title: Inhibition of adenosine deaminase (ADA)-mediated metabolism of cordycepin by natural substances.
abstract: Cordycepin, which is an analogue of a nucleoside adenosine, exhibits a wide variety of pharmacological activities including anticancer effects. In this study, ADA1- and ADA2-expressing HEK293 cells were established to determine the major ADA isoform responsible for the deamination of cordycepin. While the metabolic rate of cordycepin deamination was similar between ADA2-expressing and Mock cells, extensive metabolism of cordycepin was observed in the ADA1-expressing cells with K m and V max values of 54.9 μmol/L and 45.8 nmole/min/mg protein. Among five natural substances tested in this study (kaempferol, quercetin, myricetin, naringenin, and naringin), naringin strongly inhibited the deamination of cordycepin with K i values of 58.8 μmol/L in mouse erythrocytes and 168.3 μmol/L in human erythrocytes. A treatment of Jurkat cells with a combination of cordycepin and naringin showed significant cytotoxicity. Our in silico study suggests that not only small molecules such as adenosine derivatives but also bulky molecules like naringin can be a potent ADA1 inhibitor for the clinical usage.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Li
authors.affiliation: School of Pharmacy, Kitasato University 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakagome
authors.affiliation: School of Pharmacy, Kitasato University 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.affiliation: School of Pharmacy, Kitasato University 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: School of Pharmacy, Kitasato University 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
keywords: ADA; adenosine deaminase; docking study; enzyme inhibition; naringin