Abstract
ABSTRACTIn humans, a single enzyme 2-aminoadipic semialdehyde synthase (AASS) catalyzes 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 metabolic genetic diseases 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, show that AASS is rate-limiting upon high lysine exposure of mice, and present the crystal structure of the human LOR domain, which should enable future efforts to identify inhibitors of this novel drug target.
Publisher
Cold Spring Harbor Laboratory
Reference34 articles.
1. Identification of the α-Aminoadipic Semialdehyde Synthase Gene, Which Is Defective in Familial Hyperlysinemia
2. Lysine degradation through the saccharopine pathway in bacteria: LKR and SDH in bacteria and its relationship to the plant and animal enzymes
3. Genetic basis of hyperlysinemia
4. Clinical, biochemical, molecular and therapeutic aspects of 2 new cases of 2-aminoadipic semialdehyde synthase deficiency
5. Goodman, S. I. , Duran, M. In Physician’s guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases; Blau, N. , Duran, M. , Gibson, K. M. , Dionisi-Vici, C. , Eds., Springer Verlag: Heidelberg, 2014, p 691.