering the same fate as the traditional therapies and yet a biological understanding of the mechanisms of resistance has, until recently, not been described. This review describes recent work which has identified the mechanism of resista...

Battling malaria will be a persistent struggle without the proper means to diagnose the parasitic infection. However, the inherent limitations of microscopy, the conventional method of diagnosing malaria, affect the accuracy of diagnosis. The present study aimed to compare the accuracy of two different set of primers targeting the small subunit ribosomal RNA (ssRNA) and the dihydrofolate reduct...