GliP, a multimodular nonribosomal peptide synthetase in Aspergillus fumigatus, makes the diketopiperazine scaffold of gliotoxin.

Abstract:

: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.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Balibar CJ,Walsh CT

doi

10.1021/bi061845b

subject

Has Abstract

pub_date

2006-12-19 00:00:00

pages

15029-38

issue

50

eissn

0006-2960

issn

1520-4995

journal_volume

45

pub_type

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