Li Rongfeng, Lichstrahl Michael S, Zandi Trevor A, Kahlert Lukas, Townsend Craig A
Department of Chemistry, The Johns Hopkins University, 3400 N Charles St, Baltimore, MD, USA.
T. C. Jenkins Department of Biophysics, The Johns Hopkins University, Baltimore, MD, USA.
iScience. 2024 Feb 12;27(3):109202. doi: 10.1016/j.isci.2024.109202. eCollection 2024 Mar 15.
Non-ribosomal peptide synthetases (NRPSs) assemble metabolites of medicinal and commercial value. Both serine and threonine figure prominently in these processes and separately can be converted to the additional NRPS building blocks 2,3-diaminopropionate (Dap) and 2,3-diaminobutyrate (Dab). Here we bring extensive bioinformatics, and experimentation to compose a unified view of the biosynthesis of these widely distributed non-canonical amino acids that both derive by pyridoxal-mediated β-elimination of the activated -phosphorylated substrates followed by β-addition of an amine donor. By examining monobactam biosynthesis in and in species where it is silent, we show that (2,3)-Dab synthesis depends on an l-threonine kinase (DabA), a β-replacement reaction with l-aspartate (DabB) and an argininosuccinate lyase-like protein (DabC). The growing clinical importance of monobactams to both withstand Ambler Class B metallo-β-lactamases and retain their antibiotic activity make reprogrammed precursor and NRPS synthesis of modified monobactams a feasible and attractive goal.
非核糖体肽合成酶（NRPSs）可组装具有药用和商业价值的代谢产物。丝氨酸和苏氨酸在这些过程中都起着重要作用，并且它们可分别转化为另外的NRPS构件2,3-二氨基丙酸（Dap）和2,3-二氨基丁酸（Dab）。在此，我们运用广泛的生物信息学和实验方法，以构建这些广泛分布的非经典氨基酸生物合成的统一观点，这些氨基酸均通过吡哆醛介导的活化磷酸化底物的β-消除反应，随后进行胺供体的β-加成反应而产生。通过研究在其体内有单环β-内酰胺生物合成以及在无此合成的物种中的情况，我们表明（2,3）-Dab的合成依赖于一种L-苏氨酸激酶（DabA）、一种与L-天冬氨酸的β-取代反应（DabB）以及一种精氨琥珀酸裂解酶样蛋白（DabC）。单环β-内酰胺在耐受安布勒B类金属β-内酰胺酶并保持其抗生素活性方面日益增长的临床重要性，使得对修饰的单环β-内酰胺进行重新编程的前体和NRPS合成成为一个可行且有吸引力的目标。
