GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites.
GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites.
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DOI：
10.1371/journal.ppat.1010803
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发表时间：
2022-09
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
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控制全球疟疾健康危机的努力因抗疟疾耐药性而受到破坏。识别抗药性的机制将揭示恶性疟疾寄生虫的潜在生物学，这些寄生虫可以逃避我们最有希望的治疗方法，并可能揭示新的药物靶点。我们利用磷霉素(FSM)作为化学抑制剂，通过甲基赤藓糖醇磷酸(MEP)途径抑制胞质中类异戊二烯的生物合成。因此，我们已经确定了疟疾寄生虫中一种不寻常的代谢调节机制，它是通过必需的糖酵解酶--3-磷酸甘油醛脱氢酶(GAPDH)实现的。在GAPDH中，两个平行的遗传筛选汇聚在独立但功能相似的抗性等位基因上。对FSM抗性GAPDH突变寄生虫的代谢图谱表明，这两个突变都不会扰乱总体糖酵解输出。虽然抗FSM的GAPDH变异蛋白具有催化活性，但它们减少了组装成野生型GAPDH所青睐的同源四聚体状态。抗FSM的GAPDH变异蛋白的中断齐聚伴随着酶的协同作用的改变和对游离血红素抑制的敏感性降低。总之，我们的数据确定了一个新的FSM抗性的遗传生物标记物，并揭示了GAPDH在MEP途径控制和抗疟疾敏感性中的核心作用。疟疾是一种威胁生命的蚊媒感染，在全球范围内仍是一个巨大的公共卫生威胁，仅在2020年就报告了60多万人死亡。导致疟疾的寄生虫入侵并在人类红细胞内复制。这种独特的环境为疟疾寄生虫提供了几乎无限的葡萄糖形式的糖，寄生虫将其用作能量，并作为生长和分裂的基石。寄生虫分解葡萄糖，必须使用这些分解产物来制造新的分子，包括一种非常重要的化合物，称为异戊二烯。疟疾寄生虫通常在接受一种名为磷霉素的药物治疗时死亡，这种药物可以抑制这一过程。为了了解寄生虫是如何调节这一关键功能的，在这项研究中，我们鉴定了对磷霉素具有抗药性的寄生虫。这些对磷霉素耐药的细胞在一种名为甘油醛磷酸脱氢酶(GAPDH)的酶上发生了突变，这种酶是糖分解的关键。我们发现，带有突变的GAPDH酶的寄生虫仍然正常分解糖，但不会被磷霉素处理后细胞中发生的其他变化所抑制。这些结果揭示了GAPDH酶作为疟疾寄生虫下游代谢控制点的新的重要作用。
Efforts to control the global malaria health crisis are undermined by antimalarial resistance. Identifying mechanisms of resistance will uncover the underlying biology of the Plasmodium falciparum malaria parasites that allow evasion of our most promising therapeutics and may reveal new drug targets. We utilized fosmidomycin (FSM) as a chemical inhibitor of plastidial isoprenoid biosynthesis through the methylerythritol phosphate (MEP) pathway. We have thus identified an unusual metabolic regulation scheme in the malaria parasite through the essential glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Two parallel genetic screens converged on independent but functionally analogous resistance alleles in GAPDH. Metabolic profiling of FSM-resistant gapdh mutant parasites indicates that neither of these mutations disrupt overall glycolytic output. While FSM-resistant GAPDH variant proteins are catalytically active, they have reduced assembly into the homotetrameric state favored by wild-type GAPDH. Disrupted oligomerization of FSM-resistant GAPDH variant proteins is accompanied by altered enzymatic cooperativity and reduced susceptibility to inhibition by free heme. Together, our data identifies a new genetic biomarker of FSM-resistance and reveals the central role of GAPDH in MEP pathway control and antimalarial sensitivity. Malaria is a life-threatening mosquito-borne infection that remains an enormous public health threat worldwide, with over 600,000 deaths reported in 2020 alone. The parasites that cause malaria invade and replicate within human red blood cells. This unique environment provides the malaria parasite with almost unlimited supply of sugar in the form of glucose, which the parasite uses for energy and as building blocks to grow and divide. Parasites break down glucose, and must use these breakdown products to make new molecules, including a very important class of compounds called isoprenoids. Malaria parasites normally die when they are treated with a drug, called fosmidomycin, that inhibits this process. To understand how parasites regulate this critical function, in this study we identified parasites that were resistant to fosmidomycin. These fosmidomycin-resistant cells had mutations in an enzyme that is critical for sugar breakdown, called glyceraldehyde phosphate dehydrogenase (GAPDH). We find that parasites with mutant GAPDH enzymes still break down sugar normally, but are not inhibited by other changes in the cell that happen upon fosmidomycin treatment. These results reveal a new and important role for the enzyme GAPDH as a control-point for downstream metabolism in malaria parasites.
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影响因子：
6.4
作者：
Guggisberg AM;Frasse PM;Jezewski AJ;Kafai NM;Gandhi AY;Erlinger SJ;Odom John AR
通讯作者：
Odom John AR
DOI：
10.1073/pnas.1615195114
发表时间：
2017-03-14
影响因子：
11.1
作者：
Abshire JR;Rowlands CJ;Ganesan SM;So PT;Niles JC
通讯作者：
Niles JC
影响因子：
5.2
作者：
Imlay, Leah;Odom, Audrey R
通讯作者：
Odom, Audrey R
柬埔寨恶性疟原虫疟疾中的双氢青蒿素-哌喹抗药性：一项多地点前瞻性队列研究。
DOI：
10.1016/s1473-3099(15)00487-9
发表时间：
2016-03
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Amaratunga C;Lim P;Suon S;Sreng S;Mao S;Sopha C;Sam B;Dek D;Try V;Amato R;Blessborn D;Song L;Tullo GS;Fay MP;Anderson JM;Tarning J;Fairhurst RM
通讯作者：
Fairhurst RM
影响因子：
3.9
作者：
Kalanon, Ming;McFadden, Geoffrey I.
通讯作者：
McFadden, Geoffrey I.