Abstract
Oncometabolites are known to drive metabolic adaptations in oral cancer. Several oncometabolites are known to be shared between cancer cells and non-cancer cells including microbiotas to modulate the tumor microenvironment. Among potential oncometabolites, succinylaminoimidazolecarboxamide ribose5′-phosphate (SAICAR) supports the growth and invasiveness of cancer cells by pyruvate kinase M2 (PKM2) enzyme in a glucose starved tumor microenvironment. There is a significant gap that shows the detection of SAICAR in biological samples including nails of oral cancer patients. Metabolite identification of SAICAR was investigated in the nails of oral cancer patients using novel vertical tube gel electrophoresis (VTGE) and LC-HRMS. Further molecular docking and molecular dynamics simulations (MDS) were employed to determine the nature of molecular interactions of SAICAR (CHEBI ID:18319) with PKM2 (PDB ID: 4G1N). Molecular docking of SAICAR (CHEBI ID:18319) was performed against pyruvate kinase M2 (PDB ID: 4G1N). Data suggest the presence of oncometabolite SAICAR in nails of oral cancer. Molecular docking of SAICAR with PKM2 showed appreciable binding affinity (−8.0 kcal/mol) with residues including ASP407, THR405, GLU410, ARG443, GLY321, ARG436, HIS439, LYS266, and TYR466. Furthermore, MDS confirmed the specific binding of SAICAR within the activator site of PKM2 and the stability of SAICAR and PKM2 molecular interactions. In conclusion, SAICAR is a promising oncometabolite biomarker present in the nails of oral cancer patients. A significant activation potential of SAICAR exists with the PKM2 enzyme.
Highlights
In line with existing views, the authors report on a novel approach to the detection of succinylaminoimidazolecarboxamide ribose5 -phosphate (SAICAR) in the nails of oral cancer patients with the assistance of a novel and in-house vertical tube gel electrophoresis (VTGE) tool [26,29] (27)
SAICAR shows effective allosteric binding the nails of oral cancer patients
SAICAR shows effective allosteric binding upon the pyruvate kinase M2 (PKM2) enzyme
Summary
Tumor heterogeneity is contributed by various components including cellular and noncellular components such as oncometabolite [1,2]. The importance of oncometabolite in various types of cancers, including oral cancer, is widely appreciated in the basic understanding of metabolic heterogeneity and is envisaged as a potential source of biomarkers [5,6,7]. Cancer cells and cancer supporting stroma including microbiome establish a source and link partnership for the exchange of key oncometabolites including SAICAR, for growth and proliferation [21,22,23,24,25,26,27,28,29]. We report on the detection of SAICAR in the nail of oral cancer patients by using our novel and validated vertical tube gel electrophoresis (VTGE) methodology and molecular docking and MD simulations to predict the molecular interactions between
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