Niedzwicki J G, Abernethy D R
Division of Clinical Pharmacology, Brown University, Providence, Rhode Island.
Biochem Pharmacol. 1991 Jun 1;41(11):1615-24. doi: 10.1016/0006-2952(91)90162-x.
Diethylaminoethyl-cellulose chromatography was used to separate the two isoenzymes of adenosine deaminase (EC3.5.4.4), adenosine deaminase1 (ADA1) and adenosine deaminase2 (ADA2), in human plasma. One hundred and fifteen purine base, nucleoside, and nucleotide analogs were tested as inhibitors of this partially purified preparation of ADA2. Coformycin and 2'-deoxycoformycin were by far the most potent inhibitors of this isoenzyme (apparent Ki values 20 and 19 nM, respectively). ADA2 was also inhibited by nebularine (apparent Ki 1.5 mM) but was resistant to the potent ADA1 inhibitor (+)-erythro-9(2-S-hydroxy-3-R-nonyl)adenine. alpha-D-Adenosine also inhibited ADA2, as did several halogenated purine and adenine base analogs. Structural requirements for the binding of purine analogs to ADA2 are presented which provide a general basis for the design of specific inhibitors of ADA2. Such inhibitors may be useful in studies designed to provide an understanding of the physiological role of ADA2 both in the normal state and in diseases such as human immunodeficiency virus-1 infection where levels in plasma are increased markedly.
采用二乙氨基乙基纤维素色谱法分离人血浆中腺苷脱氨酶（EC3.5.4.4）的两种同工酶，即腺苷脱氨酶1（ADA1）和腺苷脱氨酶2（ADA2）。测试了115种嘌呤碱、核苷和核苷酸类似物作为这种部分纯化的ADA2制剂的抑制剂。助间型霉素和2'-脱氧助间型霉素是迄今为止该同工酶最有效的抑制剂（表观Ki值分别为20和19 nM）。ADA2也受到杀结核菌素的抑制（表观Ki为1.5 mM），但对强效的ADA1抑制剂（+）-赤型-9（2-S-羟基-3-R-壬基）腺嘌呤具有抗性。α-D-腺苷以及几种卤代嘌呤和腺嘌呤碱基类似物也能抑制ADA2。本文提出了嘌呤类似物与ADA2结合的结构要求，为设计ADA2特异性抑制剂提供了总体依据。此类抑制剂可能有助于开展研究，以了解ADA2在正常状态以及在诸如人类免疫缺陷病毒1感染等血浆水平显著升高的疾病中的生理作用。
