Interaction of 31 β-lactam antibiotics with the H+/peptide symporter PEPT2:: analysis of affinity constants and comparison with PEPT1
Interaction of 31 β-lactam antibiotics with the H+/peptide symporter PEPT2:: analysis of affinity constants and comparison with PEPT1
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DOI：
10.1016/j.ejpb.2004.07.008
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发表时间：
2005-01-01
影响因子：
4.9
通讯作者：
Brandsch, M
中科院分区：
文献类型：
--
作者：
Luckner, P;Brandsch, M
肾脏肽转运体PEPT2和PEPT1的活性决定了治疗期间青霉素和头孢菌素的循环半衰期，以及肝脏和血浆代谢稳定性等其他因素。本研究旨在系统地研究β -内酰胺类抗生素与PEPT2的相互作用。31种头孢菌素和青霉素与载体蛋白的相互作用通过测量它们抑制肾SKPT细胞摄取[C-14]Gly-Sar的能力来表征。PEPT2对头孢丙塞、头孢克洛、环西林、头孢定、头孢氨苄和莫拉西坦具有非常高的亲和力，可与天然二肽相媲美（K-i = 3-100 muM）。头孢布顿、双氯西林、阿莫西林、氨苄西林、氯西林、氨苄西林、头孢克肟、头孢曼多尔、奥西林和头孢美唑与PEPT2的相互作用具有中等亲和力（K-i = 0.1-5 mM）。对于其他β -内酰胺类抗生素，相互作用非常低或无法测量（K-i > - 5 mM）。β -内酰胺类抗生素在rPEPT2和hPEPT1位点的亲和常数有显著相关，但等级顺序不相同。PEPT1和PEPT2对化合物n端部分识别的决定性差异变得明显。此外，β -内酰胺类抗生素亲和常数的大数据集将有助于PEPT2的结构-运输（结合）分析。(C) 2004 Elsevier B.V.版权所有
The activity of the renal peptide transporters PEPT2 and PEPT1 determines-among other factors such as metabolic stability in liver and plasma-the circulatory half-life of penicillins and cephalosporins during therapy. This study was initiated to examine systematically the interaction of beta-lactam antibiotics with PEPT2. Interaction of 31 cephalosporins and penicillins with the carrier protein was characterized by measuring their ability to inhibit the uptake of [C-14]Gly-Sar into renal SKPT cells. Cefadroxil, cefaclor, cyclacillin, cephradine, cephalexin and moxalactam were recognized by PEPT2 with very high affinity comparable to that of natural dipeptides (K-i = 3-100 muM). Ceftibuten, dicloxacillin, amoxicillin, metampicillin, cloxacillin, ampicillin, cefixime, cefamandole, oxacillin and cefmetazole interacted with PEPT2 with medium affinity (K-i = 0.1-5 mM). For the other beta-lactam antibiotics studied interaction was very low or not measurable (K-i > 5 mM). The affinity constants of beta-lactam antibiotics at rPEPT2 and hPEPT1 are significantly correlated, but the rank orders are not identical. Decisive differences between PEPT1 and PEPT2 recognition of the N-terrninal part of the compounds became evident. Moreover, this large data set of affinity constants of beta-lactam antibiotics will be useful for structure-transport (binding) analyses of PEPT2. (C) 2004 Elsevier B.V. All rights reserved.