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首页> 外文期刊>The Biochemical Journal >Crystal structures of SCP2-thiolases of trypanosomatidae, human pathogens causing widespread tropical diseases: the importance for catalysis of the cysteine of the unique HDCF loop.
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Crystal structures of SCP2-thiolases of trypanosomatidae, human pathogens causing widespread tropical diseases: the importance for catalysis of the cysteine of the unique HDCF loop.

机译：锥虫科的SCP2-硫蛋白的晶体结构，是导致广泛的热带疾病的人类病原体：独特HDCF环的半胱氨酸催化的重要性。

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摘要

Thiolases are essential CoA-dependent enzymes in lipid metabolism. In the present study we report the crystal structures of trypanosomal and leishmanial SCP2 (sterol carrier protein, type-2)-thiolases. Trypanosomatidae cause various widespread devastating (sub)-tropical diseases, for which adequate treatment is lacking. The structures reveal the unique geometry of the active site of this poorly characterized subfamily of thiolases. The key catalytic residues of the classical thiolases are two cysteine residues, functioning as a nucleophile and an acid/base respectively. The latter cysteine residue is part of a CxG motif. Interestingly, this cysteine residue is not conserved in SCP2-thiolases. The structural comparisons now show that in SCP2-thiolases the catalytic acid/base is provided by the cysteine residue of the HDCF motif, which is unique for this thiolase subfamily. This HDCF cysteine residue is spatially equivalent to the CxG cysteine residue of classical thiolases. The HDCF cysteine residue is activated for acid/base catalysis by two main chain NH-atoms, instead of two water molecules, as present in the CxG active site. The structural results have been complemented with enzyme activity data, confirming the importance of the HDCF cysteine residue for catalysis. The data obtained suggest that these trypanosomatid SCP2-thiolases are biosynthetic thiolases. These findings provide promise for drug discovery as biosynthetic thiolases catalyse the first step of the sterol biosynthesis pathway that is essential in several of these parasites.
机译：硫醇酶是脂质代谢中必需的CoA依赖性酶。在本研究中，我们报告了锥虫和利什曼虫SCP2（固醇载体蛋白，2型）-硫蛋白的晶体结构。锥虫科引起各种广泛的破坏性（亚）热带疾病，但缺乏适当的治疗方法。这些结构揭示了该硫蛋白的亚家族特征不充分的活性部位的独特几何形状。经典硫磺酶的关键催化残基是两个半胱氨酸残基，分别用作亲核试剂和酸/碱。后者的半胱氨酸残基是CxG基序的一部分。有趣的是，这种半胱氨酸残基在SCP2-硫酶中不保守。现在的结构比较表明，在SCP2-硫酶中，催化酸/碱基由HDCF基序的半胱氨酸残基提供，这对于该硫解酶亚家族是唯一的。该HDCF半胱氨酸残基在空间上等同于经典硫磺酶的CxG半胱氨酸残基。 HDCF半胱氨酸残基被两个主链NH原子而不是两个存在于CxG活性位点的水分子激活，以进行酸/碱催化。结构结果已被酶活性数据所补充，证实了HDCF半胱氨酸残基对于催化的重要性。获得的数据表明，这些锥虫形SCP2-硫酶是生物合成的硫酶。这些发现为药物发现提供了希望，因为生物合成的硫代酶催化了固醇生物合成途径的第一步，这是其中一些寄生虫必不可少的。

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