{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:28:50Z","timestamp":1781105330212,"version":"3.54.1"},"reference-count":31,"publisher":"National Academy of Sciences","issue":"9","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1998,4,28]]},"abstract":"<jats:p>\n                    A trans-dominant mutational strategy was used to down-regulate trypanothione reductase (TR) activity levels in\n                    <jats:italic>Leishmania donovani,<\/jats:italic>\n                    the causative agent of visceral leishmaniasis in humans. TR, regarded as an ideal drug target against trypanosomatid infections, is a homodimeric flavoprotein oxidoreductase unique to these organisms that plays a central role in the enzymatic regeneration of the thiol pool. Extrachromosomal, heterologous expression of a trans-dominant mutant version of the\n                    <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                    enzyme in\n                    <jats:italic>L. donovani<\/jats:italic>\n                    resulted in the formation of inactive cross-species heterodimers and in a dramatic decrease of endogenous TR activity levels. Recombinant cells depleted of up to 85% of TR activity were significantly impaired in their ability to regenerate dihydrotrypanothione from trypanothione disulfide following oxidation with diamide. Nonetheless trans-dominant mutant recombinants were still capable of maintaining a reduced intracellular environment during cell growth in culture and were able to metabolize hydrogen peroxide at wild-type rates\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Importantly, however, cells expressing the trans-dominant mutant enzyme displayed a decreased ability to survive inside activated macrophages in a murine model of\n                    <jats:italic>Leishmania<\/jats:italic>\n                    infection. The apparent inability of\n                    <jats:italic>Leishmania<\/jats:italic>\n                    to modulate the expression of active TR homodimers in response to the expression of trans-dominant mutant protein suggests that specific inhibitors of this enzyme should be useful anti-leishmanial agents.\n                  <\/jats:p>","DOI":"10.1073\/pnas.95.9.5311","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:42:40Z","timestamp":1027680160000},"page":"5311-5316","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":146,"title":["Down-regulation of\n                    <i>Leishmania donovani<\/i>\n                    trypanothione reductase by heterologous expression of a trans-dominant mutant homologue: Effect on parasite intracellular survival"],"prefix":"10.1073","volume":"95","author":[{"given":"Jorge","family":"Tovar","sequence":"first","affiliation":[{"name":"Department of Tropical and Infectious Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark L.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Department of Tropical and Infectious Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aden C.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Tropical and Infectious Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon L.","family":"Croft","sequence":"additional","affiliation":[{"name":"Department of Tropical and Infectious Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan H.","family":"Fairlamb","sequence":"additional","affiliation":[{"name":"Department of Tropical and Infectious Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1998,4,28]]},"reference":[{"key":"e_1_3_2_1_2","first-page":"529","volume-title":"Immunology and Molecular Biology of Parasitic Infections","author":"Peters W","year":"1993","unstructured":"W Peters Immunology and Molecular Biology of Parasitic Infections, ed K S Warren (Blackwell Scientific, Oxford), pp. 529\u2013566 (1993)."},{"key":"e_1_3_2_2_2","volume-title":"Handbook of Drugs for Tropical Parasitic Diseases","author":"Gustafsson L L","year":"1987","unstructured":"L L Gustafsson, B Beerman, Y A Abdi Handbook of Drugs for Tropical Parasitic Diseases (Taylor & Francis, London, 1987)."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.mi.46.100192.003403"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1993.tb18348.x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/24.15.2942"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.10.2590"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.153.5.1302"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.36.3.1023-1027.1982"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1995.tb20319.x"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/20.15.3963"},{"key":"e_1_3_2_11_2","volume-title":"Molecular Cloning: A Laboratory Manual","author":"Sambrook J","year":"1989","unstructured":"J Sambrook, E F Fritsch, T Maniatis Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Lab. 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