脂質結合糖鎖の新規分解機構を解明~アスパラギン結合型糖鎖代謝制御の全容解明に向けた一歩~

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2025-09-29 理化学研究所,東京大学,トロント大学

理化学研究所・東京大学・トロント大学の国際共同研究チームは、N型糖鎖の前駆体である「ドリコール結合糖鎖(DLO)」を分解する酵素 DLO-ピロフォスファターゼ(DLO-PP’ase) の遺伝子を、パン酵母で世界で初めて同定し「LLP1」と命名した。LLP1はカビや酵母に保存され、一部のバクテリアではバンコマイシン耐性に関与するVanZ遺伝子と相同関係を持つことが判明。LLP1欠損株では異常なDLOが蓄積し、ゴルジ体局在の本酵素が糖鎖の量・質の制御に必須であることが示された。脂質結合糖鎖分解の新機構を解明した本成果は、糖鎖代謝異常疾患や創薬研究に大きな意義を持つ。

脂質結合糖鎖の新規分解機構を解明~アスパラギン結合型糖鎖代謝制御の全容解明に向けた一歩~
DLO-PP’ase、LLP1の機能

<関連情報>

LLP1はドリコール結合オリゴ糖の恒常性維持と品質管理に関与するピロホスファターゼである
LLP1 is a pyrophosphatase involved in homeostasis/quality control of dolichol-linked oligosaccharide

Sheng-Tao Li,Katsuhiko Kamada,Akinobu Honda,Junichi Seino,Tsugiyo Matsuda,Takehiro Suzuki,Naoshi Dohmae,Yuichi Shichino,Shintaro Iwasaki,Yoichi Noda,Michael Costanzo,Charles Boone,Tadashi Suzuki
Journal of Cell Biology  Published:September 29 2025
DOI:https://doi.org/10.1083/jcb.202501239

Dolichol-linked oligosaccharide (DLO) is the precursor for asparagine (N)-linked protein glycosylation. DLO synthesis can be impaired by genetic and environmental factors, leading to the accumulation of various immature DLO intermediates that are subsequently cleaved into phosphorylated oligosaccharides (POSs). Despite the fact that its activity has been known since the 1970s, the identity of the enzyme has not been clarified. Here, we identified a Saccharomyces cerevisiae gene encoding a DLO-pyrophosphatase (Llp1), which converts DLO to POSs. Intriguingly, LLP1 mRNA was translated through a programmed +1 translational frameshifting. LLP1 orthologs encode members of VanZ family proteins, which are found in various bacteria and fungi. Llp1 and its substrate DLO are likely to be localized in the Golgi, and when LLP1 was knocked out, abnormal DLO modified by Golgi mannosyltransferases accumulated, which is consistent with a role in DLO homeostasis/quality control. This study provides insights into how the cellular levels and quality of DLOs are maintained in eukaryotes.

有機化学・薬学
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