Disease relevance of PF14_0192

• Our results corroborate the concept that intraerythrocytic inhibition of glutathione reductase mimicks the biochemistry of drug-sensitive glucose-6-phosphate dehydrogenase deficiency (favism), an inherited condition which confers protection from malaria [1].

High impact information on PF14_0192

• The crystal structure of modified human GR at 1.9-A resolution provides the first picture of protein inactivation by peroxynitrite and reveals that this is due to the exclusive nitration of 2 Tyr residues (residues 106 and 114) at the glutathione disulfide-binding site [2].
• By oxidizing the catalytic dithiol to a disulfide, peroxynitrite itself can act as a substrate of unmodified and bisnitrated P. falciparum glutathione reductase [2].
• The homodimeric flavoenzyme glutathione reductase (GR) maintains high intracellular concentrations of the antioxidant glutathione (GSSG + NADPH + H(+) <--> 2 GSH + NADP(+)) [3].
• The malarial parasite Plasmodium falciparum is known to be sensitive to oxidative stress, and thus the antioxidant enzyme glutathione reductase (GR; NADPH+GSSG+H(+) <==> NADP(+)+2 GSH) has become an attractive drug target for antimalarial drug development [4].
• The antimalarial mode of action appears to be multifaceted and includes extensive damage to membranes, the alteration of intracellular organelles, and enzymatic inhibition not only of DHFR-TS but also of glutathione reductase and thioredoxin reductase [5].

Biological context of PF14_0192

• These regions are of particular interest since they represent binding sites of known GR inhibitors [6].

Anatomical context of PF14_0192

• Glutathione reductase-deficient erythrocytes as host cells of malarial parasites [1].

Associations of PF14_0192 with chemical compounds

• These systems are NADPH-dependent and based on the catalytic activity of the flavoenzymes glutathione reductase, trypanothione reductase and thioredoxin reductase (TrxR), respectively [7].
• To direct both a 4-aminoquinoline and a GR inhibitor to the parasite, double-drugs were designed and synthesized [8].
• Quinoline-based alcohols (with known antimalarial activity) were combined with a GR inhibitor via a metabolically labile ester bond to give double-headed prodrugs [8].
• Antimalarial action of flavin analogues seems not be due to inhibition of glutathione reductase of host erythrocytes [9].
• The two drugs were used for preparing red cell populations with various levels of glutathione reductase activity; complete inhibition (greater than or equal to 98%) was only achieved when the medium contained glucose as a source of reducing equivalents [1].

Other interactions of PF14_0192

• Purification, characterization and kinetic properties of the multifunctional thioredoxin-glutathione reductase from Taenia crassiceps metacestode (cysticerci) [10].

Analytical, diagnostic and therapeutic context of PF14_0192

• Molecular cloning and characterization of a putative glutathione reductase gene, the PfGR2 gene, from Plasmodium falciparum [11].

References