Explorations of catalytic domains in non-ribosomal peptide synthetase enzymology.
Explorations of catalytic domains in non-ribosomal peptide synthetase enzymology.
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DOI：
10.1039/c2np20025b
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发表时间：
2012-10
影响因子：
11.9
通讯作者：
Burkart MD
中科院分区：
文献类型：
--
作者：
Hur GH;Vickery CR;Burkart MD
今天市场上的许多药物都属于一大类被称为非核糖体肽(NRPs)的天然产品。这些源于细菌和真菌的多肽类天然产物不仅含有典型的20种L氨基酸，还含有非蛋白生成氨基酸、杂环、糖和脂肪酸，产生了巨大的化学多样性。因此，这些次级代谢产物表现出从抗菌到抗癌的广泛生物活性。这些复杂化合物的生物合成是由被称为非核糖体多肽合成酶(NRPS)的大的多模块巨酶执行的。每个模块负责将单体单位结合到天然产物多肽中，并由执行不同催化反应的各个结构域组成。对这些酶的生化和生物信息学研究揭示了NRP合成的关键原理，扩大了它们的酶过程的制药潜力。在操作这种生物合成机制方面取得了进展，以开发新的化学酶方法来合成具有更高效力的新的药物制剂。本文综述了近年来在NRPS结构阐明、分子机制和化学生物学方面的最新发现和突破。
Many pharmaceuticals on the market today belong to a large class of natural products called nonribosomal peptides (NRPs). Originating from bacteria and fungi, these peptide-based natural products consist not only of the 20 canonical L-amino acids, but also non-proteinogenic amino acids, heterocyclic rings, sugars, and fatty acids, generating tremendous chemical diversity. As a result, these secondary metabolites exhibit a broad array of bioactivity ranging from antimicrobial to anticancer. The biosynthesis of these complex compounds is carried out by large multimodular megaenzymes called nonribosomal peptide synthetases (NRPSs). Each module is responsible for incorporation of a monomeric unit into the natural product peptide and is composed of individual domains that perform different catalytic reactions. Biochemical and bioinformatic investigations of these enzymes have uncovered the key principles of NRP synthesis, expanding the pharmaceutical potential of their enzymatic processes. Progress has been made in the manipulation of this biosynthetic machinery to develop new chemoenzymatic approaches for synthesizing novel pharmaceutical agents with increased potency. This review focuses on the recent discoveries and breakthroughs in the structural elucidation, molecular mechanism, and chemical biology underlying the discrete domains within NRPSs.