肌苷酸脱氢酶：抗白血病药物噻唑呋林的抑制作用

IMP dehydrogenase: inhibition by the anti-leukemic drug, tiazofurin.

作者信息

Yamada Y, Natsumeda Y, Yamaji Y, Jayaram H N, Tricot G J, Hoffman R, Weber G

机构信息

Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46223.

出版信息

Leuk Res. 1989;13(2):179-84. doi: 10.1016/0145-2126(89)90143-4.

DOI:10.1016/0145-2126(89)90143-4

PMID:2564451

Abstract

Tiazofurin through its active metabolite thiazole-4-carboxamide adenine dinucleotide (TAD) inhibits IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis. IMP dehydrogenase activity in human leukemic cell extracts (33.4 +/- 0.1 nmol/h/mg protein) was increased 11-fold compared to normal leukocytes (3.1 +/- 0.5). Km values for IMP and NAD+ of leukemic IMP dehydrogenase were 22.7 and 44.0 microM, respectively. XMP inhibited competitively with IMP and noncompetitively with NAD+. NADH exerted mixed type inhibition with respect to both IMP and NAD+. The inhibitory pattern of TAD was quite similar to that of NADH; however, the affinity of TAD to leukemic IMP dehydrogenase (Ki = 0.1 microM) was three orders of magnitude higher than the natural product NADH (Ki = 150 microM). These results contribute to an understanding of the mechanism of action of tiazofurin in the treatment of leukemia.

摘要

噻唑呋林通过其活性代谢物噻唑 - 4 - 羧酰胺腺嘌呤二核苷酸（TAD）抑制肌苷酸脱氢酶，这是鸟苷三磷酸（GTP）生物合成的限速酶。与正常白细胞（3.1±0.5）相比，人白血病细胞提取物中的肌苷酸脱氢酶活性（33.4±0.1 nmol/h/mg蛋白质）增加了11倍。白血病肌苷酸脱氢酶对肌苷酸（IMP）和烟酰胺腺嘌呤二核苷酸（NAD +）的米氏常数（Km）分别为22.7和44.0微摩尔。黄嘌呤核苷酸（XMP）对IMP具有竞争性抑制作用，对NAD +具有非竞争性抑制作用。烟酰胺腺嘌呤二核苷酸（NADH）对IMP和NAD +均表现出混合型抑制作用。TAD的抑制模式与NADH非常相似；然而，TAD对白血病肌苷酸脱氢酶的亲和力（Ki = 0.1微摩尔）比天然产物NADH（Ki = 150微摩尔）高三个数量级。这些结果有助于理解噻唑呋林治疗白血病的作用机制。