Structure and Mechanism of the Lincosamide Antibiotic adenylyltransferase LinB
Lincosamides make up an important class of antibiotics used against a wide range of pathogens, including methicillin-resistant Staphylococcus aureus. Predictably, lincosamide-resistant microorganisms have emerged with antibiotic modification as one of their major resistance strategies. Inactivating enzymes LinB/A catalyze adenylylation of the drug; however, little is known about their mechanistic and structural properties. We determined two X-ray structures of LinB: ternary substrate and binary productbound complexes. Structural and kinetic characterization of LinB, mutagenesis, solvent isotope effect, and product inhibition studies are consistent with a mechanism involving direct in-line nucleotidyl transfer. The characterization of LinB enabled its classification as a member of a nucleotidyltransferase superfamily, along with nucleotide polymerases and aminoglycoside nucleotidyltransferases, and this relationship offers further support for the LinB mechanism. The LinB structure provides an evolutionary link to ancient nucleotide polymerases and suggests that, like protein kinases and acetyltransferases, these are proto-resistance elements from which drug resistance can evolve.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
- Sponsoring Organization:
- DOE - OFFICE OF SCIENCE
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 1020011
- Report Number(s):
- BNL-95857-2011-JA; TRN: US201115%%647
- Journal Information:
- Structure, Vol. 17, Issue 12; ISSN 0969-2126
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
60 APPLIED LIFE SCIENCES
ANTIBIOTICS
CLASSIFICATION
ENZYMES
ISOTOPE EFFECTS
KINETICS
MICROORGANISMS
MODIFICATIONS
MUTAGENESIS
NUCLEOTIDES
NUCLEOTIDYLTRANSFERASES
PATHOGENS
PHOSPHOTRANSFERASES
POLYMERASES
PROTEINS
SOLVENTS
STAPHYLOCOCCUS
SUBSTRATES
national synchrotron light source