生物谷：Andrimid是一种相对较“新”的抗生素。最初，它是从几种不同类型的细菌中分离出来，并通过阻断细菌脂肪酸生物合成中的第一步来发挥作用。主要是由于这种新颖的作用方式，它可以用于抵抗多种药物的病原体。
现在，产生Andrimid的生物合成通道已经被确定，从而为获取具有治疗潜力的新的一类Andrimid衍生物提供了一条途径。对迄今已经测序的微生物基因组所进行的数据分析工作，发现了转谷氨酰胺酶类的酶AdmF的同源物，这种酶是Andrimid生物合成通道的关键成分，处在很多孤立生物合成基因簇当中，其天然产物尚未被识别出来。看来，这种类型的化合物是普遍存在的，更多“新”抗生素似乎正等待我们去发现。
原始出处:
Nature 448, 824-827 (16 August 2007) | doi:10.1038/nature06068; Received 22 March 2007; Accepted 9 July 2007; Published online 25 July 2007
A transglutaminase homologue as a condensation catalyst in antibiotic assembly lines
Pascal D. Fortin1,2, Christopher T. Walsh1 & Nathan A. Magarvey1,2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
These authors contributed equally to this work.
Correspondence to: Christopher T. Walsh1 Correspondence and requests for materials should be addressed to C.T.W. (Email: christopher_walsh@hms.harvard.edu).
The unrelenting emergence of antibiotic-resistant bacterial pathogens demands the investigation of antibiotics with new modes of action. The pseudopeptide antibiotic andrimid is a nanomolar inhibitor of the bacterial acetyl-CoA carboxylase that catalyses the first committed step in prokaryotic fatty acid biosynthesis1. Recently, the andrimid (adm) biosynthetic gene cluster was isolated and heterologously expressed in Escherichia coli2. This establishes a heterologous biological host in which to rapidly probe features of andrimid formation and to use biosynthetic engineering to make unnatural variants of this important and promising new class of antibiotics. Bioinformatic analysis of the adm cluster revealed a dissociated biosynthetic assembly system lacking canonical amide synthases between the first three carrier protein domains. Here we report that AdmF, a transglutaminase (TGase) homologue, catalyses the formation of the first amide bond, an N-acyl--peptide link, in andrimid biosynthesis. Hence, AdmF is a newly discovered biosynthetic enzyme that acts as a stand-alone amide synthase between protein-bound, thiotemplated substrates in an antibiotic enzymatic assembly line. TGases (enzyme class (EC) 2.3.2.13) normally catalyse the cross-linking of (poly)peptides by creating isopeptidic bonds between the -carboxamide group of a glutamine side chain of one protein and various amine donors, including lysine side chains3. To the best of our knowledge, the present study constitutes the first report of a TGase-like enzyme recruited for the assembly of an antibiotic. Moreover, genome mining using the AdmF sequence yielded additional TGases in unassigned natural product biosynthetic pathways. With many more microbial genomes being sequenced, such a strategy could potentially unearth biosynthetic pathways producing new classes of antibiotics.
