8e8v
From Proteopedia
Structure of the short LOR domain of human AASS bound to N-ethylsuccinimide
Structural highlights
DiseaseAASS_HUMAN Hyperlysinemia;Saccharopinuria. The disease is caused by mutations affecting the gene represented in this entry. The protein represented in this entry is involved in disease pathogenesis. A selective decrease in mitochondrial NADP(H) levels due to NADK2 mutations causes a deficiency of NADPH-dependent mitochondrial enzymes, such as DECR1 and AASS.[1] FunctionAASS_HUMAN Bifunctional enzyme that catalyzes the first two steps in lysine degradation. The N-terminal and the C-terminal contain lysine-ketoglutarate reductase and saccharopine dehydrogenase activity, respectively. Publication Abstract from PubMedIn 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. Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1.,Leandro J, Khamrui S, Suebsuwong C, Chen PJ, Secor C, Dodatko T, Yu C, Sanchez R, DeVita RJ, Houten SM, Lazarus MB Open Biol. 2022 Sep;12(9):220179. doi: 10.1098/rsob.220179. Epub 2022 Sep 21. PMID:36128717[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
