Limited genetic variation in the Plasmodium falciparum heme detoxification protein (HDP).
Limited genetic variation in the Plasmodium falciparum heme detoxification protein (HDP).
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恶性疟原虫血红素解毒蛋白（HDP）的遗传变异有限。
DOI：
10.1016/j.meegid.2008.12.004
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Udhayakumar,Venkatachalam
中科院分区：
文献类型：
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作者：
Vinayak,Sumiti;Rathore,Dharmendar;Kariuki,Simon;Slutsker,Laurence;Shi,YaPing;Villegas,Leopoldo;Escalante,AnaniasA;Udhayakumar,Venkatachalam
疟疾寄生虫感染宿主红细胞，通过将血红素解毒成疟原虫色素来降解血红蛋白。血红素向疟原虫色素的转化是由一种名为血红素解毒蛋白（HDP）的有效蛋白质完成的，这使得HDP成为抗疟药物开发的一个有吸引力的靶点。我们研究了恶性疟原虫HDP的遗传变异，并调查了HDP是否因其参与血红素解毒途径而受到任何潜在的氯喹（CQ）选择压力。我们从已知CQ敏感性的5个恶性疟原虫实验室菌株和来自委内瑞拉（n=26）和肯尼亚（n=24）的50个具有高水平CQ抗性的田间分离株中，对包含3个外显子和2个内含子（内含子1中的AT和ATTT重复序列;内含子2中的AT重复序列）的完整HDP基因进行了测序。测序发现两个突变，C41 F和F91 L分别在外显子1和外显子2。F41突变仅存在于CQ敏感（CQS）HB 3菌株中。然而，除CQS 3D 7菌株外，所有分离株均携带91 L突变。内含子2区的测序显示AT重复的数目没有变化。相比之下，内含子1中的AT和ATTT重复序列变化很大。总体而言，就内含子1重复而言，委内瑞拉分离株（预期杂合性，He=0.685）与肯尼亚分离株（He=0.986）相比显示出较少的遗传变异。此外，我们还对pfcrt基因的72-76个密码子进行了基因分型，但没有观察到pfcrt CQ抗性基因型（SVMNT或CVIET）与HDP变异的任何相关性，因此表明HDP不处于任何CQ选择压力下。总之，HDP是未来抗疟药物开发的保守靶点。
Malaria parasites infecting host red blood cells degrade hemoglobin by detoxifying heme into hemozoin. This conversion of heme to hemozoin is performed by a potent protein called heme detoxification protein (HDP), making HDP an attractive target for antimalarial drug development. We studied the genetic variation in Plasmodium falciparum HDP and also investigated if HDP due to its involvement in the heme detoxification pathway is under any potential chloroquine (CQ) selection pressure. We sequenced the complete HDP gene encompassing three exons and two introns (AT and ATTT repeats in intron 1; AT repeats in intron 2) from five P. falciparum laboratory strains with known CQ sensitivity and 50 field isolates from Venezuela (n=26) and Kenya (n=24), with high levels of CQ resistance. Sequencing revealed two mutations, C41F and F91L in exon 1 and exon 2, respectively. The F41 mutation was present only in the CQ sensitive (CQS) HB3 strain. However, all the isolates harbored the 91L mutation, except for the CQS 3D7 strain. The sequencing of the intron 2 region revealed no variation in the number of AT repeats. In contrast, there was a wide variation in the AT and ATTT repeats in intron 1. Overall with respect to the intron 1 repeats, the Venezuelan isolates (Expected heterozygosity, He=0.685) showed less genetic variation as compared to the Kenyan isolates (He=0.986). Furthermore, we also genotyped the 72–76 codons of the pfcrt gene but did not observe any correlation of the pfcrt CQ resistant genotypes (SVMNT or CVIET) with variation in the HDP, thus indicating HDP not to be under any CQ selection pressure. In conclusion, HDP is a conserved target for future antimalarial development.