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Edited by Douglas C. Rees, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, and approved August 20, 2013 (received for review June 27, 2013)
Significance
AdoMet radical enzymes harness the power of radical-based chemistry to carry out complex chemical transformations. The structure of butirosin biosynthethic enzyme BtrN reveals both unforeseen differences and surprising similarities compared with other members of this rapidly expanding enzyme superfamily. In particular, variations in how BtrN binds S-adenosyl-L-methionine (AdoMet) warrant redefinition of the core fold responsible for adenosyl-radical generation whereas similarities in how BtrN binds an auxiliary iron–sulfur cluster provide the basis for assignment of a previously undescribed structural motif.
Abstract
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 (β5/α4) 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.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: cdrennan{at}mit.edu.
Author contributions: P.J.G., T.L.G., S.J.B., and C.L.D. designed research; P.J.G. performed crystallographic studies; T.L.G. contributed protein samples; and P.J.G. and C.L.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 4M7S and 4M7T).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1312228110/-/DCSupplemental.
Structure of BtrN, an AdoMet radical dehydrogenase
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