Department of Microbiology and Biotechnology, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
University of Almería, Carr. Sacramento, s/n, 04120 La Cañada, Almería, Spain.
FEMS Microbiol Lett. 2023 Jan 17;370. doi: 10.1093/femsle/fnad096.
In this work, we present the first inhibitor of GlnA2Sc, a gamma-glutamylpolyamine synthetase, which allows Streptomyces coelicolor to detoxify high concentrations of polyamines and to utilize them as a carbon or nitrogen source. GlnA2 belongs to the class of glutamine synthetase-like (GS-like) enzymes that catalyze the glutamylation of different nitrogen-containing compounds. Whereas a number of inhibitors for GS are known, none of them are known to inhibit GlnA2. In this work, PPU268, an inhibitor for GlnA2 is presented that is structurally derived from the prototypic GS inhibitor-methionine sulfoximine (MSO). It combines two features: the binding mechanism of MSO and the amine substrate specificity of GlnA2Sc. This inhibitor is a novel compound to block the polyamine utilization in bacteria resulting in the inability to detoxify polyamines. This may offer a possibility to develop novel therapeutic strategies to combat actinobacterial human pathogens that encounter polyamines in the course of the infection processes.
在这项工作中，我们首次提出了 GlnA2Sc 的抑制剂，它是一种γ-谷氨酰多胺合成酶，使草分枝杆菌能够解毒高浓度的多胺，并将其用作碳源或氮源。GlnA2 属于谷氨酰胺合成酶样（GS-like）酶类，能够催化不同含氮化合物的谷氨酸化。虽然已经有一些 GS 的抑制剂，但没有一种已知能够抑制 GlnA2。在这项工作中，我们提出了 PPU268，它是 GlnA2 的抑制剂，其结构来源于典型的 GS 抑制剂-甲硫氨酸亚砜（MSO）。它结合了两个特点：MSO 的结合机制和 GlnA2Sc 的胺底物特异性。这种抑制剂是一种新型化合物，可以阻断细菌中多胺的利用，导致无法解毒多胺。这可能为开发新的治疗策略提供了可能性，以对抗在感染过程中遇到多胺的放线菌人类病原体。
