SAT1 (gene) explained

Diamine acetyltransferase 1 is an enzyme that in humans is encoded by the SAT1 gene found on the X chromosome.^{[1] [2] [3]}

Function

Spermidine/spermine N(1)-acetyltransferase (SPD/SPM acetyltransferase) 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.^[3] The SAT1 gene is used to help regulate polyamine levels inside the cell by regulating their transport in and out of the cell.^{[4] [5]} SAT1 is also involved in the first step to synthesize N-acetylputrescine from putrescine. PMF1 and NRF2 work together to transcript the SAT1 gene.

Structure

The SAT1 gene is 3,069 base pairs long. There are 171 amino acids and its molecular mass is 20024 Da (daltons). In 1992 at The Johns Hopkins University School of Medicine, Lei Xiao and several others cloned over 4000 base pairs of the region containing the coding sequence of the SAT1 gene also referred to as SSAT-1, SSAT, SAT, KFSD, DC21, KFSDX gene.^[6] This gene is located on the X chromosome in the region Xp22.1. The primer extension analysis indicated that the transcription started 179 bases upstream from the translational start site. Furthermore, they determined that it appeared to be controlled by a "TATA-less" promoter. Normally, there would be a TATA box where RNA polymerase II would be involved in assisting with initiation by properly positioning the enzyme, however in a TATA-less promoter situation the TATA box is absent.^[7]

Clinical significance

An association with keratosis follicularis spinulosa decalvans (KFSD) has been suggested.^[8] Data shows that keratosis follicularis spinulosa decalvans could be caused by mutations in the SAT 1 gene. KSFD is also believed to be X-linked, which helps prove that the disease is caused by a mutation found in the SAT 1 gene which is located on the X chromosome.^[9] The mutation most likely occurs at the location Xp22.1.^[10] KDSF mostly affects men, which makes sense for it to be an X-linked disease, caused by a mutation of the SAT1 gene.^[11]

Elevated levels of RNA transcripts of SAT1 in the bloodstream have been associated with a higher risk of suicide.^{[12] [13] [14]}

The SAT1 gene has implications with NLS-2 Neu–Laxova syndrome, type 2 (NLS). It is inherited as an autosomal recessive trait and is considered a rare lethal congenital disorder. Severe growth delays before birth including low birth weight and shorter than normal length occur. After birth, outward observable characteristics include significant small skull size (microcephaly), wider than normal spaced eyes, sloped forehead and other disfiguring facial features. There may also be random places of fluid retention (edema) throughout the body and permanent joint limitations due to limb malformations. NLS can be detected in pregnant woman with ultrasound examination. In some people of Neu-Laxova syndrome, other areas were severely affected such as skin, genitals, and other internal organs including the heart. Males and females are equally affected and could be most closely associated with persons of Pakistani origin. However, there have been cases reported in several other diverse backgrounds. The prognosis is extremely poor and in most cases the infant dies shortly after birth or are stillborn. The first documented and reported case in Japan involved a baby girl exhibiting microcephaly, severe edema, and other symptoms. In her case she had a condition known as congenital vertical talus or rocker-feet. The foot is abnormally shaped in a convex position. She survived 134 days.^{[15] [16] [17]}

The SAT1 gene plays a vital role in the catabolic pathway of polyamine metabolism. It acts as a rate-limiting enzyme in the pathway of polyamine metabolism, meaning it is significant in the involvement of cell survival. Research has shown that the tumor protein known as p53 can specifically target the SAT1 gene that results in ferroptotic cell-death. Ferroptosis is when a death of a cell is caused by an iron-dependent accumulation of a lipid.^[18]

Further reading

• Lake JA, Carr J, Feng F, Mundy L, Burrell C, Li P . The role of Vif during HIV-1 infection: interaction with novel host cellular factors . Journal of Clinical Virology . 26 . 2 . 143–52 . February 2003 . 12600646 . 10.1016/S1386-6532(02)00113-0 .
• Xiao L, Celano P, Mank AR, Pegg AE, Casero RA . Characterization of a full-length cDNA which codes for the human spermidine/spermine N1-acetyltransferase . Biochemical and Biophysical Research Communications . 179 . 1 . 407–15 . August 1991 . 1652956 . 10.1016/0006-291X(91)91385-P . free .
• Libby PR, Ganis B, Bergeron RJ, Porter CW . Characterization of human spermidine/spermine N1-acetyltransferase purified from cultured melanoma cells . Archives of Biochemistry and Biophysics . 284 . 2 . 238–44 . February 1991 . 1989509 . 10.1016/0003-9861(91)90291-P .
• Casero RA, Celano P, Ervin SJ, Wiest L, Pegg AE . High specific induction of spermidine/spermine N1-acetyltransferase in a human large cell lung carcinoma . The Biochemical Journal . 270 . 3 . 615–20 . September 1990 . 2241897 . 1131776 . 10.1042/bj2700615.
• Casero RA, Gabrielson EW, Pegg AE . Immunohistochemical staining of human spermidine/spermine N1-acetyltransferase superinduced in response to treatment with antitumor polyamine analogues . Cancer Research . 54 . 15 . 3955–8 . August 1994 . 8033120 .
• Xiao L, Casero RA . Differential transcription of the human spermidine/spermine N1-acetyltransferase (SSAT) gene in human lung carcinoma cells . The Biochemical Journal . 313 . 2 . 691–6 . January 1996 . 8573111 . 1216962 . 10.1042/bj3130691.
• Coleman CS, Huang H, Pegg AE . Structure and critical residues at the active site of spermidine/spermine-N1-acetyltransferase . The Biochemical Journal . 316 . 3 . 697–701 . June 1996 . 8670140 . 1217406 . 10.1042/bj3160697.
• Bordin L, Vargiu C, Colombatto S, Clari G, Testore G, Toninello A, Grillo MA . Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues . Biochemical and Biophysical Research Communications . 229 . 3 . 845–51 . December 1996 . 8954982 . 10.1006/bbrc.1996.1890 . 11577/111983 . free .
• Bettuzzi S, Davalli P, Astancolle S, Carani C, Madeo B, Tampieri A, Corti A, Saverio B, Pierpaola D, Serenella A, Cesare C, Bruno M, Auro T, Arnaldo C . Tumor progression is accompanied by significant changes in the levels of expression of polyamine metabolism regulatory genes and clusterin (sulfated glycoprotein 2) in human prostate cancer specimens . Cancer Research . 60 . 1 . 28–34 . January 2000 . 10646846 .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–92 . September 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Coleman CS, Pegg AE . Polyamine analogues inhibit the ubiquitination of spermidine/spermine N1-acetyltransferase and prevent its targeting to the proteasome for degradation . The Biochemical Journal . 358 . Pt 1 . 137–45 . August 2001 . 11485561 . 1222041 . 10.1042/0264-6021:3580137 .
• Bordin L, Vargiu C, Clari G, Brunati AM, Colombatto S, Salvi M, Grillo MA, Toninello A . Phosphorylation of recombinant human spermidine/spermine N(1)-acetyltransferase by CK1 and modulation of its binding to mitochondria: a comparison with CK2 . Biochemical and Biophysical Research Communications . 290 . 1 . 463–8 . January 2002 . 11779193 . 10.1006/bbrc.2001.6204 .
• Nikiforova NN, Velikodvorskaja TV, Kachko AV, Nikolaev LG, Monastyrskaya GS, Lukyanov SA, Konovalova SN, Protopopova EV, Svyatchenko VA, Kiselev NN, Loktev VB, Sverdlov ED . Induction of alternatively spliced spermidine/spermine N1-acetyltransferase mRNA in the human kidney cells infected by venezuelan equine encephalitis and tick-borne encephalitis viruses . Virology . 297 . 2 . 163–71 . June 2002 . 12083816 . 10.1006/viro.2002.1456 . free .
• 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) . Human Genetics . 111 . 3 . 235–41 . September 2002 . 12215835 . 10.1007/s00439-002-0791-6 . 23842885 .
• Tomitori H, Nenoi M, Mita K, Daino K, Igarashi K, Ichimura S . Functional characterization of the human spermidine/spermine N(1)-acetyltransferase gene promoter . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1579 . 2–3 . 180–4 . December 2002 . 12427553 . 10.1016/S0167-4781(02)00545-6 .
• Izmailova E, Bertley FM, Huang Q, Makori N, Miller CJ, Young RA, Aldovini A . HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages . Nature Medicine . 9 . 2 . 191–7 . February 2003 . 12539042 . 10.1038/nm822 . 26145639 .

Notes and References

1. Casero RA, Celano P, Ervin SJ, Applegren NB, Wiest L, Pegg AE . Isolation and characterization of a cDNA clone that codes for human spermidine/spermine N1-acetyltransferase . The Journal of Biological Chemistry . 266 . 2 . 810–4 . January 1991 . 10.1016/S0021-9258(17)35245-6 . 1985966 . free .
2. Xiao L, Celano P, Mank AR, Griffin C, Jabs EW, Hawkins AL, Casero RA . Structure of the human spermidine/spermine N1-acetyltransferase gene (exon/intron gene organization and localization to Xp22.1) . Biochemical and Biophysical Research Communications . 187 . 3 . 1493–502 . September 1992 . 1417826 . 10.1016/0006-291X(92)90471-V . free .
3. Web site: Entrez Gene: SAT1 spermidine/spermine N1-acetyltransferase 1.
4. Web site: SAT1 Gene . GeneCards .
5. Pegg AE . Spermidine/spermine-N(1)-acetyltransferase: a key metabolic regulator . American Journal of Physiology. Endocrinology and Metabolism . 294 . 6 . E995–1010 . June 2008 . 18349109 . 10.1152/ajpendo.90217.2008 .
6. Spermidine/spermine N1-acetyltransferase regulates cell growth and metastasis via AKT/β-catenin signaling pathways in hepatocellular and colorectal carcinoma cells. . Oncotarget . 8 . 1 . 1092–1109 . 27901475 . 5352037 . 2017 . Wang . C. . Ruan . P. . Zhao . Y. . Li . X. . Wang . J. . Wu . X. . Liu . T. . Wang . S. . Hou . J. . Li . W. . Li . Q. . Li . J. . Dai . F. . Fang . D. . Wang . C. . Xie . S. . 10.18632/oncotarget.13582.
7. Web site: Neu Laxova Syndrome . GARD Genetic and Rare diseases Information Center . 19 November 2018.
8. 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) . Human Genetics . 111 . 3 . 235–41 . September 2002 . 12215835 . 10.1007/s00439-002-0791-6 . 23842885 .
9. Web site: Keratosis follicularis spinulosa decalvans . Genetic and Rare Diseases Information Center (GARD) – an NCATS Program . 2018-11-16.
10. Web site: Keratosis Follicularis Spinulosa Decalvans, X-Linked . Hereditary Ocular Diseases . 2018-11-16.
11. Web site: SAT1 gene . Genetics Home Reference . 17 November 2018.
12. News: 'Biological signal' of suicide risk found in blood . Honor Whiteman . Medical News Today . 21 August 2013 . 21 August 2013.
13. Le-Niculescu H, Levey DF, Ayalew M, Palmer L, Gavrin LM, Jain N, Winiger E, Bhosrekar S, Shankar G, Radel M, Bellanger E, Duckworth H, Olesek K, Vergo J, Schweitzer R, Yard M, Ballew A, Shekhar A, Sandusky GE, Schork NJ, Kurian SM, Salomon DR, Niculescu AB . Discovery and validation of blood biomarkers for suicidality . Molecular Psychiatry . 18 . 12 . 1249–64 . December 2013 . 23958961 . 10.1038/mp.2013.95 . 3835939.
14. Le-Niculescu H, Levey DF, Ayalew M, Palmer L, Gavrin LM, Jain N, Winiger E, Bhosrekar S, Shankar G, Radel M, Bellanger E, Duckworth H, Olesek K, Vergo J, Schweitzer R, Yard M, Ballew A, Shekhar A, Sandusky GE, Schork NJ, Kurian SM, Salomon DR, Niculescu AB . 6 . Discovery and validation of blood biomarkers for suicidality . Molecular Psychiatry . 18 . 12 . 1249–64 . December 2013 . 23958961 . 3835939 . 10.1038/mp.2013.95.
    • Web site: August 20, 2013 . Researchers identify biomarkers for possible blood test to predict suicide risk . Medical Xpress .
15. Hirota T, Hirota Y, Asagami C, Muto M . A Japanese case of Neu-Laxova syndrome . The Journal of Dermatology . 25 . 3 . 163–6 . March 1998 . 9575678 . 10.1111/j.1346-8138.1998.tb02373.x. 7896890 .
16. Barekatain B, Sadeghnia A, Rouhani E, Soofi GJ . A New Case of Neu-Laxova Syndrome: Infant with Facial Dysmorphism, Arthrogryposis, Ichthyosis, and Microcephalia . Advanced Biomedical Research . 7 . 68 . 2018 . 29862217 . 5952546 . 10.4103/abr.abr_143_17 . free .
17. Amini E, Azadi N, Sheikh M . New Insights on Genetic Features of Neu-Laxova Syndrome. . Iranian Journal of Neonatology IJN . March 2017 . 8 . 1 . 40–2 .
18. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD . 6 . Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease . Cell . 171 . 2 . 273–285 . October 2017 . 28985560 . 5685180 . 10.1016/j.cell.2017.09.021 .