Univ Paris-Sud, Laboratoire des Enveloppes Bactériennes et Antibiotiques, Institut de Biochimie et Biophysique Moléculaire et Cellulaire, UMR 8619, F-91405 Orsay, France.
Biochimie. 2013 Jun;95(6):1120-6. doi: 10.1016/j.biochi.2012.12.011. Epub 2012 Dec 25.
Murein peptide ligase (Mpl) is an enzyme found in Gram-negative bacteria. It catalyses the addition of tripeptide L-Ala-γ-D-Glu-meso-diaminopimelate to nucleotide precursor UDP-N-acetylmuramic acid during the recycling of peptidoglycan. Although not essential, this enzyme represents an interesting target for antibacterial compounds through the synthesis of alternate substrates whose incorporation into peptidoglycan might be deleterious for the bacterial cell. Therefore, we have synthesised 10 tripeptides L-Ala-γ-D-Glu-Xaa in which Xaa represents amino acids different from diaminopimelic acid. Tripeptide with Xaa = ε-D-Lys proved to be an excellent substrate of Escherichia coli Mpl in vitro. Tripeptides with Xaa = p-amino- or p-nitro-L-phenylalanine were poor substrates, while tripeptides with Xaa = D- or L-2-aminopimelate, DL-2-aminoheptanoic acid, L-Glu, L-norleucine, L-norvaline, L-2-aminobutyric acid or L-Ala were not substrates at all. Although a good Mpl substrate, the D-Lys-containing tripeptide was devoid of antibacterial activity against E. coli, presumably owing to poor uptake.
肽聚糖回收中，Murein 肽连接酶（Mpl）将三肽 L-Ala-γ-D-Glu-meso-二氨基庚二酸连接到核苷酸前体 UDP-N-乙酰胞壁酸上，这种酶存在于革兰氏阴性菌中。虽然不是必需的，但该酶是抗菌化合物的一个有趣靶点，因为可以通过合成替代底物来实现，这些替代底物的掺入可能对细菌细胞有害。因此，我们合成了 10 种三肽 L-Ala-γ-D-Glu-Xaa，其中 Xaa 代表与二氨基庚二酸不同的氨基酸。体外实验证明，Xaa = ε-D-Lys 的三肽是大肠杆菌 Mpl 的极好底物。Xaa = p-氨基或 p-硝基-L-苯丙氨酸的三肽是较差的底物，而 Xaa = D-或 L-2-氨基庚二酸、DL-2-氨基庚酸、L-Glu、L-正亮氨酸、L-正缬氨酸、L-2-氨基丁酸或 L-Ala 的三肽根本不是底物。尽管含有 D-Lys 的三肽是一种很好的 Mpl 底物，但它没有抗大肠杆菌的抗菌活性，可能是由于摄取不良所致。
