Surveying purine biosynthesis across the domains of life unveils promising drug targets in pathogens.,Immunology and Cell Biology

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Surveying purine biosynthesis across the domains of life unveils promising drug targets in pathogens.
Immunology and Cell Biology ( IF 3.2 ) Pub Date : 2020-08-04 , DOI: 10.1111/imcb.12389
Sheena Mh Chua ₁ , James A Fraser ₁

Affiliation

Purines play an integral role in cellular processes such as energy metabolism, cell signaling and encoding the genetic makeup of all living organisms—ensuring that the purine metabolic pathway is maintained across all domains of life. To gain a deeper understanding of purine biosynthesis via the de novo biosynthetic pathway, the genes encoding purine metabolic enzymes from 35 archaean, 69 bacterial and 99 eukaryotic species were investigated. While the classic elements of the canonical purine metabolic pathway were utilized in all domains, a subset of familiar biochemical roles was found to be performed by unrelated proteins in some members of the Archaea and Bacteria. In the Bacteria, a major differentiating feature of de novo purine biosynthesis is the increasing prevalence of gene fusions, where two or more purine biosynthesis enzymes that perform consecutive biochemical functions in the pathway are encoded by a single gene. All species in the Eukaryota exhibited the most common fusions seen in the Bacteria, in addition to new gene fusions to potentially increase metabolic flux. This complexity is taken further in humans, where a reversible biomolecular assembly of enzymes known as the purinosome has been identified, allowing short‐term regulation in response to metabolic cues while expanding on the benefits that can come from gene fusion. By surveying purine metabolism across all domains of life, we have identified important features of the purine biosynthetic pathway that can potentially be exploited as prospective drug targets.

中文翻译：

调查生命各个领域的嘌呤生物合成揭示了病原体中的有希望的药物靶点。

嘌呤在细胞过程中发挥着不可或缺的作用，例如能量代谢、细胞信号传导和编码所有生物体的基因组成——确保嘌呤代谢途径在生命的所有领域得到维持。为了获得嘌呤生物合成的更深入的了解经由所述从头生物合成途径，从35太古编码嘌呤代谢的酶的基因，69个细菌和99真核物种进行了调查。虽然经典嘌呤代谢途径的经典元素被用于所有领域，但在古细菌和细菌的一些成员中发现了一些熟悉的生化作用的子集是由不相关的蛋白质执行的。在细菌中，de novo 的一个主要区别特征嘌呤生物合成是基因融合的日益流行，其中在途径中执行连续生化功能的两种或多种嘌呤生物合成酶由单个基因编码。除了可能增加代谢通量的新基因融合外，真核生物中的所有物种都表现出细菌中最常见的融合。这种复杂性在人类身上得到了进一步发展，其中一种称为嘌呤体的酶的可逆生物分子组装已被确定，允许对代谢线索进行短期调节，同时扩大基因融合可能带来的好处。通过调查生命各个领域的嘌呤代谢，我们确定了嘌呤生物合成途径的重要特征，这些特征可能被用作潜在的药物靶点。

更新日期：2020-08-04

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