Spermidine/spermine-N¹-acetyltransferase: a key metabolic regulator

Abstract

Spermidine/spermine-N(1)-acetyltransferase (SSAT) regulates cellular polyamine content. Its acetylated products are either excreted from the cell or oxidized by acetylpolyamine oxidase. Since polyamines play critical roles in normal and neoplastic growth and in ion channel regulation, SSAT is a key enzyme in these processes. SSAT is very highly regulated. Its content is adjusted in response to alterations in polyamine content to maintain polyamine homeostasis. Certain polyamine analogs can mimic the induction of SSAT and cause a loss of normal polyamines. This may have utility in cancer chemotherapy. SSAT activity is also induced via a variety of other stimuli, including toxins, hormones, cytokines, nonsteroidal anti-inflammatory agents, natural products, and stress pathways, and by ischemia-reperfusion injury. These increases are initiated by alterations in Sat1 gene transcription reinforced by alterations at the other regulatory steps, including protein turnover, mRNA processing, and translation. Transgenic manipulation of SSAT activity has revealed that SSAT activity links polyamine metabolism to lipid and carbohydrate metabolism by means of alterations in the content of acetyl-CoA and ATP. A high level of SSAT stimulates flux through the polyamine biosynthetic pathway, since biosynthetic enzymes are induced in response to the fall in polyamines. This sets up a futile cycle in which ATP is used to generate S-adenosylmethionine for polyamine biosynthesis and acetyl-CoA is consumed in the acetylation reaction. A variety of other effects of increased SSAT activity include death of pancreatic cells, blockage of regenerative tissue growth, behavioral changes, keratosis follicularis spinulosa decalvans, and hair loss. These are very likely due to changes in polyamine and putrescine levels, although increased oxidative stress via the oxidation of acetylated polyamines may also contribute. Recently, it was found that the SSAT protein and/or a related protein, thialysine acetyltransferase, interacts with a number of other important proteins, including the hypoxia-inducible factor-1 alpha-subunit, the p65 subunit of NF-kappaB, and alpha9beta1-integrin, altering the function of these proteins. It is not yet clear whether this functional alteration involves protein acetylation, local polyamine concentration changes, or other effects. It has been suggested that SSAT may also be a useful target in diseases other than cancer, but the wide-ranging physiological and pathophysiological effects of altered SSAT expression will require very careful limitation of such strategies to the relevant cells to avoid toxic effects.

Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

“…As shown in Fig. 1A, SAT1 catalyzes the acetylation of spermidine and spermine to form N 1 -acetylspermidine and N 1 -acetylspermine, which then are either exported from the cells or converted back to putrescine or spermidine by N 1 -acetylpolyamine oxidase (26). Therefore, overexpression of SAT1 leads to an overall depletion of spermidine and spermine while increasing the levels of putrescine, N 1 -acetylspermidine, and N 1 -acetylspermine (27).…”

Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells

“…Spermidine/spermine N 1 -acetyltransferase 1 (SAT1), the key regulatory enzyme in the catabolism of polyamines (18), catalyzes acetylation of spermidine or spermine to generate N 1 -acetyl spermidine or N 1 -acetyl spermine, and N 1 , N 12 -diacetylspermine. The acetylated polyamines, in turn, are oxidatively degraded by N 1 -acetylpolyamine oxidase (APAO) to N-acetylaminopropanal and a lower polyamine.…”

“…Thus, the induction of SAT1 leads to a decrease in cellular spermidine and spermine with an increase mainly in putrescine and N 1 -acetylspermidine. The cellular level of SAT1 is normally extremely low, but it is induced rapidly by a variety of stimuli, including polyamines, polyamine analogs, toxic chemicals, certain drugs, and growth factors (18). SAT1 is regulated at the level of transcription, mRNA splicing, translation, and protein stability (18).…”

Integrative Bioinformatic Analysis of Transcriptomic Data Identifies Conserved Molecular Pathways Underlying Ionizing Radiation-Induced Bystander Effects (RIBE) 

“…In parallel, the rest of the common genes such as SAT1, TNFAIP3, CXCL2 and FGF2 were characterized as linker genes in at least one dataset. The latter, are involved in immunoregulatory processes, polyamine metabolism [40][41][42], inhibition of NF-kappa B [43], proliferation and wound healing [44].…”