Alternative titles; symbols
HGNC Approved Gene Symbol: SAT1
Cytogenetic location: Xp22.11 Genomic coordinates (GRCh38): X:23,783,173-23,786,210 (from NCBI)
Spermidine/spermine N(1)-acetyltransferase (SSAT; EC 2.3.1.57) is a rate-limiting enzyme in the catabolic pathway of polyamine metabolism. It catalyzes the N(1)-acetylation of spermidine and spermine and, by the successive activity of polyamine oxidase, spermine can be converted to spermidine and spermidine to putrescine (Casero et al., 1991).
Casero et al. (1991) isolated a 972-bp cDNA encoding a deduced protein of 171 amino acids with a predicted molecular mass of 20 kD. Xiao et al. (1991) further characterized the cDNA.
Chen et al. (2003) showed that SAT1 and SAT2 (611463) share 46% amino acid identity and 64% similarity, and both contain a general N(1)-acetyltransferase (GNAT) domain spanning 87 amino acids. All species below vertebrates had 1 copy of SSAT, whereas most all vertebrate species had functional SAT1 and SAT2 genes, with the exception of chicken and Xenopus. Northern blot and EST analysis indicated that SAT1 was expressed at higher levels than SAT2 and in a wider range of tissues. Whereas SAT1 showed a much greater preference for spermidine than spermine, SAT2 showed similar preference for the 2 polyamines.
Xiao et al. (1992) cloned 4,095 bases of the genomic region containing the coding sequence of SAT1. Primer extension analysis indicated that the transcription of SAT starts 179 bases upstream from the translational start site and appears to be under the control of a 'TATA-less' promoter. Chen et al. (2003) noted that the SAT1 gene contains 6 exons.
Xiao et al. (1992) localized the SAT1 gene to chromosome Xp22.1 by PCR analysis of somatic cell hybrids and by in situ hybridization.
Superinduction of the SSAT gene is associated with the antineoplastic activity of several antitumor polyamine analogs. Wang et al. (1999) found that PMF1 (609176) mRNA was also induced in a lung tumor cell line sensitive to polyamine analogs, but it was not induced in an insensitive lung tumor cell line. Cotransfection of PMF1 and NRF2 (NFE2L2; 600492) activated transcription from the polyamine-responsive element of the SSAT promoter in a reporter assay, and PMF1 was the rate-limiting component. Wang et al. (1999) concluded that PMF1 and NRF2 cooperate to induce transcription of the SSAT gene.
Crystal Structure
Bewley et al. (2006) determined the crystal structure of SSAT as a free dimer and in binary and ternary complexes with CoA, acetyl-CoA, spermine, and an SSAT inhibitor. They found SSAT formed symmetric and asymmetric dimers that are likely in equilibrium in solution. The symmetric dimer had 2 open surface channels capable of binding substrate or cofactor, and the asymmetric form had only 1 of those channels. Asymmetric SSAT dimers also self-acetylated lysine-26, a reaction catalyzed by acetyl-CoA in the absence of substrate.
Gimelli et al. (2002) reported the molecular characterization of an Xp22.12-p21.1 duplication present in a patient affected with features of keratosis follicularis spinulosa decalvans (KFSD) and dosage-sensitive sex reversal (DSS; 300018). The duplicated region included both the DAX1 gene (300473), responsible for DSS, and the KFSDX (308800) interval, in which the SAT1 gene is located. The proband was the product of nonconsanguineous parents and born with ambiguous external genitalia and cryptorchidism. At the age of 11 months he showed short stature (less than the 3rd percentile), muscular hypotrophy, hypotonia, and some dysmorphic features. KFSD was shown by follicular and interfollicular hyperkeratosis on the outer aspects of the upper arms, cheeks, and legs. He had thickening of the skin of the palms and soles, and the hair was sparse and thin with loss, but he did not have photophobia or eye anomalies. One X chromosome of the mother showed the same duplicated region. This X chromosome was preferentially late-replicating as shown by BrdU incorporation in cultured lymphocytes. The mother suffered from obesity, follicular hyperkeratosis, and alopecia and showed mild mental retardation. Analysis of polyamine metabolism in the cells of the patient indicated that the levels of metabolites such as putrescine, spermidine, and spermine were consistent with the overexpression of the SAT1 gene as in the mouse model. Gimelli et al. (2002) proposed that overexpression of SAT1 and the consequent putrescine accumulation are involved in the KFSD phenotype, at least in their propositus. However, Aten et al. (2010), who demonstrated that mutation in the MBTPS2 gene (300294) is responsible for most cases of KFSDX, doubted that the SAT1 gene plays a role in the disorder.
Pietila et al. (1997) generated a transgenic mouse line that overexpresses spermidine/spermine N(1)-acetyltransferase. Tissues of these mice showed markedly distorted polyamine pools, which in most cases were characterized by the appearance of N(1)-acetylspermidine, not normally found in mouse tissues, a massive accumulation of putrescine, and decreases in spermidine and/or spermine pools. The most striking phenotypic change was permanent hair loss at the age of 3 to 4 weeks which was typified histologically by the appearance of extensive follicular cysts in the dermis. The effect seemed attributable to putrescine interference with hair development, possibly with differentiation/proliferation of epidermal cells located in hair follicles. Female members of the transgenic line were found to be infertile, apparently due to ovarian hypofunction and hypoplastic uteri.
Aten, E., Brasz, L. C., Bornholdt, D., Hooijkaas, I. B., Porteous, M. E., Sybert, V. P., Vermeer, M. H., Vossen, R. H. A. M., van der Wielen, M. J. R., Bakker, E., Breuning, M. H., Grzeschik, K.-H., Oosterwijk, J. C., den Dunnen, J. T. Keratosis follicularis spinulosa decalvans is caused by mutations in MBTPS2. Hum. Mutat. 31: 1125-1133, 2010. [PubMed: 20672378] [Full Text: https://doi.org/10.1002/humu.21335]
Bewley, M. C., Graziano, V., Jiang, J., Matz, E., Studier, F. W., Pegg, A. E., Coleman, C. S., Flanagan, J. M. Structures of wild-type and mutant human spermidine/spermine N(1)-acetyltransferase, a potential therapeutic drug target. Proc. Nat. Acad. Sci. 103: 2063-2068, 2006. [PubMed: 16455797] [Full Text: https://doi.org/10.1073/pnas.0511008103]
Casero, R. A., Jr., Celano, P., Ervin, S. J., Applegren, N. B., Wiest, L., Pegg, A. E. Isolation and characterization of a cDNA clone that codes for human spermidine/spermine N(1)-acetyltransferase. J. Biol. Chem. 266: 810-814, 1991. [PubMed: 1985966]
Chen, Y., Vujcic, S., Liang, P., Diegelman, P., Kramer, D. L., Porter, C. W. Genomic identification and biochemical characterization of a second spermidine/spermine N1-acetyltransferase. Biochem. J. 373: 661-667, 2003. [PubMed: 12803540] [Full Text: https://doi.org/10.1042/BJ20030734]
Gimelli, G., Giglio, S., Zuffardi, O., Alhonen, L., Suppola, S., Cusano, R., Lo Nigro, C., Gatti, R., Ravazzolo, R., Seri, M. Gene dosage of the spermidine/spermine N(1)-acetyltransferase (SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD). Hum. Genet. 111: 235-241, 2002. [PubMed: 12215835] [Full Text: https://doi.org/10.1007/s00439-002-0791-6]
Pietila, M., Alhonen, L., Halmekyto, M., Kanter, P., Janne, J., Porter, C. W. Activation of polyamine catabolism profoundly alters tissue polyamine pools and affects hair growth and female fertility in transgenic mice overexpressing spermidine/spermine N(1)-acetyltransferase. J. Biol. Chem. 272: 18746-18751, 1997. [PubMed: 9228047] [Full Text: https://doi.org/10.1074/jbc.272.30.18746]
Wang, Y., Devereux, W., Stewart, T. M., Casero, R. A., Jr. Cloning and characterization of human polyamine-modulated factor-1, a transcriptional cofactor that regulates the transcription of the spermidine/spermine N(1)-acetyltransferase gene. J. Biol. Chem. 274: 22095-22101, 1999. [PubMed: 10419538] [Full Text: https://doi.org/10.1074/jbc.274.31.22095]
Xiao, L., Celano, P., Mank, A. R., Griffin, C., Jabs, E. W., Hawkins, A. L., Casero, R. A., Jr. Structure of the human spermidine/spermine N(1)-acetyltransferase gene (exon/intron gene organization and localization to Xp22.1). Biochem. Biophys. Res. Commun. 187: 1493-1502, 1992. [PubMed: 1417826] [Full Text: https://doi.org/10.1016/0006-291x(92)90471-v]
Xiao, L., Celano, P., Mank, A. R., Pegg, A. E., Casero, R. A., Jr. Characterization of a full-length cDNA which codes for the human spermidine/spermine N(1)-acetyltransferase. Biochem. Biophys. Res. Commun. 179: 407-415, 1991. [PubMed: 1652956] [Full Text: https://doi.org/10.1016/0006-291x(91)91385-p]