Biosynthetic Study of Cephalosporin P1 Reveals a Multifunctional P450 Enzyme and a Site-Selective Acetyltransferase.,ACS Chemical Biology

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Biosynthetic Study of Cephalosporin P1 Reveals a Multifunctional P450 Enzyme and a Site-Selective Acetyltransferase.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-26 , DOI: 10.1021/acschembio.9b00863
Zhi-Qin Cao _{1,

2} , Jian-Ming Lv ₁ , Qiu Liu ₁ , Sheng-Ying Qin ₃ , Guo-Dong Chen ₁ , Ping Dai ₁ , Yue Zhong ₂ , Hao Gao ₁ , Xin-Sheng Yao ₁ , Dan Hu ₁

Affiliation

Fusidane-type antibiotics are a group of triterpenoid antibiotics. They include helvolic acid, fusidic acid, and cephalosporin P1, among which fusidic acid has been used clinically. We have recently elucidated the biosynthesis of helvolic acid and fusidic acid, which share an early biosynthetic route involving six conserved enzymes. Here, we report two separate gene clusters for cephalosporin P1 biosynthesis. One consists of the six conserved genes, and the other contains three genes encoding a P450 enzyme (CepB4), an acetyltransferase (CepD2), and a short-chain dehydrogenase/reductase (CepC2). Introduction of these three genes into Aspergillus oryzae, which harbors the six conserved genes, produced cephalosporin P1. Stepwise introduction revealed that CepB4 not only catalyzes stereoselective dual oxidation of C6 and C7, but also monooxygenation of C6 or C7. This led to the generation of five new analogues. Using monohydroxylated products as substrates, we demonstrated that CepD2 specifically acetylates C6-OH, although both C6-OH and C7-OH acetylated analogues have been identified in nature.

中文翻译：

头孢菌素P1的生物合成研究揭示了多功能P450酶和位点选择性乙酰转移酶。

Fusidane型抗生素是一组三萜类抗生素。它们包括羟乙酸，夫西地酸和头孢菌素P1，其中夫西地酸已在临床上使用。最近，我们阐明了乙二酸和夫西地酸的生物合成，它们具有涉及六种保守酶的早期生物合成途径。在这里，我们报告头孢菌素P1生物合成的两个单独的基因簇。一个由六个保守基因组成，另一个包含三个编码P450酶（CepB4），乙酰基转移酶（CepD2）和短链脱氢酶/还原酶（CepC2）的基因。将这三个基因引入具有六个保守基因的米曲霉中，产生了头孢菌素P1。逐步介绍显示CepB4不仅催化C6和C7的立体选择性双重氧化，而且还可以对C6或C7进行单加氧。这导致产生了五个新的类似物。使用单羟基化产物作为底物，我们证明了CepD2特异性乙酰化了C6-OH，尽管在自然界中已经发现了C6-OH和C7-OH乙酰化的类似物。

更新日期：2019-12-27

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