Next Article in Journal
Synthesis and Antiviral Activity of Novel 1,3,4-Thiadiazole Inhibitors of DDX3X
Previous Article in Journal
Single-Step Methylation of Chitosan Using Dimethyl Carbonate as a Green Methylating Agent
Article

Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

1
Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa
2
Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences of the Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117 Budapest, Hungary
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(21), 3987; https://doi.org/10.3390/molecules24213987
Received: 31 August 2019 / Revised: 18 October 2019 / Accepted: 24 October 2019 / Published: 4 November 2019
Human carbonic anhydrase II (CA-II) is a Zinc (Zn 2 + ) metalloenzyme responsible for maintenance of acid-base balance within the body through the reversible hydration of CO 2 to produce protons (H + ) and bicarbonate (BCT). Due to its importance, alterations to the amino acid sequence of the protein as a result of single nucleotide variations (nsSNVs) have detrimental effects on homeostasis. Six pathogenic CA-II nsSNVs, K18E, K18Q, H107Y, P236H, P236R and N252D were identified, and variant protein models calculated using homology modeling. The effect of each nsSNV was analyzed using motif analysis, molecular dynamics (MD) simulations, principal component (PCA) and dynamic residue network (DRN) analysis. Motif analysis identified 11 functionally important motifs in CA-II. RMSD data indicated subtle SNV effects, while PCA analysis revealed that the presence of BCT results in greater conformational sampling and free energy in proteins. DRN analysis showed variant allosteric effects, and the average betweenness centrality (BC) calculations identified Glu117 as the most important residue for communication in CA-II. The presence of BCT was associated with a reduction to Glu117 usage in all variants, suggesting implications for Zn 2 + dissociation from the CA-II active site. In addition, reductions to Glu117 usage are associated with increases in the usage of the primary and secondary Zn 2 + ligands; His94, His96, His119 and Asn243 highlighting potential compensatory mechanisms to maintain Zn 2 + within the active site. Compared to traditional MD simulation investigation, DRN analysis provided greater insights into SNV mechanism of action, indicating its importance for the study of missense mutation effects in proteins and, in broader terms, precision medicine related research. View Full-Text
Keywords: precision medicine; carbonic anhydrase II; single nucleotide variation; allosteric effect; dynamic residue network analysis; MD-TASK precision medicine; carbonic anhydrase II; single nucleotide variation; allosteric effect; dynamic residue network analysis; MD-TASK
Show Figures

Figure 1

MDPI and ACS Style

Sanyanga, T.A.; Nizami, B.; Tastan Bishop, Ö. Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency. Molecules 2019, 24, 3987. https://doi.org/10.3390/molecules24213987

AMA Style

Sanyanga TA, Nizami B, Tastan Bishop Ö. Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency. Molecules. 2019; 24(21):3987. https://doi.org/10.3390/molecules24213987

Chicago/Turabian Style

Sanyanga, Taremekedzwa A., Bilal Nizami, and Özlem Tastan Bishop. 2019. "Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency" Molecules 24, no. 21: 3987. https://doi.org/10.3390/molecules24213987

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop