Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters
Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters
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DOI：
10.1073/pnas.1511688112
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发表时间：
2015-11-10
影响因子：
11.1
通讯作者：
Charkoudian, Louise K.
中科院分区：
文献类型：
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作者：
Hillenmeyer, Maureen E.;Vandova, Gergana A.;Charkoudian, Louise K.
天然产物的生物合成途径产生的分子具有巨大的结构复杂性和精致的生物活性。对天然产物的研究导致了许多药剂的发现，特别是抗生素。试图利用生物合成酶系统的催化能力，用于化合物发现和工程，受到对潜在基因簇进化的理解不足的限制。我们开发了一种方法来研究进化的生物合成基因的集群范围内的规模，整合成对的基因协同进化信息与大规模的系统发育分析。我们用这种方法来推断II型聚酮基因簇的进化，追踪从单一祖先到今天幸存的基因簇的进化路径。我们在这些簇中确定了10种关键基因类型，其中大多数是从现有的细胞过程中交换进来的，随后进行了专门化。祖先的II型聚酮基因簇可能包括一组核心的五个基因，一个在整个进化过程中扩大和收缩的名册。一个关键的C24祖先多样化成较长和较短链长系统的主要类别，从C20祖先产生了大多数特征性的II型聚酮化合物抗生素。我们的研究结果表明，（i）II型聚酮结构是可预测的，从它的基因名册，（ii）只有某些基因组合是兼容的，（iii）基因交换可能是化学多样性进化的关键。关于自然选择如何驱动聚酮化合物化学创新的经验教训可以应用于合理设计和指导发现具有所需结构和性质的化学品。
Natural product biosynthetic pathways generate molecules of enormous structural complexity and exquisitely tuned biological activities. Studies of natural products have led to the discovery of many pharmaceutical agents, particularly antibiotics. Attempts to harness the catalytic prowess of biosynthetic enzyme systems, for both compound discovery and engineering, have been limited by a poor understanding of the evolution of the underlying gene clusters. We developed an approach to study the evolution of biosynthetic genes on a cluster-wide scale, integrating pairwise gene coevolution information with large-scale phylogenetic analysis. We used this method to infer the evolution of type II polyketide gene clusters, tracing the path of evolution from the single ancestor to those gene clusters surviving today. We identified 10 key gene types in these clusters, most of which were swapped in from existing cellular processes and subsequently specialized. The ancestral type II polyketide gene cluster likely comprised a core set of five genes, a roster that expanded and contracted throughout evolution. A key C24 ancestor diversified into major classes of longer and shorter chain length systems, from which a C20 ancestor gave rise to the majority of characterized type II polyketide antibiotics. Our findings reveal that (i) type II polyketide structure is predictable from its gene roster, (ii) only certain gene combinations are compatible, and (iii) gene swaps were likely a key to evolution of chemical diversity. The lessons learned about how natural selection drives polyketide chemical innovation can be applied to the rational design and guided discovery of chemicals with desired structures and properties.