Structure and mechanism of the tRNA-dependent lantibiotic dehydratase NisB

Structural and biochemical studies show that the biosynthesis of the food preservative nisin involves the tRNA-dependent glutamylation of serine and threonine. Mechanisms of lantibiotic biosynthesis Nisin, a member of the lantibiotic family of thioether-bridge containing antibiotics, has been used w...

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Published in:Nature (London) Vol. 517; no. 7535; pp. 509 - 512
Main Authors: Ortega, Manuel A., Hao, Yue, Zhang, Qi, Walker, Mark C., van der Donk, Wilfred A., Nair, Satish K.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 22.01.2015
Nature Publishing Group
Subjects:
631/45/173
631/535/1266
631/92/60
82/58
Analysis
Antibiotics
Bacterial Proteins - chemistry
Bacterial Proteins - classification
Bacterial Proteins - metabolism
Bacteriocins - biosynthesis
Bacteriocins - metabolism
Bacteriology
Biosynthesis
Chemical properties
Crystallography, X-Ray
Dehydration
E coli
Enzymes
Escherichia coli - genetics
Food contamination
Glutamic Acid - metabolism
Gram-positive bacteria
Health aspects
Humanities and Social Sciences
Hydro-Lyases - chemistry
Hydro-Lyases - classification
Hydro-Lyases - metabolism
Lactococcus lactis - enzymology
Lactococcus lactis - genetics
letter
Membrane Proteins - chemistry
Membrane Proteins - classification
Membrane Proteins - metabolism
Models, Molecular
multidisciplinary
Nisin - biosynthesis
Nisin - metabolism
Peptides
Phylogeny
Physiological aspects
Preservatives
Protein Structure, Tertiary
Proteins
RNA, Transfer, Glu - genetics
RNA, Transfer, Glu - metabolism
Science
Serine - metabolism
Structure
Threonine - metabolism
Transfer RNA
Massachusetts
Illinois
ISSN:0028-0836, 1476-4687, 1476-4687
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Summary:Structural and biochemical studies show that the biosynthesis of the food preservative nisin involves the tRNA-dependent glutamylation of serine and threonine. Mechanisms of lantibiotic biosynthesis Nisin, a member of the lantibiotic family of thioether-bridge containing antibiotics, has been used widely in the food industry for more than 40 years without substantial development of resistance. This property has become of particular interest in light of the emergence of resistance to many clinically used antibiotics. Wilfred van der Donk and colleagues present the X-ray structure of the lantibiotic dehydratase NisB, an enzyme involved in nisin biosynthesis, and use biochemical data to show that NisB utilizes glutamyl-tRNA Glu in the critical activation of Ser/Thr residues. These findings provide a basis for the functional characterization of the many lantibiotic-like dehydratases involved in the biosynthesis of other classes of natural products. Lantibiotics are a class of peptide antibiotics that contain one or more thioether bonds. The lantibiotic nisin is an antimicrobial peptide that is widely used as a food preservative to combat food-borne pathogens 1 . Nisin contains dehydroalanine and dehydrobutyrine residues that are formed by the dehydration of Ser/Thr by the lantibiotic dehydratase NisB (ref. 2 ). Recent biochemical studies revealed that NisB glutamylates Ser/Thr side chains as part of the dehydration process 3 . However, the molecular mechanism by which NisB uses glutamate to catalyse dehydration remains unresolved. Here we show that this process involves glutamyl-tRNA Glu to activate Ser/Thr residues. In addition, the 2.9-Å crystal structure of NisB in complex with its substrate peptide NisA reveals the presence of two separate domains that catalyse the Ser/Thr glutamylation and glutamate elimination steps. The co-crystal structure also provides insights into substrate recognition by lantibiotic dehydratases. Our findings demonstrate an unexpected role for aminoacyl-tRNA in the formation of dehydroamino acids in lantibiotics, and serve as a basis for the functional characterization of the many lantibiotic-like dehydratases involved in the biosynthesis of other classes of natural products.
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These authors contributed equally to this work
ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/nature13888