Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Science. 2019 Jul 19;365(6450):280-284. doi: 10.1126/science.aau6232.
Genome sequencing of environmental bacteria allows identification of biosynthetic gene clusters encoding unusual combinations of enzymes that produce unknown natural products. We identified a pathway in which a ribosomally synthesized small peptide serves as a scaffold for nonribosomal peptide extension and chemical modification. Amino acids are transferred to the carboxyl terminus of the peptide through adenosine triphosphate and amino acyl-tRNA-dependent chemistry that is independent of the ribosome. Oxidative rearrangement, carboxymethylation, and proteolysis of a terminal cysteine yields an amino acid-derived small molecule. Microcrystal electron diffraction demonstrates that the resulting product is isosteric to glutamate. We show that a similar peptide extension is used during the biosynthesis of the ammosamides, which are cytotoxic pyrroloquinoline alkaloids. These results suggest an alternative paradigm for biosynthesis of amino acid-derived natural products.
环境细菌的基因组测序可以鉴定出生物合成基因簇，这些基因簇编码产生未知天然产物的不同寻常的酶组合。我们发现了一条途径，其中核糖体合成的小肽作为非核糖体肽延伸和化学修饰的支架。通过依赖于三磷酸腺苷和氨酰-tRNA 的化学过程，将氨基酸转移到肽的羧基末端，该过程与核糖体无关。末端半胱氨酸的氧化重排、羧甲基化和蛋白水解作用产生氨基酸衍生的小分子。微晶体电子衍射表明，所得产物与谷氨酸是等排的。我们表明，在阿摩沙米德的生物合成过程中也使用了类似的肽延伸，阿摩沙米德是细胞毒性吡咯喹啉生物碱。这些结果表明了氨基酸衍生天然产物生物合成的另一种范例。
