Mechanism-based inhibition of GH127/146 cysteine glycosidases by stereospecifically functionalized L-arabinofuranosides
Mechanism-based inhibition of GH127/146 cysteine glycosidases by stereospecifically functionalized L-arabinofuranosides
复制标题
DOI：
10.1016/j.bmc.2022.117054
复制
发表时间：
2022-11-02
影响因子：
3.5
通讯作者：
Ito，Yukishige
中科院分区：
文献类型：
--
作者：
Ishiwata，Akihiro;Narita，Satoru;Ito，Yukishige
为了解糖苷水解酶（GH）家族127的确切作用机制，从人肠道菌群的长双歧杆菌（Bifidobacterium longum）中分离到一种半胱氨酸β-l-阿拉伯呋喃糖苷酶（Arafase）-HypBA 1-，并设计合成了基于作用机制的抑制剂l-Araf-卤代乙酰胺。使用α-l-Araf-叠氮衍生物作为单糖胺等效物，通过施陶丁格反应，然后在有/没有歧化的情况下形成酰胺，以高度立体选择性的方式得到β-Araf-氯乙酰胺（α/β-1-Cl）以及溴乙酰胺（α/β-1-Br）。对于HypBA 1，探针1，特别是在α/β-1-Br的情况下，抑制水解。这些意见的构象影响进行了讨论，在这份手稿。使用1-Araf-叠氮化物（α/β-5）的额外检查导致对GH 127/146半胱氨酸糖苷酶的进一步机制观察，包括作为底物的β-5的水解和使用GH 127同系物的α-5的氧化抑制。
To understand the precise mechanism of the glycoside hydrolase (GH) family 127, a cysteine β-l-arabinofuranosidase (Arafase) – HypBA1 – has been isolated fromBifidobacterium longumin the human Gut microbiota, and the design and synthesis of the mechanism-based inhibitors such asl-Araf-haloacetamides have been carried out. The α-l-Araf-azide derivative was used as the monoglycosylamine equivalent to afford thel-Araf-chloroacetamides (α/β-1-Cl) as well as bromoacetamides (α/β-1-Br) in highly stereoselective manner through Staudinger reaction followed by amide formation with/without anomerization. Against HypBA1, the probes1, especially in the case of α/β-1-Br inhibited the hydrolysis. Conformational implications of these observations are discussed in this manuscript. Additional examinations usingl-Araf-azides (α/β-5) resulted in further mechanistic observations of the GH127/146 cysteine glycosidases, including the hydrolysis of β-5as the substrate and oxidative inhibition by α-5using the GH127 homologue.