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Aminoglycoside phosphotransferases: proteins, structure, and mechanism
1Department of Biochemistry, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. wrightge@fhs.mcmaster.ca
Frontiers in Bioscience : a Journal and Virtual Library
|January 5, 1999
Summary
Aminoglycoside resistance is a growing problem caused by modifying enzymes. Understanding aminoglycoside phosphotransferases (APHs) and their similarities to other kinases may help develop new drugs to combat resistance.
Area of Science:
- Microbiology
- Biochemistry
- Drug Discovery
Background:
- Aminoglycoside antibiotics are crucial for treating bacterial infections.
- Emergence of resistant organisms threatens the efficacy of these antibiotics.
- Resistance is often mediated by aminoglycoside-modifying enzymes, particularly phosphotransferases (APHs).
Purpose of the Study:
- To review the seven classes of aminoglycoside phosphotransferases (APHs).
- To explore structural and mechanistic insights into APH enzyme function.
- To identify potential therapeutic strategies for overcoming aminoglycoside resistance.
Main Methods:
- Review of existing literature on aminoglycoside phosphotransferases.
- Analysis of structural data, including the 3D structure of APH(3')-IIIa.
- Examination of mechanistic and mutagenic studies of APH enzymes.
Main Results:
- Seven distinct classes of APH enzymes exist, with variations in sequence homology but common signature residues.
- Structural and mechanistic similarities were identified between APHs and Ser/Thr/Tyr kinases.
- The 3D structure of APH(3')-IIIa complexed with ADP provides key insights into enzyme function.
Conclusions:
- Aminoglycoside phosphotransferases are key enzymes in antibiotic resistance.
- Structural and mechanistic parallels with other kinases offer novel avenues for drug development.
- Targeting APHs could be a viable strategy to reverse aminoglycoside resistance.