8E8V

Structure of the short LOR domain of human AASS bound to N-ethylsuccinimide

8E8V の概要

• エントリーDOI: 10.2210/pdb8e8v/pdb
• 分子名称: Alpha-aminoadipic semialdehyde synthase, mitochondrial, 1-ETHYL-PYRROLIDINE-2,5-DIONE (2 entities in total)
• 機能のキーワード: lysine metabolism, ketoglutarate, mitochondrial, reductase, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 193897.11

構造登録者

Khamrui, S.,Lazarus, M.B. (登録日: 2022-08-25, 公開日: 2022-10-05, 最終更新日: 2024-11-06)

主引用文献

Leandro, J.,Khamrui, S.,Suebsuwong, C.,Chen, P.J.,Secor, C.,Dodatko, T.,Yu, C.,Sanchez, R.,DeVita, R.J.,Houten, S.M.,Lazarus, M.B.
Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1.
Open Biology, 12:220179-220179, 2022

PubMed Abstract: In humans, a single enzyme 2-aminoadipic semialdehyde synthase (AASS) catalyses the initial two critical reactions in the lysine degradation pathway. This enzyme evolved to be a bifunctional enzyme with both lysine-2-oxoglutarate reductase (LOR) and saccharopine dehydrogenase domains (SDH). Moreover, AASS is a unique drug target for inborn errors of metabolism such as glutaric aciduria type 1 that arise from deficiencies downstream in the lysine degradation pathway. While work has been done to elucidate the SDH domain structurally and to develop inhibitors, neither has been done for the LOR domain. Here, we purify and characterize LOR and show that it is activated by alkylation of cysteine 414 by N-ethylmaleimide. We also provide evidence that AASS is rate-limiting upon high lysine exposure of mice. Finally, we present the crystal structure of the human LOR domain. Our combined work should enable future efforts to identify inhibitors of this novel drug target.

PubMed: 36128717
DOI: 10.1098/rsob.220179

実験手法

X-RAY DIFFRACTION (2.45 Å)