Crystal structure of the Anopheles gambiae 3-hydroxykynurenine transaminase.
Crystal structure of the Anopheles gambiae 3-hydroxykynurenine transaminase.
复制标题
冈比亚按蚊 3-羟基犬尿氨酸转氨酶的晶体结构。
DOI：
10.1073/pnas.0510233103
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发表时间：
2006
影响因子：
11.1
通讯作者：
Rizzi,Menico
中科院分区：
文献类型：
--
作者：
Rossi,Franca;Garavaglia,Silvia;Giovenzana,GiovanniBattista;Arcà,Bruno;Li,Jianyong;Rizzi,Menico
冈比亚按蚊是最致命的疟疾寄生虫--恶性疟原虫的传播媒介，黄尿酸（XA）在疟原虫配子发生和繁殖中起着关键作用。在蚊子中，XA是通过3-羟基犬尿氨酸（3-HK）的转氨基作用产生的，这是一种代表防止潜在毒性3-HK过量积累的主要途径的反应。干扰A.因此，冈比亚似乎是开发阻断疟疾传播药物和杀虫剂的一个有吸引力的途径。测定了A的晶体结构。冈比亚3-HK转氨酶的吡哆醛5′-磷酸形式，并与新合成的竞争性酶抑制剂复合。酶活性位点的结构检查揭示了配体识别和催化的关键分子决定因素。对抑制剂结合的主要贡献是由抑制剂羧酸盐和Arg-356之间的盐桥和由一个显着的氢键网络，涉及的抑制剂的邻氨基苯甲酸部分和残基Gly-25和Asn-44的骨架原子。这项研究可能是有用的基于结构的设计的特定酶抑制剂的潜在利益作为抗疟药。
InAnopheles gambiae, the vector for the most deadly malaria parasitePlasmodium falciparum, xanthurenic acid (XA) plays a key role in parasite gametogenesis and fertility. In mosquitoes, XA is produced by transamination of 3-hydroxykynurenine (3-HK), a reaction that represents the main route to prevent the accumulation of the potentially toxic 3-HK excess. Interfering with XA metabolism inA. gambiaetherefore appears an attractive avenue for the development of malaria transmission-blocking drugs and insecticides. We have determined the crystal structure ofA. gambiae3-HK transaminase in its pyridoxal 5′-phosphate form and in complex with a newly synthesized competitive enzyme inhibitor. Structural inspection of the enzyme active site reveals the key molecular determinants for ligand recognition and catalysis. Major contributions toward inhibitor binding are provided by a salt bridge between the inhibitor carboxylate and Arg-356 and by a remarkable hydrogen bond network involving the anthranilic moiety of the inhibitor and backbone atoms of residues Gly-25 and Asn-44. This study may be useful for the structure-based design of specific enzyme inhibitors of potential interest as antimalarial agents.