Plasmodium falciparum thymidylate kinase (PfTMK) can tolerate a range of substrates, which distinguishes it from other thymidylate kinases. The enzyme not only phosphorylates TMP and dUMP but can also tolerate bulkier purines, namely, dGMP, GMP, and dIMP. In order to probe the flexibility of PfTMK in accommodating ligands of various sizes, we developed 6 mutant enzymes and subjected these to thermodynamic, inhibitory and catalytic evaluation. Kinase activity was markedly affected by introducing a larger lysine residue instead of A111. The lack of the hydroxyl group after inducing mutation of Y107F affected enzyme activity, and had a more severe impact on dGMP kinase activity. PfTMK can be inhibited by both purine and pyrimidine nucleosides, raising the possibility of developing highly selective drugs. Thermodynamic analysis revealed that enthalpic forces govern both purine and pyrimidine nucleoside monophosphate binding, and the binding affinity of both substrates was highly comparable. The heat produced due to dGMP binding is lower than that attributable to TMP. This indicates that additional interactions occur with TMP, which may be lost with larger dGMP. Targeting PfTMK not only affects thymidine nucleotide synthesis but may also affect purine nucleotides, and thus the enzyme represents an attractive antimicrobial target.

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Gentamicin (GM) is an aminoglycoside antibiotic that possesses a wide range of anti-microbial activity. Currently, uses of gentamicin are narrowed due to it supposedly induces nephrotoxicity. Therefore, the aim of this study is to evaluate the possible nephron-protective effect of wheat germ oil (WGO), and its antioxidant potential against gentamicin-induced toxicity in Wistar albino rats. Forty rats were randomly assigned to four different groups (Ten animals each); Group I was administered normal saline and acts as a control group. Group II was received WGO at a dose of (3 mg/kg by stomach gavage) daily for the 15 successive days. Group III was administered gentamicin at the dose of (100 mg/kg i.p.) daily for 10 successive days. Group IV was given WGO as group II and one hour latter rats were treated with gentamicin as in group III. Rats in group III showed significant increases (p≤0.05) in serum creatinine and blood urea nitrogen (BUN) as well as renal malondialdehyde (MDA) levels together with significant (p≤0.05) reduction in glutathione (GSH) level and catalase (CAT) and superoxide dismutase (SOD) activities. In rats of group IV, creatinine and BUN levels were significantly (p≤0.05) reduced. Furthermore, renal GSH level and CAT and SOD activities were significantly (p≤0.05) increased in comparison to group III. Histopathological examination revealed variable grades of renal tissue alterations ranged from moderate to severe degrees of glomerular atrophy, vascular congestion, hemorrhage, tubular dilatation, necrosis and hyalinization in group III. In contrast, renal tissue in rats of group IV revealed glomerular cellularity of control group, reduction of tubular injury, and decreasing of collagen deposition. Therefore, WGO can effectively decrease the GM-induced renal injury as monitored by lipid peroxidation and histopathological examination.