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Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY
Nature Communications ( IF 14.7 ) Pub Date : 2023-02-03 , DOI: 10.1038/s41467-023-36299-1
Colin Y Kim 1, 2 , Andrew J Mitchell 1 , David W Kastner 2, 3 , Claire E Albright 1 , Michael A Gutierrez 1 , Christopher M Glinkerman 1 , Heather J Kulik 3 , Jing-Ke Weng 1, 4
Affiliation  

Plants contain rapidly evolving specialized enzymes that support the biosynthesis of functionally diverse natural products. In coumarin biosynthesis, a BAHD acyltransferase-family enzyme COSY was recently discovered to accelerate coumarin formation as the only known BAHD enzyme to catalyze an intramolecular acyl transfer reaction. Here we investigate the structural and mechanistic basis for COSY’s coumarin synthase activity. Our structural analyses reveal an unconventional active-site configuration adapted to COSY’s specialized activity. Through mutagenesis studies and deuterium exchange experiments, we identify a unique proton exchange mechanism at the α-carbon of the o-hydroxylated trans-hydroxycinnamoyl-CoA substrates during the catalytic cycle of COSY. Quantum mechanical cluster modeling and molecular dynamics further support this key mechanism for lowering the activation energy of the rate-limiting trans-to-cis isomerization step in coumarin production. This study unveils an unconventional catalytic mechanism mediated by a BAHD-family enzyme, and sheds light on COSY’s evolutionary origin and its recruitment to coumarin biosynthesis in eudicots.



中文翻译:

植物香豆素合酶 COSY 中基于质子交换的异构化和内酯化机制的出现

植物含有快速进化的特殊酶,支持功能多样的天然产物的生物合成。在香豆素生物合成中,最近发现一种 BAHD 酰基转移酶家族酶 COSY 可以加速香豆素的形成,它是唯一已知的催化分子内酰基转移反应的 BAHD 酶。在这里,我们研究了 COSY 的香豆素合酶活性的结构和机制基础。我们的结构分析揭示了适应 COSY 专业活动的非常规活性位点配置。通过诱变研究和氘交换实验,我们在邻羟基式的 α-碳上确定了一种独特的质子交换机制-COSY 催化循环中的羟基肉桂酰辅酶 A 底物。量子力学团簇模型和分子动力学进一步支持这一降低香豆素生产中限速反式-顺式异构化步骤的活化能的关键机制。这项研究揭示了一种由 BAHD 家族酶介导的非常规催化机制,并阐明了 COSY 的进化起源及其在真双子叶植物中参与香豆素生物合成的过程。

更新日期:2023-02-04
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