Institute of Microbiology, Chinese Academy of Sciences, Beijing 100190, China.
Carbohydr Res. 2011 Sep 27;346(13):1714-20. doi: 10.1016/j.carres.2011.05.024. Epub 2011 May 30.
GlmM and GlmU are key enzymes in the biosynthesis of UDP-N-acetyl-d-glucosamine (UDP-GlcNAc), an essential precursor of peptidoglycan and the rhamnose-GlcNAc linker region in the mycobacterial cell wall. These enzymes are involved in the conversion of two important precursors of UDP-GlcNAc, glucosamine-6-phosphate (GlcN-6-P) and glucosamine-1-phosphate (GlcN-1-P). GlmM converts GlcN-6-P to GlcN-1-P, GlmU is a bifunctional enzyme, whereby GlmU converts GlcN-1-P to GlcNAc-1-P and then catalyzes the formation of UDP-GlcNAc from GlcNAc-1-P and uridine triphosphate. In the present study, methyl 2-amino-2-deoxyl-α-d-glucopyranoside 6-phosphate (1α), methyl 2-amino-2-deoxyl-β-d-glucopyranoside 6-phosphate (1β), two analogs of GlcN-6-P, were synthesized as GlmM inhibitors; 2-azido-2-deoxy-α-d-glucopyranosyl phosphate (2) and 2-amino-2,3-dideoxy-3-fluoro-α-d-glucopyranosyl phosphate (3), analogs of GlcN-1-P, were synthesized firstly as GlmU inhibitors. Compounds 1α, 1β, 2, and 3 as possible inhibitors of mycobacterial GlmM and GlmU are reported herein. Compound 3 showed promising inhibitory activities against GlmU, whereas 1α, 1β and 2 were inactive against GlmM and GlmU even at high concentrations.
GlmM 和 GlmU 是 UDP-N-乙酰-d-葡萄糖胺（UDP-GlcNAc）生物合成中的关键酶，UDP-GlcNAc 是肽聚糖的必需前体和分枝杆菌细胞壁中鼠李糖-GlcNAc 连接区的前体。这些酶参与 UDP-GlcNAc 的两个重要前体，即葡萄糖胺-6-磷酸（GlcN-6-P）和葡萄糖胺-1-磷酸（GlcN-1-P）的转化。GlmM 将 GlcN-6-P 转化为 GlcN-1-P，GlmU 是一种双功能酶，GlmU 将 GlcN-1-P 转化为 GlcNAc-1-P，然后催化 GlcNAc-1-P 和尿苷三磷酸形成 UDP-GlcNAc。在本研究中，甲基 2-氨基-2-脱氧-α-d-吡喃葡萄糖苷 6-磷酸（1α）和甲基 2-氨基-2-脱氧-β-d-吡喃葡萄糖苷 6-磷酸（1β），作为 GlmM 抑制剂的 GlcN-6-P 的两种类似物；2-叠氮基-2-脱氧-α-d-吡喃葡萄糖基磷酸（2）和 2-氨基-2,3-二脱氧-3-氟-α-d-吡喃葡萄糖基磷酸（3），GlcN-1-P 的类似物，首先作为 GlmU 抑制剂被合成。报道了化合物 1α、1β、2 和 3 作为潜在的分枝杆菌 GlmM 和 GlmU 抑制剂。化合物 3 对 GlmU 表现出有希望的抑制活性，而 1α、1β 和 2 即使在高浓度下对 GlmM 和 GlmU 也没有活性。
