Molecular Biotechnology Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka-1349, Bangladesh.
Bioinformatics Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka-1349, Bangladesh.
Biomed Res Int. 2022 Jun 6;2022:4558867. doi: 10.1155/2022/4558867. eCollection 2022.
HMG-CoA reductase or HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) is a rate-limiting enzyme involved in cholesterol biosynthesis. HMGCR plays an important role in the possible occurrence of hypercholesterolemia leading to atherosclerosis and coronary heart disease. This enzyme is a major target for cholesterol-lowering drugs such as "statin" which blocks the synthesis of mevalonate, a precursor for cholesterol biosynthesis. This study is aimed at characterizing deleterious mutations and classifying functional single nucleotide polymorphisms (SNPs) of the HMGCR gene through analysis of functional and structural evaluation, domain association, solvent accessibility, and energy minimization studies. The functional and characterization tools such as SIFT, PolyPhen, SNPs and GO, Panther, I-Mutant, and Pfam along with programming were employed to explore all the available SNPs in the HMGCR gene in the database. Among 6815 SNP entries from different databases, approximately 388 SNPs were found to be missense. Analysis showed that seven missense SNPs are more likely to have deleterious effects. A tertiary model of the mutant protein was constructed to determine the functional and structural effects of the HMGCR mutation. In addition, the location of the mutations suggests that they may have deleterious effects because most of the mutations are residing in the functional domain of the protein. The findings from the analysis predicted that rs147043821 and rs193026499 missense SNPs could cause significant structural and functional instability in the mutated proteins of the HMGCR gene. The findings of the current study will likely be useful in future efforts to uncover the mechanism and cause of hypercholesterolemia. In addition, the identified SNPs of HMGCR gene could set up a strong foundation for further therapeutic discovery.
羟甲基戊二酰辅酶 A 还原酶或 HMGCR（3-羟基-3-甲基戊二酰辅酶 A 还原酶）是参与胆固醇生物合成的限速酶。HMGCR 在可能导致动脉粥样硬化和冠心病的高胆固醇血症的发生中起着重要作用。这种酶是降低胆固醇药物的主要靶点，如“他汀类”药物，它可以阻断甲羟戊酸的合成，甲羟戊酸是胆固醇生物合成的前体。本研究旨在通过功能和结构评估、结构域关联、溶剂可及性和能量最小化研究，对 HMGCR 基因的有害突变和功能单核苷酸多态性（SNP）进行特征描述。本研究采用 SIFT、PolyPhen、SNP 和 GO、Panther、I-Mutant 和 Pfam 等功能和表征工具以及编程来探索数据库中 HMGCR 基因中的所有可用 SNP。在来自不同数据库的 6815 个 SNP 条目，发现大约 388 个 SNP 是错义的。分析表明，有七个错义 SNP 更有可能产生有害影响。构建了突变蛋白的三级模型，以确定 HMGCR 突变的功能和结构影响。此外，突变的位置表明它们可能具有有害影响，因为大多数突变都位于蛋白质的功能域中。分析预测，rs147043821 和 rs193026499 错义 SNP 可能导致 HMGCR 基因突变蛋白的显著结构和功能不稳定。本研究的结果可能有助于揭示高胆固醇血症的机制和原因。此外，HMGCR 基因的鉴定 SNP 可以为进一步的治疗发现奠定坚实的基础。
