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

Kramer, Debora L.; Diegelman, Paula; Jell, Jason; Vujcic, Slavoljub; Merali, Salim; Porter, Carl W.

doi:10.1074/jbc.m706806200

Cited by 75 publications

(78 citation statements)

References 54 publications

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“…Furthermore, recent studies on TETA metabolism show that its acetylation is accelerated in type 2 diabetic patients (Lu et al, 2007a). Thus, it is tempting to speculate that type 2 diabetic patients display increased SSAT1 activity and, consequently, activated ornithine decarboxylase, i.e., accelerated polyamine flux, as a physiological compensatory mechanism to enhance insulin sensitivity (Kramer et al, 2008). Furthermore, many stressful conditions have been shown to activate SSAT1/polyamine flux (Pegg, 2008), which leads to depletion of cellular ATP and generation of reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

Complex N-Acetylation of Triethylenetetramine

Cerrada-Gimenez¹,

Weisell²,

Hyvönen³

et al. 2011

Drug Metab Dispos

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Section: Discussionmentioning

confidence: 99%

Complex N-Acetylation of Triethylenetetramine

Cerrada-Gimenez¹,

Weisell²,

Hyvönen³

et al. 2011

Drug Metab Dispos

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“…The liver polyamine pools, as well as ODC and SSAT activities were analyzed as described previously (17,18).…”

Section: Methodsmentioning

confidence: 99%

Hepatocyte-specific ablation of spermine/spermidine-N¹-acetyltransferase gene reduces the severity of CCl₄-induced acute liver injury

Zahedi

Barone

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Activation of spermine/spermidine-N 1 -acetyltransferase (SSAT) leads to DNA damage and growth arrest in mammalian cells, and its ablation reduces the severity of ischemic and endotoxic injuries. Here we have examined the role of SSAT in the pathogenesis of toxic liver injury caused by carbon tetrachloride (CCl 4). The expression and activity of SSAT increase in the liver subsequent to CCl 4 administration. Furthermore, the early liver injury after CCl 4 treatment was significantly attenuated in hepatocyte-specific SSAT knockout mice (Hep-SSAT-Cko) compared with wild-type (WT) mice as determined by the reduced serum alanine aminotransferase levels, decreased hepatic lipid peroxidation, and less severe liver damage. Cytochrome P450 2e1 levels remained comparable in both genotypes, suggesting that SSAT deficiency does not affect the metabolism of CCl 4. Hepatocyte-specific deficiency of SSAT also modulated the induction of cytokines involved in inflammation and repair as well as leukocyte infiltration. In addition, Noxa and activated caspase 3 levels were elevated in the livers of WT compared with Hep-SSAT-Cko mice. Interestingly, the onset of cell proliferation was significantly more robust in the WT compared with Hep-SSAT Cko mice. The inhibition of polyamine oxidases protected the animals against CCl4-induced liver injury. Our studies suggest that while the abrogation of polyamine back conversion or inhibition of polyamine oxidation attenuate the early injury, they may delay the onset of hepatic regeneration. hepatotoxicity; carbon tetrachloride; polyamine POLYAMINES INTERACT WITH NUCLEIC acids and proteins and through these interactions play important roles in gene transcription, signal transduction, and cell proliferation (6,12,14,15,20). The cellular levels of polyamines are tightly regulated through import, export, synthesis and catabolism (Fig. 1). The initial step in polyamine synthesis is the decarboxylation of ornithine by ornithine decarboxylase (ODC) to form putrescine (Put). Sequential addition of aminopropyl residues to Put and spermidine (Spd) lead to the formation of Spd and spermine (Spm). Polyamines are degraded through their back conversion by Spm/Spd-N 1 -acetyltransferase (SSAT) and N 1 -acetylpolyamine oxidase (APAO) or by oxidation of Spm by Spm oxidase (SMO). Oxidation of acetylated Spm and Spd by APAO and Spm by SMO generates cytotoxic molecules such as H 2 O 2 and aldehydes (i.e., 3-aminopropanal and 3-acetoaminopropanal; Fig. 1).The expression and activity of SSAT increases in organs (e.g., liver, kidney, and brain) subjected to ischemia-reperfusion and septic and traumatic injuries (4,35,37,39). The ablation of the SSAT gene reduces the severity of renal and hepatic ischemia-reperfusion and endotoxin-induced renal injuries (35,37). Transgenic animals that express high levels of SSAT develop several pathologies, including skin lesions and pancreatitis (1,24,25). In vitro, expression of SSAT causes oxidative stress, DNA damage, cell cycle arrest, and apoptosis (7, 11). These results sugg...

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“…Studies with SSAT1 gene knock-out and transgenic animals (12) suggest a role for SSAT1 in calorie consumption, fatty acid metabolism (13)(14)(15), and in pathological conditions such as pancreatitis (16), obesity, and diabetes (13)(14)(15). SSAT1 has also been implicated in cancer, for its growth-suppressive effects through depletion of polyamines, and also for its transforming effects due to increased tissue putrescine or due to reactive oxygen species generated from oxidation of acetylpolyamines (12,17).…”

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confidence: 99%

Suppression of Exogenous Gene Expression by Spermidine/Spermine N1-Acetyltransferase 1 (SSAT1) Cotransfection

Lee

Park

Woster

et al. 2010

Journal of Biological Chemistry

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Spermidine/spermine N 1 -acetyltransferase 1 (SSAT1), which catalyzes the N 1 -acetylation of spermidine and spermine to form acetyl derivatives, is a rate-limiting enzyme in polyamine catabolism. We now report a novel activity of transiently transfected SSAT1 in suppressing the exogenous expression of other proteins, i.e. green fluorescent protein (GFP) or GFP-eIF5A. Spermidine/spermine N 1 -acetyltransferase 2 (SSAT2) or inactive SSAT1 mutant enzymes (R101A or R101K) were without effect. The loss of exogenous gene expression is not due to accelerated protein degradation, because various inhibitors of proteases, lysosome, or autophagy did not mitigate the effects. This SSAT1 effect cannot be attributed to the depletion of overall cellular polyamines or accumulation of The polyamines, putrescine, spermidine, and spermine, are naturally occurring polycations that are essential for cell proliferation (1). They regulate cellular activities at transcriptional, translational, and post-translational levels. Normally, polyamine homeostasis is maintained by highly regulated mechanisms involving control of biosynthesis, catabolism, and transport. Overaccumulation of polyamines has been associated with cell transformation or apoptosis, whereas their reduction/depletion causes inhibition of cell growth, migration, and embryonic development. Deregulation of cellular polyamines or polyamine pathway enzymes has been associated with pathological conditions, including cancer, and polyamine pathways have been targeted for cancer chemotherapy and chemoprevention.Spermidine/spermine N 1 -acetyltransferase 1 (SSAT1 or SAT1), the key enzyme in the metabolism of polyamines, catalyzes acetylation of spermidine or spermine at the N 1 of the aminopropyl moiety (for a review see Ref. 2). The N 1 -monoacetylated spermidine or spermine can be oxidatively degraded by N 1 -acetylpolyamine oxidase to N-acetylaminopropanal and a smaller polyamine, reversing the biosynthetic reactions. The acetylated polyamines may also be directly excreted from cells. Thus induction/activation of SSAT1 leads to a decrease in cellular spermidine and spermine with an increase in putrescine and N 1 -acetylpolyamines. The SSAT1 level is normally very low, but it can be induced rapidly by a variety of stimuli, including polyamines, polyamine analogs, toxic chemicals, certain drugs, and growth factors.SSAT1 is highly regulated at multiple levels, including transcription, mRNA processing, mRNA translation, and protein stability/degradation (2). Polyamines and their analogs induce SSAT1 (3) by increasing the transcription rate, the stability of SSAT mRNA, and its translation (4). Furthermore, polyamines and analogs bind to the SSAT1 protein and prevent its ubiquitination and degradation by the 26 S proteosome (5-7). Thus, the half-life of SSAT1 (normally Յ30 min) is increased to Ͼ Ͼ12 h in the presence of polyamine analogs. A polyamine analog, N 1 ,N 11 -bis(ethyl)norspermine (BENSpm) 2 (8), causes a dramatic induction of SSAT1, depletion of cellular polyamines, and i...

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

Cited by 75 publications

References 54 publications

Complex N-Acetylation of Triethylenetetramine

Complex N-Acetylation of Triethylenetetramine

Hepatocyte-specific ablation of spermine/spermidine-N¹-acetyltransferase gene reduces the severity of CCl₄-induced acute liver injury

Suppression of Exogenous Gene Expression by Spermidine/Spermine N1-Acetyltransferase 1 (SSAT1) Cotransfection

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

Cited by 75 publications

References 54 publications

Complex N-Acetylation of Triethylenetetramine

Complex N-Acetylation of Triethylenetetramine

Hepatocyte-specific ablation of spermine/spermidine-N1-acetyltransferase gene reduces the severity of CCl4-induced acute liver injury

Suppression of Exogenous Gene Expression by Spermidine/Spermine N1-Acetyltransferase 1 (SSAT1) Cotransfection

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Hepatocyte-specific ablation of spermine/spermidine-N¹-acetyltransferase gene reduces the severity of CCl₄-induced acute liver injury