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J. Biol. Chem., Vol. 283, Issue 7, 4241-4251, February 15, 2008

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Polyamine Acetylation Modulates Polyamine Metabolic Flux, a Prelude to Broader Metabolic Consequences^*

Debora L. Kramer, Paula Diegelman, Jason Jell, Slavoljub Vujcic, Salim Merali, and Carl W. Porter¹

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263 and Fels Institute and Biochemistry Department, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Recent studies suggest that overexpression of the polyamine-acetylating enzyme spermidine/spermine N¹-acetyltransferase (SSAT) significantly increases metabolic flux through the polyamine pathway. The concept derives from the observation that SSAT-induced acetylation of polyamines gives rise to a compensatory increase in biosynthesis and presumably to increased flow through the pathway. Despite the strength of this deduction, the existence of heightened polyamine flux has not yet been experimentally demonstrated. Here, we use the artificial polyamine precursor 4-fluoro-ornithine to measure polyamine flux by tracking fluorine unit permeation of polyamine pools in human prostate carcinoma LNCaP cells. Conditional overexpression of SSAT was accompanied by a massive increase in intracellular and extracellular acetylated spermidine and by a 6-20-fold increase in biosynthetic enzyme activities. In the presence of 300 µM 4-fluoro-ornithine, SSAT overexpression led to the sequential appearance of fluorinated putrescine, spermidine, acetylated spermidine, and spermine. As fluorinated polyamines increased, endogenous polyamines decreased, so that the total polyamine pool size remained relatively constant. At 24 h, 56% of the spermine pool in the induced SSAT cells was fluorine-labeled compared with only 12% in uninduced cells. Thus, SSAT induction increased metabolic flux by 5-fold. Flux could be interrupted by inhibition of polyamine biosynthesis but not by inhibition of polyamine oxidation. Overall, the findings are consistent with a paradigm whereby flux is initiated by SSAT acetylation of spermine and particularly spermidine followed by a marked increase in key biosynthetic enzymes. The latter sustains the flux cycle by providing a constant supply of polyamines for subsequent acetylation by SSAT. The broader metabolic implications of this futile metabolic cycling are discussed in detail.

Received for publication, August 15, 2007 , and in revised form, November 6, 2007.

This paper is dedicated to the memory of Professor Nikolaus Seiler, an out-standing scientist who, before others, understood the biological importance of polyamine acetylation and catabolism and whose pioneering metabolic studies in this area greatly facilitated the studies and interpretations presented here.

^* This work was supported by National Institutes of Health (NIH) Grants CA-22153, CA 109619, and CA-76428 and NIH Predoctoral Training Grant CA-09072. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263. Tel.: 716-845-3002; Fax: 716-845-2353; E-mail: carl.porter{at}roswellpark.org.

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