Structural effect of the H992D/H418D mutation of angiotensin-converting enzyme in the Indian population: implications for health and disease

Abstract

The Non synonymous SNPs (nsSNPs) of the renin-angiotensin-system (RAS) pathway, unique to the Indian population were investigated in view of its importance as an endocrine system. nsSNPs of the RAS pathway genes were mined from the IndiGenome database. Damaging nsSNPs were predicted using SIFT, PredictSNP, SNP and GO, Snap2 and Protein Variation Effect Analyzer. Loss of function was predicted based on protein stability change using I mutant, PremPS and CONSURF. The structural impact of the nsSNPs was predicted using HOPE and Missense3d followed by modeling, refinement, and energy minimization. Molecular Dynamics studies were carried out using Gromacsv2021.1. 23 Indian nsSNPs of the RAS pathway genes were selected for structural analysis and 8 were predicted to be damaging. Further sequence analysis showed that HEMGH zinc binding motif changes to HEMGD in somatic ACE-C domain (sACE-C) H992D and Testis ACE (tACE) H418D resulted in loss of zinc coordination, which is essential for enzymatic activity in this metalloprotease. There was a loss of internal interactions around the zinc coordination residues in the protein structural network. This was also confirmed by Principal Component Analysis, Free Energy Landscape and residue contact maps. Both mutations lead to broadening of the AngI binding cavity. The H992D mutation in sACE-C is likely to be favorable for cardiovascular health, but may lead to renal abnormalities with secondary impact on the heart. H418D in tACE is potentially associated with male infertility.

Communicated by Ramaswamy H. Sarma

Keywords:

• RAS pathway
• single nucleotide polymorphisms
• angiotensin converting enzyme
• molecular dynamics simulation
• Indian population

Author contribution statement

AK – Conception, planning, data collection, analysis, manuscript writing; SB – Conception, planning, manuscript editing and supervision.

Competing interest

The Authors have no relevant financial or non-financial interest to disclose.

Data availability statement

* Supplementary files are provided for further information.

Disclosure statement

No potential conflict of interest was reported by the authors.

Statements and declaration

The authors have no conflicts of interest to declare.

Additional information

Funding

The authors would like to acknowledge funding from Departmentof Biotechnology grant number BT/PR40197/BTIS/137/68/2023.