{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,7]],"date-time":"2025-06-07T19:04:24Z","timestamp":1749323064590},"reference-count":246,"publisher":"The Royal Society of Chemistry","isbn-type":[{"value":"9781782628897","type":"print"},{"value":"9781782628897","type":"print"},{"value":"9781788012584","type":"electronic"},{"value":"9781788010177","type":"electronic"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,11,1]]},"abstract":"<jats:p>Viability of Leishmania in their hosts depends on the competence of these parasites to preserve redox homeostasis, that is, to maintain a balance between the generation and elimination of reactive oxygen and nitrogen species (ROS and RNS). In Leishmania this is achieved through the activity of several superoxide dismutases and heme peroxidases, as well as of a series of thiol-containing proteins that directly or indirectly depend on trypanothione, a conjugate of glutathione and spermidine uniquely found in trypanosomatids. The singularity of this thiol, added to the fact that it fuels many other essential parasite functions, namely heavy metal detoxification and DNA replication and repair, strengthens the prospects that the trypanothione metabolism can be exploited for improved leishmaniases chemotherapy. After briefly considering the endogenous and exogenous sources of ROS and RNS that Leishmania are subjected to during their development, we review here, from a drug-development perspective, the strategies employed by these parasites to maintain redox balance, with special emphasis on the trypanothione system. We contemplate current information and progress towards the functional characterization and validation as drug targets of the different parasite antioxidant enzymes and components of the thiol metabolism, including the pathways that lead to glutathione and spermidine uptake and biosynthesis and their conjugation to yield trypanothione. From the results of this analysis it is apparent that a strategy aimed at inhibiting trypanothione synthetase, the crucial enzyme in charge of trypanothione formation, should constitute the primary objective of an effective antioxidant chemotherapeutic strategy.<\/jats:p>","DOI":"10.1039\/9781788010177-00316","type":"book-chapter","created":{"date-parts":[[2017,10,26]],"date-time":"2017-10-26T11:00:25Z","timestamp":1509015625000},"page":"316-347","source":"Crossref","is-referenced-by-count":1,"title":["The Redox Metabolism and Oxidative Stress in<i>Leishmania<\/i>as a Crossroads for the Lethal Effect of Drugs"],"prefix":"10.1039","author":[{"given":"Helena","family":"Castro","sequence":"first","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto Portugal hcastro@ibmc.up.pt atomas@ibmc.up.pt"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto Rua Alfredo Allen 208 4200-135 Porto Portugal"}]},{"given":"Margarida","family":"Duarte","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto Portugal hcastro@ibmc.up.pt atomas@ibmc.up.pt"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto Rua Alfredo Allen 208 4200-135 Porto Portugal"}]},{"given":"Ana M.","family":"Tom\u00e1s","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto Portugal hcastro@ibmc.up.pt atomas@ibmc.up.pt"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto Rua Alfredo Allen 208 4200-135 Porto Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto Rua de Jorge Viterbo Ferreira 228 4050-313 Porto Portugal"}]}],"member":"292","reference":[{"key":"2023052005483488000_BK9781782628897-00316-cit1","doi-asserted-by":"crossref","first-page":"5344","DOI":"10.1128\/AAC.00790-10","volume":"54","author":"Carvalho","year":"2010","journal-title":"Antimicrob. 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