Structural basis for differential induction of spermidine/spermine N-1-acetyltransferase activity by novel spermine analogs

被引:44
作者
FogelPetrovic, M
Kramer, DL
Vujcic, S
Miller, J
McManis, JS
Bergeron, RJ
Porter, CW
机构
[1] NEW YORK STATE DEPT HLTH, ROSWELL PK MEM INST, GRACE CANC DRUG CTR, BUFFALO, NY 14263 USA
[2] UNIV FLORIDA, DEPT MED CHEM, GAINESVILLE, FL 32610 USA
关键词
D O I
10.1124/mol.52.1.69
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The spermine analog N-1,N-11 -diethylnorspermine (DE-333, also known as DENSPM or BENSPM) is regarded as the most potent known inducer of the polyamine catabolic enzyme, spermidine/spermine N-1-acetyltransferase (SSAT), increasing activity by more than 200- to 1000-fold in certain cell types. The relative ability of a series of eight systematically modified DE-333 analogs to affect SSAT expression was examined in Malme-3M human melanoma cells, one of several cell lines known to be especially responsive to induction of this enzyme. In particular, we examined the relative contribution of induction of enzyme mRNA and prolongation of enzyme half-life to analog-mediated increases in enzyme activity. Induction of enzyme mRNA was most influenced by intra-amine carbon distances; relative effectiveness was found to be proportional to the number of three-carbon units. Stabilization of enzyme was most determined by the terminal N-alkyl substituent size; among methyl, ethyl and propyl groups, methyl was least effective. Thus, DE-333, which most potently induces SSAT mRNA and effectively stabilizes SSAT enzyme activity, produces the greatest increase in enzyme activity. Although other contributing mechanisms may be involved, the relative abilities of the various analogs to induce enzyme activity is at least partially attributable to their combined effects on enzyme mRNA and protein half-life. These data reveal the highly sensitive structure-activity relationships that underlie and control spermine analog induction of SSAT activity. Pending further definition of the relationship between SSAT induction and antitumor growth and toxicity in vivo, these relationships may be used to optimize therapeutic efficacy.
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页码:69 / 74
页数:6
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