Type 2 Diabetes Mellitus pathogenesis and role of Peptidylglycine Alpha-Amidating Monooxygenase (PAM) Gene elaboration by In-silico Analysis

Type 2 Diabetes Mellitus (T2DM) is caused by pancreatic beta cell failure and alpha cell dysfunction that are central to this disease pathophysiology. For T2DM, the Peptidylglycine Alpha-Amidating Monooxygenase (PAM) gene has susceptible locus as identified by Genome-wide association studies (GWAS) though underlying molecular mechanisms remained poorly characterised. This study have explored comprehensive in-silico characterization of the PAM gene potential role in T2DM. InterPro was employed to identify protein family and it was observed it belongs to Peptidylglycine alpha-hydroxylating monooxygenase/peptidyl-hydroxyglycine alpha-amidating lyase family (IR000720), consisting of two catalytic domains and nine active regions. Clinically significant 153 genetic variants including non-synonymous SNPs within the locus were identified after analysis of dbSNP through UCSC Genome Browser. Intrinsically disrupted large region (aa 290-495) was observed during protein disorder prediction by utilizing IUPred-3. Ensembl and NCBI BLAST were used to analyse evolutionary conservation sites. This analysis resulted in high sequence similarity with common model organisms Mus musculus and Rattus norvegicus with similarity 90% and 89% respectively. These computational findings suggest specific PAM variants likely to disrupt protein function, providing validated future direction for experimental studies to confirm PAM gene pivotal role in T2DM.