Different substrate recognition motifs of human and trypanosome nucleobase transporters. Selective uptake of purine antimetabolites.
The therapeutic index of antimetabolites such as purine analogues is in large part determined by the extent to which it is selectively accumulated by the target cell. In the current study we have compared the transport of purine nucleobase analogues by the H2 transporter of bloodstream form Trypanosoma brucei brucei and the equilibrative nucleobase transporter of human erythrocytes. The H2 transporter forms hydrogen bonds with hypoxanthine at positions N3, N7, N(1)H, and N(9)H of the purine ring, with apparent Delta G(0) of 7.7-12.6 kJ/mol. The transporter also appears to H-bond with the amine group of adenine. The human transporter forms hydrogen bonds that form to (6)NH(2) and N1 of adenine. An H-bond is also formed with N3 and the 6-keto and amine groups of guanine but not with the protonated N1, thus explaining the low affinity for hypoxanthine. N7 and N9 do not directly interact with the human transporter in the form of H-bonds, and it is proposed that pi-pi stacking interactions contribute significantly to permeant binding. The potential for selective uptake of antimetabolites by the parasite transporter was demonstrated.
Wallace
Lynsey J M
LJ
Institute of Biomedical and Life Sciences, Division of Infection and Immunity, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom.
Candlish
Denise
D
De Koning
Harry P
HP
D000225:Adenine / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism*; D006147:Guanine / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D019271:Hypoxanthine / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D033703:Nucleoside Transport Proteins; D011485:Protein Binding; D011487:Protein Conformation; D011687:Purines / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000378:metabolism*
D000963:Antimetabolites; D002352:Carrier Proteins; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; D011687:Purines; D019271:Hypoxanthine; D006147:Guanine; D000225:Adenine