Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with <i>α</i>-Carbonic Anhydrase II Deficiency
Human carbonic anhydrase II (CA-II) is a Zinc (Zn<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mrow> <mn>2</mn> <mo>+</mo> </mrow> </msup> </semantics> </math> </inline...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/21/3987 |
| _version_ | 1818581750001958912 |
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| author | Taremekedzwa Allan Sanyanga Bilal Nizami Özlem Tastan Bishop |
| author_facet | Taremekedzwa Allan Sanyanga Bilal Nizami Özlem Tastan Bishop |
| author_sort | Taremekedzwa Allan Sanyanga |
| collection | DOAJ |
| description | Human carbonic anhydrase II (CA-II) is a Zinc (Zn<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mrow> <mn>2</mn> <mo>+</mo> </mrow> </msup> </semantics> </math> </inline-formula>) metalloenzyme responsible for maintenance of acid-base balance within the body through the reversible hydration of CO<inline-formula> <math display="inline"> <semantics> <msub> <mrow></mrow> <mn>2</mn> </msub> </semantics> </math> </inline-formula> to produce protons (H<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mo>+</mo> </msup> </semantics> </math> </inline-formula>) 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 <i>betweenness centrality (BC)</i> 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<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mrow> <mn>2</mn> <mo>+</mo> </mrow> </msup> </semantics> </math> </inline-formula> 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<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mrow> <mn>2</mn> <mo>+</mo> </mrow> </msup> </semantics> </math> </inline-formula> ligands; His94, His96, His119 and Asn243 highlighting potential compensatory mechanisms to maintain Zn<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mrow> <mn>2</mn> <mo>+</mo> </mrow> </msup> </semantics> </math> </inline-formula> 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. |
| first_indexed | 2024-12-16T07:38:27Z |
| format | Article |
| id | doaj.art-55b55ab23858495e9cb006f72af4baa9 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-16T07:38:27Z |
| publishDate | 2019-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-55b55ab23858495e9cb006f72af4baa92022-12-21T22:39:08ZengMDPI AGMolecules1420-30492019-11-012421398710.3390/molecules24213987molecules24213987Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with <i>α</i>-Carbonic Anhydrase II DeficiencyTaremekedzwa Allan Sanyanga0Bilal Nizami1Özlem Tastan Bishop2Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South AfricaResearch Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South AfricaResearch Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South AfricaHuman carbonic anhydrase II (CA-II) is a Zinc (Zn<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mrow> <mn>2</mn> <mo>+</mo> </mrow> </msup> </semantics> </math> </inline-formula>) metalloenzyme responsible for maintenance of acid-base balance within the body through the reversible hydration of CO<inline-formula> <math display="inline"> <semantics> <msub> <mrow></mrow> <mn>2</mn> </msub> </semantics> </math> </inline-formula> to produce protons (H<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mo>+</mo> </msup> </semantics> </math> </inline-formula>) 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 <i>betweenness centrality (BC)</i> 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<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mrow> <mn>2</mn> <mo>+</mo> </mrow> </msup> </semantics> </math> </inline-formula> 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<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mrow> <mn>2</mn> <mo>+</mo> </mrow> </msup> </semantics> </math> </inline-formula> ligands; His94, His96, His119 and Asn243 highlighting potential compensatory mechanisms to maintain Zn<inline-formula> <math display="inline"> <semantics> <msup> <mrow></mrow> <mrow> <mn>2</mn> <mo>+</mo> </mrow> </msup> </semantics> </math> </inline-formula> 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.https://www.mdpi.com/1420-3049/24/21/3987precision medicinecarbonic anhydrase iisingle nucleotide variationallosteric effectdynamic residue network analysismd-task |
| spellingShingle | Taremekedzwa Allan Sanyanga Bilal Nizami Özlem Tastan Bishop Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with <i>α</i>-Carbonic Anhydrase II Deficiency Molecules precision medicine carbonic anhydrase ii single nucleotide variation allosteric effect dynamic residue network analysis md-task |
| title | Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with <i>α</i>-Carbonic Anhydrase II Deficiency |
| title_full | Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with <i>α</i>-Carbonic Anhydrase II Deficiency |
| title_fullStr | Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with <i>α</i>-Carbonic Anhydrase II Deficiency |
| title_full_unstemmed | Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with <i>α</i>-Carbonic Anhydrase II Deficiency |
| title_short | Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with <i>α</i>-Carbonic Anhydrase II Deficiency |
| title_sort | mechanism of action of non synonymous single nucleotide variations associated with i α i carbonic anhydrase ii deficiency |
| topic | precision medicine carbonic anhydrase ii single nucleotide variation allosteric effect dynamic residue network analysis md-task |
| url | https://www.mdpi.com/1420-3049/24/21/3987 |
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