Noncanonical coproporphyrin-dependent bacterial heme biosynthesis pathway that does not use protoporphyrin
Noncanonical coproporphyrin-dependent bacterial heme biosynthesis pathway that does not use protoporphyrin
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DOI：
10.1073/pnas.1416285112
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发表时间：
2015-02-17
影响因子：
11.1
通讯作者：
Phillips, John D.
中科院分区：
文献类型：
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作者：
Dailey, Harry A.;Gerdes, Svetlana;Phillips, John D.
人们普遍认为，原血红素(Heme)的生物合成使用一组共同的核心代谢中间体，其中包括原卟啉。在这里，我们表明，放线杆菌和菲米库特(高GC和低GC革兰氏阳性细菌)不能合成原卟啉。取而代之的是，他们将共比例卟啉原氧化为共比例卟啉，加入亚铁生成铁比例卟啉(辅血红素)，然后脱羧辅基血红素生成原血红素。这一途径由三个基因决定，分别命名为Hemy、hemH和hemQ。对982个具有代表性的原核生物基因组的分析表明，这条途径是真细菌中最古老的血红素合成途径。我们的结果确定了一个以前未知的四吡咯合成分支，支持从目前的细菌血红素和叶绿素合成进化模型的重大转变。因为一些拥有这种共比例卟啉依赖分支的生物是人类疾病的主要原因，所以hemQ是一个具有重要治疗意义的新的药理靶点，特别是考虑到这些病原体中的高耐药率。
It has been generally accepted that biosynthesis of protoheme (heme) uses a common set of core metabolic intermediates that includes protoporphyrin. Herein, we show that the Actinobacteria and Firmicutes (high-GC and low-GC Gram-positive bacteria) are unable to synthesize protoporphyrin. Instead, they oxidize coproporphyrinogen to coproporphyrin, insert ferrous iron to make Fecoproporphyrin (coproheme), and then decarboxylate coproheme to generate protoheme. This pathway is specified by three genes named hemY, hemH, and hemQ. The analysis of 982 representative prokaryotic genomes is consistent with this pathway being the most ancient heme synthesis pathway in the Eubacteria. Our results identifying a previously unknown branch of tetrapyrrole synthesis support a significant shift from current models for the evolution of bacterial heme and chlorophyll synthesis. Because some organisms that possess this coproporphyrin-dependent branch are major causes of human disease, HemQ is a novel pharmacological target of significant therapeutic relevance, particularly given high rates of antimicrobial resistance among these pathogens.