Wu Ming-Jie, Jiang Yan, Yan Yong-Bin
Key Laboratory of Bio-Resources and Eco-Environment of MOE, College of Life Science, Sichuan University, Chengdu 610064, China; E-Mail:
Int J Mol Sci. 2011;12(5):2797-807. doi: 10.3390/ijms12052797. Epub 2011 Apr 28.
The deficiency of human carbonic anhydrase II (HCAII) has been recognized to be associated with a disease called CAII deficiency syndrome (CADS). Among the many mutations, the P237H mutation has been characterized to lead to a significant decrease in the activity of the enzyme and in the Gibbs free energy of folding. However, sequence alignment indicated that the 237th residue of CAII is not fully conserved across all species. The FoldX theoretical calculations suggested that this residue did not significantly contribute to the overall folding of HCAII, since all mutants had small ΔΔG values (around 1 kcal/mol). The experimental determination indicated that at least three mutations affect HCAII folding significantly and the P237H mutation was the most deleterious one, suggesting that Pro237 was important to HCAII folding. The discrepancy between theoretical and experimental results suggested that caution should be taken when using the prediction methods to evaluate the details of disease-related mutations.
人类碳酸酐酶II（HCAII）的缺陷已被认为与一种名为碳酸酐酶II缺乏综合征（CADS）的疾病有关。在众多突变中，P237H突变的特征是导致该酶的活性以及折叠的吉布斯自由能显著降低。然而，序列比对表明，CAII的第237位残基在所有物种中并非完全保守。FoldX理论计算表明，该残基对HCAII整体折叠的贡献不大，因为所有突变体的ΔΔG值都很小（约1千卡/摩尔）。实验测定表明，至少有三个突变对HCAII折叠有显著影响，而P237H突变是最有害的一个，这表明Pro237对HCAII折叠很重要。理论和实验结果之间的差异表明，在使用预测方法评估与疾病相关突变的细节时应谨慎。
