Wright G D, Thompson P R
Department of Biochemistry, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
Front Biosci. 1999 Jan 1;4:D9-21. doi: 10.2741/wright.
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.
氨基糖苷类抗生素是一类临床上重要的有用药物，但耐药菌的出现使其受到威胁。临床上的氨基糖苷类耐药主要是由于存在能使抗生素发生N - 乙酰化、O - 腺苷酸化或O - 磷酸化的修饰酶。后一类酶被称为氨基糖苷磷酸转移酶或激酶，也是本综述的主题。氨基糖苷磷酸转移酶有七类（APH(3')、APH(2'')、APH(3'off')、APH(6)、APH(9)、APH(4)、APH(7'')），每类中有许多同工酶，尽管这些酶之间总体上几乎没有普遍的序列同源性，但某些特征性残基和序列是常见的。最近测定了与产物ADP复合的广谱氨基糖苷激酶APH(3') - IIIa的三维结构，此外对该酶及相关酶进行了机制和诱变研究，这极大地增进了我们对这类抗生素耐药酶的理解。特别是，APH与丝氨酸/苏氨酸激酶和酪氨酸激酶之间结构和机制相似性的揭示，为未来的抑制研究奠定了基础，这些研究可能对逆转氨基糖苷类耐药具有重要意义。
