LimF is a versatile prenyltransferase for histidine-C-geranylation on diverse non-natural substrates
LimF is a versatile prenyltransferase for histidine-C-geranylation on diverse non-natural substrates
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DOI：
10.1038/s41929-022-00822-2
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发表时间：
2022-08
期刊：
影响因子：
37.8
通讯作者：
Yuchen Zhang;K. Hamada;D. T. Nguyen;Sumika Inoue;Masayuki Satake;Shunsuke Kobayashi;Chikako Okada;K. Ogata;Masahiro Okada;T. Sengoku;Yuki Goto;H. Suga
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文献类型：
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作者：
Yuchen Zhang;K. Hamada;D. T. Nguyen;Sumika Inoue;Masayuki Satake;Shunsuke Kobayashi;Chikako Okada;K. Ogata;Masahiro Okada;T. Sengoku;Yuki Goto;H. Suga
异戊烯化在次生代谢产物结构和功能的多样化中起着重要的作用。虽然几个cyanobactin异戊二烯基转移酶的特点，其化学主要限于富电子杂原子的修饰。在这里，我们报告了异戊烯基转移酶，LimF，从Limnothrixsp。CACIAM 69 d，香叶基化His咪唑的缺电子C2原子。有趣的是，除了其天然底物，LimF还修饰了多种外来肽，包括硫醚封闭的大环化合物。我们还意外地发现Tyr-O-geranylating活性作为LimF的次要功能，提供了对cyanobactin PT酶产生的异戊烯化肽的不同库的进化见解。LimF与五肽底物和异戊烯基供体类似物复合的晶体学分析为其His识别和其双功能性提供了结构基础。我们还显示了异戊烯化能力的LimF对各种生物活性分子含有咪唑基团，包括非氨基酸小分子，突出其作为一种通用的生物催化剂化学挑战性的imidazoleC-香叶基化的潜力。
Prenylation plays an important role in diversifying the structure and function of secondary metabolites. Although several cyanobactin prenyltransferases have been characterized, their chemistries are mainly limited to the modification of electron-rich heteroatoms. Here we report a prenyltransferase, LimF, fromLimnothrixsp. CACIAM 69d, geranylating the electron-deficientC2 atom of His imidazole. Interestingly, in addition to its native substrate, LimF also modifies diverse exotic peptides, including thioether-closed macrocycles. We have also serendipitously uncovered Tyr-O-geranylating activity as the secondary function of LimF, providing evolutional insight into the divergent repertoire of prenylated peptides produced by cyanobactin PTases. Crystallographic analysis of LimF complexed with a pentapeptide substrate and a prenyl donor analogue provides the structural basis for its His recognition and its bifunctionality. We also show the prenylation ability of LimF on various bioactive molecules containing an imidazole group, including non-amino acid small molecules, highlighting its potential as a versatile biocatalyst for chemically challenging imidazoleC-geranylation.