Comprehensive mutations analyses of FTO (fat mass and obesity-associated gene) and their effects on FTO’s substrate binding implicated in obesity

Abstract

An excessive amount of fat deposition in the body leads to obesity which is a complex disease and poses a generic threat to human health. It increases the risk of various other diseases like diabetes, cardiovascular disease, and multiple types of cancer. Genomic studies have shown that the expression of the fat mass obesity (FTO) gene was highly altered and identified as one of the key biomarkers for obesity. This study has been undertaken to investigate the mutational profile of the FTO gene and elucidates its effect on the protein structure and function. Harmful effects of various missense mutations were predicted using different independent tools and it was observed that all mutations were highly pathogenic. Molecular dynamics (MD) simulations were performed to study the structure and function of FTO protein upon different mutations and it was found that mutations decreased the structure stability and affected protein conformation. Furthermore, a protein residue network analysis suggested that the mutations affected the overall residues bonding and topology. Finally, molecular docking coupled with MD simulation suggested that mutations affected FTO substrate binding by changing the protein-ligand affinity. Hence, the results of this finding would help in an in-depth understanding of the molecular biology of the FTO gene and its variants and lead to the development of effective therapeutics against associated diseases and disorders.

Multiplexed LC‐MS/MS quantification of salivary RNA modifications in periodontitis

“…37 Its expression was identified as one of the key biomarkers for obesity. 38 The FTO genetic variant has been also linked to major markers of insulin resistance and inflammation, with an increased risk of type 2 diabetes. 39 Diabetes is a major risk factor for the development and progression of periodontal disease, 30,40 as well as obesity.…”

“…The FTO gene was found to be highly dysregulated and contributed to obesity 37 . Its expression was identified as one of the key biomarkers for obesity 38 . The FTO genetic variant has been also linked to major markers of insulin resistance and inflammation, with an increased risk of type 2 diabetes 39 .…”

In silico profiling of nonsynonymous SNPs of fat mass and obesity-associated gene: possible impacts on the treatment of non-alcoholic fatty liver disease

“…This approach is possible with evolving in silico approaches that provide statistically significant results with visually vibrant and easy-to-understand data with a very low false discovery rate. Recently, Kumar et al, (2022) [ 16 ] displayed via in silico analysis the mutational profile of the FTO gene and explained how it affects protein structure and function. In detail, they analyzed the FTO gene's mutational profile and monitored the influence of nonsynonymous (missense) mutations on the structure, dynamics, conformation, and substrate binding of the FTO protein.…”

Assessment of the Effect of Flavonoids Biomolecules on Fat Mass and Obesity Associated (FTO) Protein as Anti-Obesity Agents: An In-Silico Study

“…14,15 As radical scavengers, flavonoids are capable of hampering the oxidation of lowdensity lipoprotein (LDL) and then exert their inhibitory action against atherosclerosis. 14 Through molecular docking and simulation studies, different flavonoids such as quercetin, exemestane, kaempferol, letrozole, rutin, 22 catechins, epicatechin, epigallocatechin and gallocatechin 10 are reported to have inhibitory interaction with FTO protein in the adipocytes, where they exert their anti-obesity effects through lipolytic mechanism by reducing adipogenesis and enhancing lipolysis. 10,22 Molecular docking studies have also reported the activity of other flavonoids such as flavonols, 23 apigenin, naringenin, 24 and taiwaniaquinoids 25 as anti-obesity agent targeting the FTO protein.…”

“…14 Through molecular docking and simulation studies, different flavonoids such as quercetin, exemestane, kaempferol, letrozole, rutin, 22 catechins, epicatechin, epigallocatechin and gallocatechin 10 are reported to have inhibitory interaction with FTO protein in the adipocytes, where they exert their anti-obesity effects through lipolytic mechanism by reducing adipogenesis and enhancing lipolysis. 10,22 Molecular docking studies have also reported the activity of other flavonoids such as flavonols, 23 apigenin, naringenin, 24 and taiwaniaquinoids 25 as anti-obesity agent targeting the FTO protein. This study investigated the anti-obesity potentials of flavonoids including quercetin, epigallocatechin, pcoumarin, caffeic acid, naphthoresorcinol, gallic acid, and sinapic acid, isolated from methanol flavonoid-rich fraction of fresh lime juice (MFLJ) and ethylacetate flavonoid-rich fraction of honey (EAFH) via in silico approach.…”