X-ray analysis of butirosin biosynthetic enzyme BtrN redefines structural motifs for AdoMet radical chemistry

The 2-deoxy- scyllo -inosamine (DOIA) dehydrogenases are key enzymes in the biosynthesis of 2-deoxystreptamine–containing aminoglycoside antibiotics. In contrast to most DOIA dehydrogenases, which are NAD-dependent, the DOIA dehydrogenase from Bacillus circulans (BtrN) is an S -adenosyl- l -methioni...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (40), p.15949-15954
Main Authors: Goldman, Peter J., Grove, Tyler L., Booker, Squire J., Drennan, Catherine L.
Format: Article
Language:English
Subjects:
Aminoglycosides
Bacillus - enzymology
Bacteria
Biochemistry
Biological Sciences
Biosynthesis
Biosynthetic Pathways - genetics
Butirosin Sulfate - biosynthesis
Carbohydrate Dehydrogenases - chemistry
Carbohydrate Dehydrogenases - metabolism
Chemistry
Crystallization
Dehydrogenases
DNA Primers - genetics
Enzymes
Hydrogen
Hydrogen bonds
Iron Compounds - metabolism
Models, Molecular
Molecular Structure
Oxidation
Physical Sciences
Protein Binding
Protein Conformation
Proteins
S-Adenosylmethionine - metabolism
Spasms
Substrates
Sulfur Compounds - metabolism
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Summary:The 2-deoxy- scyllo -inosamine (DOIA) dehydrogenases are key enzymes in the biosynthesis of 2-deoxystreptamine–containing aminoglycoside antibiotics. In contrast to most DOIA dehydrogenases, which are NAD-dependent, the DOIA dehydrogenase from Bacillus circulans (BtrN) is an S -adenosyl- l -methionine (AdoMet) radical enzyme. To examine how BtrN employs AdoMet radical chemistry, we have determined its structure with AdoMet and substrate to 1.56 Å resolution. We find a previously undescribed modification to the core AdoMet radical fold: instead of the canonical (β/α) ₆ architecture, BtrN displays a (β ₅/α ₄) motif. We further find that an auxiliary [4Fe-4S] cluster in BtrN, thought to bind substrate, is instead implicated in substrate–radical oxidation. High structural homology in the auxiliary cluster binding region between BtrN, fellow AdoMet radical dehydrogenase anSME, and molybdenum cofactor biosynthetic enzyme MoaA provides support for the establishment of an AdoMet radical structural motif that is likely common to ∼6,400 uncharacterized AdoMet radical enzymes.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1312228110