Berges D A, DeWolf W E, Dunn G L, Grappel S F, Newman D J, Taggart J J, Gilvarg C
J Med Chem. 1986 Jan;29(1):89-95. doi: 10.1021/jm00151a015.
Succinyl-CoA:tetrahydrodipicolinate-N-succinyltransferase is a key enzyme in the biosynthesis of diaminopimelic acid (DAP), a component of the cell wall peptidoglycan of nearly all bacteria. This enzyme converts the cyclic precursor tetrahydrodipicolinic acid (THDPA) to a succinylated acyclic product. L-2-Aminopimelic acid (L-1), an acyclic analogue of THDPA, was found to be a good substrate for this enzyme and was shown to cause a buildup of THDPA in a cell-free enzyme system but was devoid of antibacterial activity. Incorporation of 1 into a di- or tripeptide yielded derivatives that exhibited antibacterial activity against a range of Gram-negative organisms. Of the five peptide derivatives tested, (L-2-aminopimelyl)-L-alanine (6) was the most potent. These peptides were shown to inhibit DAP production in intact resting cells. High levels (30 mM) of 2-aminopimelic acid were achieved in the cytoplasm of bacteria as a result of efficient uptake of the peptide derivatives through specific peptide transport systems followed, presumably, by cleavage by intracellular peptidases. Finally, the antibacterial activity of these peptides could be reversed by DAP or a DAP-containing peptide. These results demonstrate that the peptides containing L-2-aminopimelic acid exert their antibacterial action by inhibition of diaminopimelic acid biosynthesis.
琥珀酰辅酶A：四氢二吡啶甲酸-N-琥珀酰转移酶是二氨基庚二酸（DAP）生物合成中的关键酶，DAP是几乎所有细菌细胞壁肽聚糖的组成成分。该酶将环状前体四氢二吡啶甲酸（THDPA）转化为琥珀酰化的非环状产物。L-2-氨基庚二酸（L-1）是THDPA的非环状类似物，被发现是该酶的良好底物，在无细胞酶系统中显示会导致THDPA积累，但没有抗菌活性。将1掺入二肽或三肽中得到的衍生物对一系列革兰氏阴性菌具有抗菌活性。在所测试的五种肽衍生物中，（L-2-氨基庚二酰基）-L-丙氨酸（6）活性最强。这些肽在完整的静息细胞中能抑制DAP的产生。由于肽衍生物通过特定的肽转运系统有效摄取，随后可能被细胞内肽酶裂解，细菌细胞质中可达到高浓度（30 mM）的2-氨基庚二酸。最后，这些肽的抗菌活性可被DAP或含DAP的肽逆转。这些结果表明，含L-2-氨基庚二酸的肽通过抑制二氨基庚二酸生物合成发挥抗菌作用。
