Name: leishmaniasis and trypanothione reductase
Uploaded: 2026-05-20T14:39:49.401Z
Duration: 1 min 21 s
Channel: JoVE

Heavy metal drugs are effective antiprotozoal agents.For example, sodium stibogluconate, or SSG, contains the heavy metal antimony and is widely used to treat Leishmania infections.In the host, Leishmania lives inside macrophages.Once administered, the drug enters the macrophages and then enters the parasite through aquaglyceroporin channels.Thiol systems inside the parasite and the macrophages change SSG&#x2019;s pentavalent antimony into the active trivalent form.This active form blocks the enzyme trypanothione reductase, disrupting the parasite&#x2019;s redox system.Trivalent antimony also binds to free thiols and interferes with iron-sulfur cluster enzymes and zinc-binding proteases.As a result, reactive oxygen species accumulate within the cell, damaging its proteins and membrane lipids.The active drug then promotes the efflux of intracellular thiols, further weakening the parasite&#x2019;s defense.These effects ultimately result in the death of Leishmania and their removal from the host&#x2019;s body.

antiprotozoika

Antiprotozoal Agents

Leishmaniose ist eine weit verbreitete parasit&#xE4;re Erkrankung, die durch mehrere Leishmania-Arten verursacht wird. Sie betrifft jedes Jahr Millionen von Menschen und stellt in Endemiegebieten nach wie vor ein gro&#xDF;es Problem f&#xFC;r die &#xF6;ffentliche Gesundheit dar. Die Erstlinientherapie beruht auf f&#xFC;nfwertigen Antimonverbindungen, darunter Megluminantimoniat und Natriumstibogluconat. Dennoch ist die Wirkungsweise dieser Arzneimittel noch nicht vollst&#xE4;ndig gekl&#xE4;rt, insbesondere ihre Wechselwirkung mit parasitenspezifischen biochemischen Stoffwechselwegen. Ein wichtiges Ziel ist die Trypanothion-Reduktase, oder TR, ein Enzym, das das Redoxgleichgewicht bei Leishmania aufrechterh&#xE4;lt. TR fehlt in S&#xE4;ugetierwirten, was dieses Enzym zu einem selektiven Ziel f&#xFC;r die Chemotherapie macht.
<h3>Redoxstoffwechsel bei Leishmania</h3>
S&#xE4;ugetierzellen sind auf das Glutathion/Glutathionreduktase-System angewiesen, aber Leishmania nutzt einen eigenen Thiolweg, der auf Trypanothion [N&#xB9;,N&#x2078;-Bis(glutathionyl)spermidin] und TR basiert. Dieses System fungiert als wichtigste antioxidative Abwehr und als Redoxregulator bei Trypanosomatiden. TR reduziert oxidiertes Trypanothiondisulfid (TS&#x2082;) mithilfe von NADPH zu seiner Dithiolform. Dieser Weg ist f&#xFC;r die Entgiftung reaktiver Sauerstoffspezies und die Unterst&#xFC;tzung des &#xDC;berlebens von Parasiten unter oxidativem Stress entscheidend.
<h3>TR-Hemmung durch Antimonverbindungen</h3>
Kristallstrukturen von Leishmania infantum-TR im oxidierten und reduzierten Zustand zeigen, dass Sb(III), das durch intrazellul&#xE4;re Reduktion f&#xFC;nfwertiger Antimonverbindungen erzeugt wird, an das aktive Zentrum von TR bindet. Sb(III) koordiniert mit Cys52, Cys57, Thr335 und His461&#x2032; aus der gegen&#xFC;berliegenden Untereinheit des TR-Dimers. Diese Wechselwirkung st&#xF6;rt die TS&#x2082;-Reduktion und blockiert den Redoxzyklus.
<h3>Biochemische und strukturelle Implikationen</h3>
Enzymassays zeigen, dass Sb(III) TR (Ki 1,5 &#xB1; 0,4 &#x3BC;M) stark und wirksamer hemmt als As(III). Konservierte Bindungsregionen &#xFC;ber verschiedene Arten hinweg weisen auf einen gemeinsamen Mechanismus hin. Die Kristallstrukturen (PDB 2JK6 und 2W0H) offenbaren die Sb(III)-Koordinationsgeometrie und heben His461&#x2032; und die TR-Dimerisierung als Schl&#xFC;sselmerkmale f&#xFC;r die Wirkstoffbindung hervor. Diese Erkenntnisse unterst&#xFC;tzen die Entwicklung verbesserter antileishmanieller Wirkstoffe, die mit besserer Spezifit&#xE4;t und geringerer Toxizit&#xE4;t auf das TR-Trypanothion-System abzielen.

Antiprotozoika

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Antiprotozoale Mittel

leishmaniasis and trypanothione reductase

Leishmaniasis is a parasitic disease caused by several Leishmania species. It affects millions of people each year and remains a major public health problem in endemic regions. Treatment often relies on pentavalent antimonials, including meglumine antimoniate and sodium stibogluconate.

The way these drugs work has not been fully clear. One important target is trypanothione reductase, or TR, an enzyme that helps keep Leishmania in redox balance. TR is not found in mammalian hosts, so it is a selective target for chemotherapy.

Leishmania uses a thiol-based redox system that is different from the glutathione/glutathione reductase system used by mammalian cells. Its main antioxidant defense depends on trypanothione, [N¹,N⁸-bis(glutathionyl)spermidine], and TR. TR reduces oxidized trypanothione disulfide, TS₂, to the dithiol form with NADPH. This reaction helps detoxify reactive oxygen species and supports parasite survival during oxidative stress.

Crystal structures of Leishmania infantum TR in oxidized and reduced states show how antimonials interfere with this enzyme. Sb(III), which forms inside the parasite after intracellular reduction of pentavalent antimonials, binds in the TR active site. It coordinates with Cys52, Cys57, Thr335, and His461′ from the opposite subunit of the TR dimer.

This binding disrupts TS₂ reduction and blocks the redox cycle. Enzyme assays show that Sb(III) inhibits TR strongly, with a Ki of 1.5 ± 0.4 μM, and it is more effective than As(III). The structures, including PDB 2JK6 and 2W0H, also show that His461′ and TR dimerization are important for drug binding. These conserved binding regions across species point to a shared mechanism and may help guide improved antileishmanial drugs with better specificity and lower toxicity.

Leishmaniasis and Trypanothione Reductase

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Leishmaniasis is a parasitic disease caused by several Leishmania species. It affects millions of people each year and remains a major public health problem in endemic regions. Treatment often relies on pentavalent antimonials, including meglumine antimoniate and sodium stibogluconate. The way these drugs work has not been fully clear. One important target is trypanothione reductase, or TR, an enzyme that helps keep Leishmania in redox balance. TR is not found in mammalian hosts, so it is a...

key terms and concepts

Learn how antimonials target trypanothione reductase in Leishmania, blocking redox balance and helping explain a key mechanism in leishmaniasis treatment.

Leishmaniasis and Trypanothione Reductase | JoVE K12

JoVE Core Microbiology provides an engaging introduction to the microbial world and its influence on health, industry, and the environment. This comprehensive collection covers key concepts such as microbial structure, metabolism, genetics, and ecology. It introduces essential laboratory techniques and microscopy methods through visually engaging animations. Corresponding scientist-in-action videos bridge classroom concepts with real-world research and applications.

microbiology

Leishmaniasis and Trypanothione Reductase

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