Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Nat Struct Mol Biol. 2024 Oct;31(10):1502-1508. doi: 10.1038/s41594-024-01315-5. Epub 2024 May 20.
Lysosomal transmembrane acetylation of heparan sulfates (HS) is catalyzed by HS acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), whose dysfunction leads to lysosomal storage diseases. The mechanism by which HGSNAT, the sole non-hydrolase enzyme in HS degradation, brings cytosolic acetyl-coenzyme A (Ac-CoA) and lysosomal HS together for N-acyltransferase reactions remains unclear. Here, we present cryogenic-electron microscopy structures of HGSNAT alone, complexed with Ac-CoA and with acetylated products. These structures explain that Ac-CoA binding from the cytosolic side causes dimeric HGSNAT to form a transmembrane tunnel. Within this tunnel, catalytic histidine and asparagine approach the lumen and instigate the transfer of the acetyl group from Ac-CoA to the glucosamine group of HS. Our study unveils a transmembrane acetylation mechanism that may help advance therapeutic strategies targeting lysosomal storage diseases.
溶酶体跨膜乙酰化肝素硫酸（HS）由 HS 乙酰辅酶 A：α-葡糖胺 N-乙酰转移酶（HGSNAT）催化，其功能障碍导致溶酶体贮积病。HGSNAT 是 HS 降解中唯一的非水解酶，它将胞质乙酰辅酶 A（Ac-CoA）和溶酶体 HS 结合在一起进行 N-酰基转移反应的机制尚不清楚。在这里，我们展示了单独的 HGSNAT、与 Ac-CoA 以及与乙酰化产物结合的冷冻电镜结构。这些结构解释了 Ac-CoA 从胞质侧结合导致二聚体 HGSNAT 形成跨膜隧道。在这个隧道内，催化组氨酸和天冬酰胺接近内腔，并引发乙酰基从 Ac-CoA 转移到 HS 的葡萄糖胺基团。我们的研究揭示了一种跨膜乙酰化机制，可能有助于推进针对溶酶体贮积病的治疗策略。
