| Polyamine acetylation modulates polyamine metabolic flux, a prelude to broader metabolic consequences. | |
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MedLine Citation:
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PMID: 18089555 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Recent studies suggest that overexpression of the polyamine-acetylating enzyme spermidine/spermine N(1)-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 microM 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 approximately 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. |
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Authors:
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Debora L Kramer; Paula Diegelman; Jason Jell; Slavoljub Vujcic; Salim Merali; Carl W Porter |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-12-18 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 283 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2008 Feb |
Date Detail:
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Created Date: 2008-02-11 Completed Date: 2008-05-05 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 4241-51 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation Acetyltransferases / metabolism Biogenic Polyamines / metabolism* Cell Division Cell Line, Tumor Chromatography, High Pressure Liquid Humans Male |
| Grant Support | |
ID/Acronym/Agency:
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CA 109619/CA/NCI NIH HHS; CA-09072/CA/NCI NIH HHS; CA-22153/CA/NCI NIH HHS; CA-76428/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Biogenic Polyamines; EC 2.3.1.-/Acetyltransferases; EC 2.3.1.57/diamine N-acetyltransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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