Humans have lost the ability to convert urate into the more soluble allantoin with the evolutionary inactivation of three enzymes of the uricolytic pathway. Restoration of this function through enzyme replacement therapy can treat severe hyperuricemia and Lesch-Nyhan disease. Through a genomic exploration of natural gene fusions, we found that plants and diatoms independently evolved a fusion protein (allantoin synthase) complementing two human pseudogenes. The 1.85-Å-resolution crystal structure of allantoin synthase from the diatom Phaeodactylum tricornutum provides a rationale for the domain combinations observed in the metabolic pathway, suggesting that quaternary structure is key to the evolutionary success of protein domain fusions. Polyethylene glycol (PEG) conjugation experiments indicate that a PEG-modified form of the natural fusion protein provides advantages over separate enzymes in terms of activity maintenance and manufacturing of the bioconjugate. These results suggest that the combination of different activities in a single molecular unit can simplify the production and chemical modification of recombinant proteins for multifunctional enzyme therapy.

中文翻译：

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硅藻尿囊素合酶为天然融合蛋白治疗提供结构见解

随着尿液溶解途径的三种酶的进化失活，人类已经失去了将尿酸盐转化成更易溶解的尿囊素的能力。通过酶替代疗法恢复此功能可治疗严重的高尿酸血症和Lesch-Nyhan病。通过对天然基因融合体的基因组探索，我们发现植物和硅藻独立地进化了一种互补蛋白质（丙氨酸合酶），可互补两个人类假基因。硅藻Phaeodactylum tricornutum尿囊素合酶的1.85Å分辨率晶体结构提供了在代谢途径中观察到的结构域组合的基本原理，表明四级结构是蛋白质结构域融合蛋白进化成功的关键。聚乙二醇（PEG）结合实验表明，就活性维持和生物缀合物的生产而言，天然融合蛋白的PEG修饰形式提供了优于单独酶的优势。这些结果表明在单个分子单元中不同活性的组合可以简化用于多功能酶治疗的重组蛋白的生产和化学修饰。