Mootz Henning D, Schwarzer Dirk, Marahiel Mohamed A
Philipps-University of Marburg, Fachbereich Chemie/Biochemie, Hans-Meerwein-Strasse, 35032 Marburg, Germany.
Chembiochem. 2002 Jun 3;3(6):490-504. doi: 10.1002/1439-7633(20020603)3:6<490::AID-CBIC490>3.0.CO;2-N.
Nonribosomal peptide synthetases (NRPSs) catalyze the assembly of a large number of complex peptide natural products, many of which display therapeutically useful activity. Each cycle of chain extension is carried out by a dedicated module of the multifunctional enzymes. A module harbors all the catalytic units, which are referred to as domains, necessary for recognition, activation, covalent binding, and optionally modification of a single building block monomer, as well as for peptide-bond formation with the growing chain. A terminal domain releases the full-length peptide chain from the enzyme complex. Recent characterization of many NRPS systems revealed several examples where the sequence of the product does not directly correspond to the linear arrangement of modules and domains within the enzyme(s). It is now obvious that these systems cannot be regarded as rare exceptions of the common NRPS architecture but rather represent more complicated variations of the NRPS repertoire to increase their biosynthetic potential. In most of these cases unusual peptide structures of the products are observed, such as structures with side-chain acylation, cyclization involving the peptide backbone and/or side chains, and transfer of the peptide chain onto soluble small-molecule substrates. These findings indicate a previously unexpected higher versatility of the modules and domains in terms of both catalytic potential and interaction within the multifunctional protein templates. We propose to classify the known NRPS systems into three groups, linear NRPSs (type A), iterative NRPSs (type B), and nonlinear NRPSs (type C), according to their biosynthetic logic. Understanding the various biosynthetic strategies of NRPSs will be crucial to fully explore their potential for engineered combinatorial biosynthesis.
非核糖体肽合成酶（NRPSs）催化大量复杂肽类天然产物的组装，其中许多具有治疗活性。链延伸的每个循环由多功能酶的一个特定模块执行。一个模块包含所有催化单元，即结构域，这些结构域对于识别、激活、共价结合以及对单个构建块单体进行任选修饰，以及与生长中的链形成肽键都是必需的。一个末端结构域从酶复合物中释放出全长肽链。最近对许多NRPS系统的表征揭示了几个例子，其中产物的序列并不直接对应于酶内模块和结构域的线性排列。现在很明显，这些系统不能被视为常见NRPS结构的罕见例外，而更代表了NRPS库中更复杂的变体，以增加其生物合成潜力。在大多数这些情况下，观察到产物具有不寻常的肽结构，例如具有侧链酰化、涉及肽主链和/或侧链的环化以及肽链转移到可溶性小分子底物上的结构。这些发现表明，就多功能蛋白质模板内的催化潜力和相互作用而言，模块和结构域具有前所未有的更高通用性。我们建议根据其生物合成逻辑将已知的NRPS系统分为三组：线性NRPSs（A型）、迭代NRPSs（B型）和非线性NRPSs（C型）。了解NRPSs的各种生物合成策略对于充分挖掘其在工程化组合生物合成中的潜力至关重要。
