Spermidine/spermine acetyltransferase SSAT

Cells treated with 5-FU undergo cell cycle arrest or apoptosis by inhibition of DNA synthesis. When human oral squamous cell carcinomas (HSC-2, HSC-3, HSC-4) were treated with 5-FU, viable cell numbers declined dose-dependently (CC50 determined after 24 hours treatment 3.4,6.9 and 1.7 p,M, respectively). The intracellular putrescine concentration slightly declined (Table 2) [29]. The combination treatment of 5-FU with N(l),N(ll)-diethylnorspermine (DEN-SPM), which is an inducer of spermidine/spermine N(l)-acetyltransferase (SSAT) that depletes polyamine, has been reported to augment the cytotoxic activity of 5-FU, suggesting possible clinical application [30]. 

Wang Y, Devereux W, Stewart TM, Casero RA Jr. 2001. Characterization of the interaction between the transcription factors human polyamine modulated factor (PMF-1) and NF-E2-related factor 2 (Nrf2) in the transcriptional regulation of the spermidine/spermine iV -acetyltransferase (SSAT) gene. Biochem. J. 355 45 9... 

The phosphinic acid polyamine analogue 370 is reported to be an effective inhibitor of purified human spermidine/spermine-N I-acetyltransferase (SSAT) and is claimed to be only the second example of a functional, non-superinducing inhibitor of human SSAT. The long-chain phosphonate analogues 371 and 372 are reported to exhibit cytostatic activity in vitro " ... 

Saab, N.H., West, E.E., Bieszk, N.C., Pteuss, C.V., Mank, A.R., Casero, R.A. Jr, and Woster, PJ. (1993) Synthesis and evaluation of unsymmetrically substituted polyamine analogues as modulators of human spermidine/spermine-lV -acetyltransferase (SSAT) and as potential antitumor agents. J. Med. Chem. 36 2998-3004. 

In mammalian cells, the catabolism of spermine to spermidine occurs via one of two distinct pathways. As a substrate for spermidine/spermine IV -acetyltransferase (SSAT), spermine can be converted to A -acetylspermine, which is subsequently oxidized by the FAD-dependent acetylpolyamine oxidase (APAO) to form spermidine. Conversely, spermine can be directly oxidized by spermine oxidase (SMOX) to form spermidine. Spermidine is then back-converted to putrescine through the two-step SSAT/APAO reaction that includes an Af-acetylspermidine intermediate (Fig. 5.1). 

Fig. 5.1 The mammalian polyamine catabolic pathway. Spermine (Spm) is back-converted to spermidine (Spd) by either spermine oxidase SMOX) or spermidine/spermine Af-acetyltransferase SSAT) followed by acetylpolyamine oxidase APAO). Spermidine is further back-converted to putrescine Put) through the same SSAT/APAO mechanism. Both oxidation reactions generate the reactive oxygen species ROS) precursor H2O2 and aldehydes as by-products. The resulting reduction in spermine and spermidine pools implies diminished antioxidant and antiinflammatory functions...

Babbar N.GernerEW, Casero RA Jr (2006a) Induction of spermidine/spermine N1 -acetyltransferase (SSAT) by aspirin in Caco-2 colon cancer cells. Biochem J 394 317-324 Babbar N, Hacker A, Huang Y, Casero RA Jr (2006b) Tumor necrosis factor alpha induces spermidine/spermine N 1-acetyltransferase through nuclear factor kappaB in non-small cell lung cancer cells. J Biol Chem 281 24182-24192... 

Translational control of polyamine catabolism has been reported in mammals (Ivanov et al. 2010 Perez-Leal and Merali 2012). Spermidine/spermine V -acetyltransferase (SSAT) is the rate-Umiting enzyme for PA catabolism and is... 

Fig. 24.1 Polyamine and glutathione metaboUc pathway differences in parasite and mammalian ceU enzymes involved in polyamine biosynthesis (purple font inside solid ovcds), catabolic enzymes black font inside dashed ovals), and enzymes involved in glutathione metabolism (red font inside solid ovals). ODC ornithine decarboxylase, AdoMetDC S-adenosylmethionine decarboxylase, SpdSyn spermidine synthase, SpmSyn spermine synthase, SMO spermine oxidase, SSAT spermidine/spermine N acetyltransferase, APAO JV acetyl polyamine oxidase, yGCS...

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