生物谷：Andrimid是一種相對較“新”的抗生素,。最初,，它是從幾種不同類型的細菌中分離出來，并通過阻斷細菌脂肪酸生物合成中的第一步來發(fā)揮作用,。主要是由于這種新穎的作用方式,，它可以用于抵抗多種藥物的病原體,。
現(xiàn)在，產生Andrimid的生物合成通道已經被確定,，從而為獲取具有治療潛力的新的一類Andrimid衍生物提供了一條途徑,。對迄今已經測序的微生物基因組所進行的數(shù)據(jù)分析工作，發(fā)現(xiàn)了轉谷氨酰胺酶類的酶AdmF的同源物,，這種酶是Andrimid生物合成通道的關鍵成分,，處在很多孤立生物合成基因簇當中，其天然產物尚未被識別出來,?？磥恚@種類型的化合物是普遍存在的,，更多“新”抗生素似乎正等待我們去發(fā)現(xiàn),。
原始出處:
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: [email protected]).
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.
