Asset Details
Do you wish to reserve the book?
Investigation of the threonine metabolism of Echinococcus multilocularis: the threonine dehydrogenase as a potential drug target in alveolar echinococcosis
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
Investigation of the threonine metabolism of Echinococcus multilocularis: the threonine dehydrogenase as a potential drug target in alveolar echinococcosis
Do you wish to request the book?
Investigation of the threonine metabolism of Echinococcus multilocularis: the threonine dehydrogenase as a potential drug target in alveolar echinococcosis
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Paper
Investigation of the threonine metabolism of Echinococcus multilocularis: the threonine dehydrogenase as a potential drug target in alveolar echinococcosis
2024
Overview
Alveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. We recently showed that E. multilocularis metacestode vesicles scavenge large amounts of L-threonine from the culture medium that were neither stored nor overused for protein synthesis. This motivated us to study the effect of L-threonine on the parasite and how it is metabolized. We established a novel metacestode vesicle growth assay with an automated readout, which showed that L-threonine treatment led to significantly increased parasite growth. In addition, L-threonine increased the formation of novel metacestode vesicles from primary parasite cell cultures in contrast to the non-proteinogenic threonine analog 3-hydroxynorvaline. Tracing of [U-13C]-L-threonine and metabolites in metacestode vesicles and culture medium resulted in the detection of [U-13C]-labeling in aminoacetone and glycine, indicating that L-threonine was metabolized by threonine dehydrogenase (TDH). In addition, the detection of [13C2]-glutathione, suggested that E. multilocularis metacestode vesicles synthesize glutathione via L-threonine-derived glycine. EmTDH-mediated threonine metabolism in the E. multilocularis metacestode stage was further confirmed by quantitative real-time PCR, which demonstrated high expression of emtdh in in vitro cultured metacestode vesicles and also in metacestode samples obtained from infected animals. EmTDH was enzymatically active in metacestode vesicle extracts. Thus, the drugs disulfiram, myricetin, quercetin, sanguinarine and seven quinazoline carboxamides were assessed for inhibition of recombinantly expressed EmTDH, and the most potent inhibitors disulfiram, myricetin and sanguinarine were further tested for activity against E. multilocularis metacestode vesicles and primary parasite cells. Sanguinarine exhibited significant in vitro activity and IC50-values for metacestode vesicles, primary parasite cells, as well as mammalian cells were determined. Our results suggest that sanguinarine treatment should be further assessed in vivo employing suitable AE mouse models. Furthermore, the EmTDH assay could serve as high-throughput target-based discovery platform for novel anti-echinococcal compounds.
Publisher
Cold Spring Harbor Laboratory
Subject
