Title

Aminoglycoside phosphotransferases: proteins, structure, and mechanism

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

1999-01-01

Document Type

Article

Subjects

Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Microbial; Evolution, Molecular; Gram-Negative Bacteria; Gram-Positive Bacteria; *Kanamycin Kinase; inhibitors; Models, Molecular; Mycobacterium; Protein Conformation; Substrate Specificity; Terminology as Topic

Disciplines

Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics

Abstract

Aminoglycoside antibiotics constitute an important class of clinically useful drugs which are imperiled by the emergence of resistant organisms. Aminoglycoside resistance in the clinics is primarily due to the presence of modifying enzymes which N-acetylate, O-adenylate or O-phosphorylate the antibiotics. The latter family of enzymes are termed the aminoglycoside phosphotransferases or kinases and are the subject of this review. There are seven classes of aminoglycoside phosphotransferases (APH(3'), APH(2''), APH(3'off'), APH(6), APH(9), APH(4), APH(7'')) and many isozymes in each class, and although there is very little overall general sequence homology among these enzymes, certain signature residues and sequences are common. The recent determination of the three-dimensional structure of the broad spectrum aminoglycoside kinase APH(3')-IIIa complexed with the product ADP, in addition to mechanistic and mutagenic studies on this and related enzymes, has added a great deal to our understanding of this class of antibiotic resistance enzyme. In particular, the revelation of structural and mechanistic similarities between APHs and Ser/Thr and Tyr kinases has set the stage for future inhibition studies which could prove important in reversing aminoglycoside resistance.

Source

Front Biosci. 1999 Jan 1;4:D9-21.

Journal/Book/Conference Title

Frontiers in bioscience : a journal and virtual library

Comments

At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

Related Resources

Link to Article in PubMed

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