Laboratory of Genomics and Human Genetics, Institut Pasteur du Maroc, Casablanca, Morocco; Laboratory of Physiopathology and Molecular Genetics, Department of Biology, Faculty of Sciences Ben M'Sik, Hassan II University, Casablanca, Morocco.
Laboratory of Genomics and Human Genetics, Institut Pasteur du Maroc, Casablanca, Morocco.
Comput Biol Chem. 2023 Oct;106:107937. doi: 10.1016/j.compbiolchem.2023.107937. Epub 2023 Aug 2.
The process of steroidogenesis plays a vital role in human physiology as it governs the biosynthesis of mineralocorticoids, glucocorticoids, and androgens. These three classes of steroid hormones are primarily produced in the adrenal and gonadal glands through steroidogenesis pathways. Initiated by the side chain cleavage of cholesterol (CLR), this process leads to the conversion of cholesterol into pregnenolone and isocaproic aldehyde. The enzyme CYP11A1, encoded by the CYP11A1 gene, plays a key role in catalyzing the side chain cleavage of CLR. Several single nucleotide polymorphisms (SNPs) have been identified in the CYP11A1 gene, which may predispose carriers to disorders associated with abnormal steroidogenesis. Specifically, missense SNPs in the CYP11A1 gene have the potential to negatively impact the interaction between CYP11A1 and CLR, thus affecting the overall metabolome of steroid hormones. In this computational study, we focused on a specific set of missense SNPs reported in the CYP11A1 gene, aiming to identify variants that directly impact the interaction between CYP11A1 and CLR. The three-dimensional structure of the CYP11A1-CLR complex was obtained from the RCSB Protein Data Bank, while missense SNPs in the CYP11A1 gene were retrieved from Ensembl. To predict the most deleterious variants, we utilized the ConSurf server, SIFT, and PolyPhen. Furthermore, we assessed the impact of induced amino acid (AA) substitutions on the CYP11A1-CLR interaction using the PRODIGY server, PyMol, and Ligplot programs. Additionally, molecular dynamics (MD) simulations were conducted to analyze the effects of deleterious variants on the structural dynamics of the CYP11A1-CLR complex. Among the 8096 retrieved variants, we identified ten missense SNPs (E91K, W147G, R151W, R151Q, S391C, V392M, Q395K, Q416E, R460W, and R460Q) as deleterious for the interaction between CYP11A1 and CLR. MD simulations of the CYP11A1-CLR complexes carrying these deleterious AA substitutions revealed that Q416E, W147G, R460Q, and R460W had the most pronounced impacts on the structural dynamics of the complex. Consequently, these missense SNPs were considered the most deleterious ones. Further functional tests are recommended to assess the impact of these four missense SNPs on the enzymatic activity of CYP11A1. Moreover, Genome-Wide Association Studies (GWAS) should be conducted to determine the significance of their association with abnormal steroidogenesis diseases in various patient groups.
类固醇生成过程在人类生理学中起着至关重要的作用，因为它控制着矿物质皮质激素、糖皮质激素和雄激素的生物合成。这三类甾体激素主要通过类固醇生成途径在肾上腺和性腺中产生。该过程由胆固醇（CLR）的侧链裂解启动，导致胆固醇转化为孕烯醇酮和异己醛。CYP11A1 基因编码的酶 CYP11A1 在催化 CLR 的侧链裂解中起着关键作用。CYP11A1 基因中已经鉴定出几个单核苷酸多态性（SNP），这些 SNP 可能使携带者易患与异常类固醇生成相关的疾病。具体来说，CYP11A1 基因中的错义 SNP 有可能对 CYP11A1 和 CLR 之间的相互作用产生负面影响，从而影响类固醇激素的整体代谢组。在这项计算研究中，我们专注于 CYP11A1 基因中报告的一组特定的错义 SNP，旨在确定直接影响 CYP11A1 和 CLR 相互作用的变体。CYP11A1-CLR 复合物的三维结构从 RCSB 蛋白质数据库获得，而 CYP11A1 基因中的错义 SNP 从 Ensembl 获得。为了预测最具破坏性的变体，我们使用了 ConSurf 服务器、SIFT 和 PolyPhen。此外，我们使用 PRODIGY 服务器、PyMol 和 Ligplot 程序评估诱导氨基酸（AA）取代对 CYP11A1-CLR 相互作用的影响。此外，进行了分子动力学（MD）模拟，以分析有害变体对 CYP11A1-CLR 复合物结构动力学的影响。在所检索的 8096 个变体中，我们确定了十个错义 SNP（E91K、W147G、R151W、R151Q、S391C、V392M、Q395K、Q416E、R460W 和 R460Q）作为 CYP11A1 和 CLR 相互作用的有害 SNP。对携带这些有害 AA 取代的 CYP11A1-CLR 复合物进行 MD 模拟表明，Q416E、W147G、R460Q 和 R460W 对复合物的结构动力学有最显著的影响。因此，这些错义 SNP 被认为是最具破坏性的 SNP。建议进行进一步的功能测试，以评估这四个错义 SNP 对 CYP11A1 酶活性的影响。此外，应进行全基因组关联研究（GWAS），以确定它们与各种患者群体中异常类固醇生成疾病的相关性的意义。
