Pyridoxal-5'-phosphate-dependent bifunctional enzyme catalyzed biosynthesis of indolizidine alkaloids in fungi

摘要: Indolizidine alkaloids such as anticancer drugs vinblastine and vincristine are exceptionally attractive due to their widespread occurrence, prominent bioactivity, complex structure, sophisticated involvement in the chemical defense for producing organisms. However, versatility of indolizidine alkaloid biosynthesis remains incompletely addressed since knowledge about biosynthetic machineries is only limited several representatives. Herein, we describe gene cluster (BGC) curvulamine, a skeletally unprecedented antibacterial from Curvularia sp. IFB-Z10. The molecular architecture curvulamine results functional collaboration highly reducing polyketide synthase (CuaA), pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (CuaB), an NADPH-dependent dehydrogenase (CuaC), FAD-dependent monooxygenase (CuaD), with its transportation abundance regulated by major facilitator superfamily permease (CuaE) Zn(II)Cys6 transcription factor (CuaF), respectively. In contrast expectations, CuaB bifunctional capable catalyzing Claisen condensation form new C-C bond α-hydroxylation alanine moiety exposure dioxygen. Inspired guided distinct function CuaB, our genome mining effort discovers bipolamines A-I (bipolamine G more than curvulamine), which represent collection previously undescribed silent BGC Bipolaris maydis ATCC48331. work provides insight into nature's arsenal indolizidine-coined skeletal formation adds evidence support PLP-dependent enzymes fungi.