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They produce hazardous mycotoxins for human and animals. On the other hand, the fungal metabolites including mycotoxins are important drug candidates and the enzymes involved in the biosynthesis of these compounds are valuable biocatalysts for production of designed compounds. One of the enzyme groups are members of the dimethylallyl tryptophan synthase superfamily, which mainly catalyze prenylations of tryptophan and tryptophan-containing cyclodipeptides (CDPs). Decoration of CDPs in the biosynthesis of multiple prenylated metabolites in nature is usually initiated by regiospecific<jats:italic>C2<\/jats:italic>-prenylation at the indole ring, followed by second and third ones as well as by other modifications. However, the strict substrate specificity can prohibit the further prenylation of unnatural<jats:italic>C2<\/jats:italic>-prenylated compounds. To overcome this, we firstly obtained<jats:italic>C4<\/jats:italic>-,<jats:italic>C5<\/jats:italic>-,<jats:italic>C6<\/jats:italic>-, and<jats:italic>C7<\/jats:italic>-prenylated<jats:italic>cyclo<\/jats:italic>-<jats:sc>l<\/jats:sc>-Trp-<jats:sc>l<\/jats:sc>-Pro. These products were then used as substrates for the promiscuous<jats:italic>C2<\/jats:italic>-prenyltransferase EchPT1, which normally uses the unprenylated CDPs as substrates. Four unnatural diprenylated<jats:italic>cyclo<\/jats:italic>-<jats:sc>l<\/jats:sc>-Trp-<jats:sc>l<\/jats:sc>-Pro including the unique unexpected<jats:italic>N1<\/jats:italic>,<jats:italic>C6<\/jats:italic>-diprenylated derivative with significant yields were obtained in this way. Our study provides an excellent example for increasing structural diversity by reprogramming the reaction orders of natural biosynthetic pathways. Furthermore, this is the first report that EchPT1 can also catalyze<jats:italic>N1<\/jats:italic>-prenylation at the indole ring.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:italic>\u2022 Prenyltransferases as biocatalysts for unnatural substrates.<\/jats:italic><\/jats:p><jats:p><jats:italic>\u2022 Chemoenzymatic synthesis of designed molecules.<\/jats:italic><\/jats:p><jats:p><jats:italic>\u2022 A cyclodipeptide prenyltransferase as prenylating enzyme of already prenylated products.<\/jats:italic><\/jats:p><\/jats:sec><jats:sec><jats:title>Graphical Abstract<\/jats:title><\/jats:sec>","DOI":"10.1007\/s00253-022-12303-4","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T11:04:06Z","timestamp":1669633446000},"page":"261-271","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Diprenylated cyclodipeptide production by changing the prenylation sequence of the nature\u2019s synthetic machinery"],"prefix":"10.1007","volume":"107","author":[{"given":"Wen","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Coby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4583-2655","authenticated-orcid":false,"given":"Shu-Ming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,28]]},"reference":[{"key":"12303_CR1","doi-asserted-by":"publisher","first-page":"717","DOI":"10.2174\/0929867053202241","volume":"12","author":"B Botta","year":"2005","unstructured":"Botta B, Vitali A, Menendez P, Misiti D, Delle MG (2005) Prenylated flavonoids: pharmacology and biotechnology. 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