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Replacing Mn(2+) with Co(2+) in human arginase i enhances cytotoxicity toward l-arginine auxotrophic cancer cell lines.

Abstract：

:Replacing the two Mn(2+) ions normally present in human Arginase I with Co(2+) resulted in a significantly lowered K(M) value without a concomitant reduction in k(cat). In addition, the pH dependence of the reaction was shifted from a pK(a) of 8.5 to a pK(a) of 7.5. The combination of these effects led to a 10-fold increase in overall catalytic activity (k(cat)/K(M)) at pH 7.4, close to the pH of human serum. Just as important for therapeutic applications, Co(2+) substitution lead to significantly increased serum stability of the enzyme. Our data can be explained by direct coordination of l-Arg to one of the Co(2+) ions during reaction, consistent with previously reported model studies. In vitro cytotoxicity experiments verified that the Co(2+)-substituted human Arg I displays an approximately 12- to 15-fold lower IC(50) value for the killing of human hepatocellular carcinoma and melanoma cell lines and thus constitutes a promising new candidate for the treatment of l-Arg auxotrophic tumors.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Stone EM,Glazer ES,Chantranupong L,Cherukuri P,Breece RM,Tierney DL,Curley SA,Iverson BL,Georgiou G

doi

10.1021/cb900267j

subject

Has Abstract

pub_date

2010-03-19 00:00:00

pages

333-42

issue

3

eissn

1554-8929

issn

1554-8937

journal_volume

5

pub_type

杂志文章

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