Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Tangail, Bangladesh.
Cancer Rep (Hoboken). 2024 Jul;7(7):e2130. doi: 10.1002/cnr2.2130.
The human SAT1 gene encodes spermidine/spermine N1-acetyltransferase 1 (SSAT1), a regulatory biological catalyst of polyamine catabolism. Numerous essential biological processes, such as cellular proliferation, differentiation, and survival, depend on polyamines like spermidine and spermine. Thus, SSAT1 is involved in key cellular activities such as proliferation and survival of cells and mediates various diseases including cancer. A plethora of studies established the involvement of missense single nucleotide polymorphisms (SNPs) in numerous pathological conditions due to their ability to adversely affect the structure and subsequent function of the protein.
To date, an in silico study to identify the pathogenic missense SNPs of the human SAT1 gene has not been accomplished yet. This study aimed to filter the missense SNPs that were functionally detrimental and pathogenic.
The rs757435207 (I21N) was ascertained to be the most deleterious and pathogenic by all algorithmic tools. Stability and evolutionary conservation analysis tools also stated that I21N variant decreased the stability and was located in the highly conserved residue. Molecular dynamics simulation revealed that I21N caused substantial alterations in the conformational stability and dynamics of the SSAT1 protein. Consequently, the I21N variant could disrupt the native functional roles of the SSAT1 enzyme.
Therefore, the I21N variant was identified and concluded to be an oncogenic missense variant of the human SAT1 gene. Overall, the findings of this study would be a great directory of future experimental research to develop personalized medicine.
人类 SAT1 基因编码精脒/精胺 N1-乙酰基转移酶 1（SSAT1），这是多胺分解代谢的调节生物催化剂。许多重要的生物学过程，如细胞增殖、分化和存活，都依赖于精脒和精胺等多胺。因此，SSAT1 参与细胞增殖和存活等关键细胞活动，并介导包括癌症在内的各种疾病。大量研究表明，由于错义单核苷酸多态性（SNP）能够对蛋白质的结构和后续功能产生不利影响，因此它们参与了许多病理状况。
迄今为止，尚未对人类 SAT1 基因的致病错义 SNP 进行计算机研究。本研究旨在筛选具有功能损伤和致病性的错义 SNP。
所有算法工具均确定 rs757435207（I21N）为最具危害性和致病性的 SNP。稳定性和进化保守性分析工具还表明，I21N 变体降低了稳定性，并位于高度保守的残基中。分子动力学模拟表明，I21N 导致 SSAT1 蛋白构象稳定性和动力学发生实质性变化。因此，I21N 变体可能破坏 SSAT1 酶的天然功能作用。
因此，确定 I21N 变体为人 SAT1 基因的致癌错义变体。总的来说，本研究的发现将成为未来开发个性化药物的实验研究的重要指南。
