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

重金属药物是有效的抗原虫剂。例如，葡萄糖酸锑钠（SSG）含有重金属锑，被广泛用于治疗Leishmania感染。在宿主体内，Leishmania 生活在巨噬细胞内。给药后，该药物进入巨噬细胞，然后通过水甘油通道蛋白通道进入寄生虫体内。寄生虫和巨噬细胞内的巯基系统将喷他脒的五价锑转化为具有活性的三价形式。这种活性形式可阻断锥虫硫醇还原酶，破坏寄生虫的氧化还原系统。三价锑还可与游离巯基结合，并干扰铁硫簇酶和锌结合蛋白酶。因此，活性氧在细胞内积聚，损伤其蛋白质和膜脂质。该活性药物随后促进细胞内硫醇的外排，进一步削弱寄生虫的防御能力。这些效应最终导致细胞死亡 利什曼原虫 及其从宿主体内清除的过程。

抗原虫药物

Antiprotozoal Agents

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<h3>&#x5229;&#x4EC0;&#x66FC;&#x539F;&#x866B;&#x7684;&#x6C27;&#x5316;&#x8FD8;&#x539F;&#x4EE3;&#x8C22;</h3>
&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x7EC6;&#x80DE;&#x4F9D;&#x8D56;&#x4E8E;&#x8C37;&#x80F1;&#x7518;&#x80BD;/&#x8C37;&#x80F1;&#x7518;&#x80BD;&#x8FD8;&#x539F;&#x9176;&#x7CFB;&#x7EDF;&#xFF0C;&#x4F46;&#x5229;&#x4EC0;&#x66FC;&#x539F;&#x866B;&#x4F7F;&#x7528;&#x57FA;&#x4E8E;&#x9525;&#x866B;&#x786B;&#x9187; [N&#xB9;,N&#x2078;-&#x53CC;&#xFF08;&#x8C37;&#x80F1;&#x7518;&#x80BD;&#x57FA;&#xFF09;&#x4E9A;&#x7CBE;&#x80FA;] &#x548C; TR &#x7684;&#x72EC;&#x7279;&#x786B;&#x9187;&#x9014;&#x5F84;&#x3002;&#x8BE5;&#x7CFB;&#x7EDF;&#x662F;&#x9525;&#x866B;&#x7C7B;&#x539F;&#x866B;&#x4E2D;&#x4E3B;&#x8981;&#x7684;&#x6297;&#x6C27;&#x5316;&#x9632;&#x5FA1;&#x548C;&#x6C27;&#x5316;&#x8FD8;&#x539F;&#x8C03;&#x8282;&#x7CFB;&#x7EDF;&#x3002;TR &#x4F7F;&#x7528; NADPH &#x5C06;&#x6C27;&#x5316;&#x578B;&#x9525;&#x866B;&#x786B;&#x9187;&#x4E8C;&#x786B;&#x5316;&#x7269;&#xFF0C;&#x6216; TS&#x2082;&#xFF0C;&#x8FD8;&#x539F;&#x4E3A;&#x5176;&#x4E8C;&#x786B;&#x9187;&#x5F62;&#x5F0F;&#x3002;&#x8BE5;&#x9014;&#x5F84;&#x5BF9;&#x4E8E;&#x6D3B;&#x6027;&#x6C27;&#x7684;&#x89E3;&#x6BD2;&#x548C;&#x652F;&#x6301;&#x5BC4;&#x751F;&#x866B;&#x5728;&#x6C27;&#x5316;&#x5E94;&#x6FC0;&#x4E0B;&#x7684;&#x751F;&#x5B58;&#x81F3;&#x5173;&#x91CD;&#x8981;&#x3002;
<h3>&#x9511;&#x5242;&#x5BF9; TR &#x7684;&#x6291;&#x5236;</h3>
&#x5A74;&#x513F;&#x5229;&#x4EC0;&#x66FC;&#x539F;&#x866B; TR &#x7684;&#x6C27;&#x5316;&#x6001;&#x548C;&#x8FD8;&#x539F;&#x6001;&#x6676;&#x4F53;&#x7ED3;&#x6784;&#x8868;&#x660E;&#xFF0C;&#x7531;&#x4E94;&#x4EF7;&#x9511;&#x5242;&#x5728;&#x7EC6;&#x80DE;&#x5185;&#x8FD8;&#x539F;&#x4EA7;&#x751F;&#x7684; Sb(III) &#x4E0E; TR &#x6D3B;&#x6027;&#x4F4D;&#x70B9;&#x7ED3;&#x5408;&#x3002;Sb(III) &#x4E0E; TR &#x4E8C;&#x805A;&#x4F53;&#x5BF9;&#x4FA7;&#x4E9A;&#x57FA;&#x7684; Cys52&#x3001;Cys57&#x3001;Thr335 &#x548C; His461&#x2032; &#x914D;&#x4F4D;&#x3002;&#x8FD9;&#x79CD;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x4F1A;&#x7834;&#x574F; TS&#x2082; &#x8FD8;&#x539F;&#x5E76;&#x963B;&#x65AD;&#x6C27;&#x5316;&#x8FD8;&#x539F;&#x5FAA;&#x73AF;&#x3002;
<h3>&#x751F;&#x5316;&#x548C;&#x7ED3;&#x6784;&#x610F;&#x4E49;</h3>
&#x9176;&#x6D4B;&#x5B9A;&#x8868;&#x660E;&#xFF0C;Sb(III) &#x5F3A;&#x70C8;&#x6291;&#x5236; TR&#xFF08;Ki 1.5 &#xB1; 0.4 &#x3BC;M&#xFF09;&#xFF0C;&#x6BD4; As(III) &#x66F4;&#x6709;&#x6548;&#x3002;&#x8DE8;&#x7269;&#x79CD;&#x7684;&#x4FDD;&#x5B88;&#x7ED3;&#x5408;&#x533A;&#x57DF;&#x8868;&#x660E;&#x5B58;&#x5728;&#x5171;&#x540C;&#x673A;&#x5236;&#x3002;&#x6676;&#x4F53;&#x7ED3;&#x6784;&#xFF08;PDB 2JK6 &#x548C; 2W0H&#xFF09;&#x63ED;&#x793A;&#x4E86; Sb(III) &#x914D;&#x4F4D;&#x51E0;&#x4F55;&#x7ED3;&#x6784;&#xFF0C;&#x5E76;&#x5F3A;&#x8C03; His461&#x2032; &#x548C; TR &#x4E8C;&#x805A;&#x5316;&#x662F;&#x836F;&#x7269;&#x7ED3;&#x5408;&#x7684;&#x5173;&#x952E;&#x7279;&#x5F81;&#x3002;&#x8FD9;&#x4E9B;&#x89C1;&#x89E3;&#x652F;&#x6301;&#x8BBE;&#x8BA1;&#x4EE5; TR&#x2013;&#x9525;&#x866B;&#x786B;&#x9187;&#x7CFB;&#x7EDF;&#x4E3A;&#x9776;&#x70B9;&#x3001;&#x5177;&#x6709;&#x66F4;&#x597D;&#x7279;&#x5F02;&#x6027;&#x548C;&#x66F4;&#x4F4E;&#x6BD2;&#x6027;&#x7684;&#x6539;&#x8FDB;&#x578B;&#x6297;&#x5229;&#x4EC0;&#x66FC;&#x539F;&#x866B;&#x836F;&#x7269;&#x3002;

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Education

教育

JoVE Core

Microbiology

微生物学

Unit

单元

Antimicrobial Agents

抗微生物药物

KEY TERMS AND CONCEPTS

关键术语与概念

抗原虫剂

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.

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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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