GliP, a Multimodular Nonribosomal Peptide Synthetase inAspergillus fumigatus, Makes the Diketopiperazine Scaffold of Gliotoxin

作者：Carl J. Balibar, Christopher T. Walsh · 发表于：Biochemistry · 年份：2006 · DOI：10.1021/bi061845b · 被引用次数：152 · 研究领域：Microbial Natural Products and Biosynthesis、RNA and protein synthesis mechanisms、Bacterial Genetics and Biotechnology

The fungal metabolite gliotoxin has a redox-active disulfide bridge spanning carbons 3 and 6 of a diketopiperazine (DKP) scaffold. The proposed DKP synthetase, GliP, from Aspergillus fumigatus Af293, is a three module (A1-T1-C1-A2-T2-C2-T3) 236 kDa protein that can be overproduced in soluble form in Escherichia coli. Once primed on its three thiolation domains with phosphopantetheine prosthetic groups, GliP activates and tethers l-Phe on T1 and l-Ser on T2, before generating the l-Phe-l-Ser-S-T2 dipeptidyl enzyme intermediate. Release of the dipeptide as the cyclic DKP happens slowly both in wild-type GliP and in enzyme forms where C2 and T3 have been mutationally inactivated. The lack of a thioesterase domain in GliP may account both for the slow release and for the directed fate of intramolecular cyclization to create the DKP scaffold for subsequent elaboration to gliotoxin.