Pyridoxal-5′-phosphate dependent bifunctional enzyme catalyzed biosynthesis of indolizidine alkaloids in fungi
Pyridoxal-5′-phosphate dependent bifunctional enzyme catalyzed biosynthesis of indolizidine alkaloids in fungi
复制标题
吡哆醛-5'-磷酸依赖性双功能酶催化真菌中吲哚里西啶生物碱的生物合成
DOI：
10.1073/pnas.1914777117
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发表时间：
2020-01-14
影响因子：
11.1
通讯作者：
Tan, Ren Xiang
中科院分区：
文献类型：
--
作者：
Dai, Guang Zhi;Han, Wen Bo;Tan, Ren Xiang
吲哚里西啶类生物碱如长春碱、长春新碱等因其分布广泛、生物活性突出、结构复杂、参与生产生物的化学防御而备受关注。然而，吲哚里西啶生物碱生物合成的多功能性仍然没有完全解决，因为有关这种生物合成机制的知识仅限于几个代表。在此，我们描述了生物合成基因簇（BGC）的生物合成弯孢胺，一个前所未有的抗菌吲哚里西啶生物碱从弯孢属IFB-Z10。弯孢胺的分子结构由高度还原的聚酮合酶（CuaA）、吡哆醛-5 '-磷酸（PLP）依赖性氨基转移酶（CuaB）、NADPH依赖性脱氢酶（CuaC）和FAD依赖性单加氧酶（CuaD）的功能协作产生，其运输和丰度由主要易化剂超家族通透酶（CuaE）和Zn（II）Cys（6）转录因子（CuaF）调节，分别与预期相反，CuaB是双官能的，并且能够催化Claisen缩合以形成新的C-C键和丙氨酸部分在暴露于分子氧时的α-羟基化。受CuaB独特功能的启发和指导，我们的基因组挖掘工作发现了bipolamines A-I（bipolamine G比curvulamine更具抗菌性），这代表了以前未描述的聚酮生物碱的集合，来自玉米小斑病菌ATCC 48331中的沉默BGC。这项工作提供了对大自然中吲哚嗪创造的骨骼形成武器库的深入了解，并增加了支持真菌中PLP依赖酶功能多样性的证据。
Indolizidine alkaloids such as anticancer drugs vinblastine and vincristine are exceptionally attractive due to their widespread occurrence, prominent bioactivity, complex structure, and sophisticated involvement in the chemical defense for the producing organisms. However, the versatility of the indolizidine alkaloid biosynthesis remains incompletely addressed since the knowledge about such biosynthetic machineries is only limited to several representatives. Herein, we describe the biosynthetic gene cluster (BGC) for the biosynthesis of curvulamine, a skeletally unprecedented antibacterial indolizidine alkaloid from Curvularia sp. IFB-Z10. The molecular architecture of curvulamine results from the functional collaboration of a highly reducing polyketide synthase (CuaA), a pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (CuaB), an NADPH-dependent dehydrogenase (CuaC), and a FAD-dependent monooxygenase (CuaD), with its transportation and abundance regulated by a major facilitator superfamily permease (CuaE) and a Zn(II)Cys(6) transcription factor (CuaF), respectively. In contrast to expectations, CuaB is bifunctional and capable of catalyzing the Claisen condensation to form a new C-C bond and the alpha-hydroxylation of the alanine moiety in exposure to dioxygen. Inspired and guided by the distinct function of CuaB, our genome mining effort disccovers bipolamines A-I (bipolamine G is more antibacterial than curvulamine), which represent a colletion of previously undescribed polyketide alkaloids from a silent BGC in Bipolaris maydis ATCC48331. The work provides insight into nature's arsenal for the indolizidine-coined skeletal formation and adds evidence in support of the functional versatility of PLP-dependent enzymes in fungi.