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. 2021 Oct 26;18(21):11225.
doi: 10.3390/ijerph182111225.

Detection of Nail Oncometabolite SAICAR in Oral Cancer Patients and Its Molecular Interactions with PKM2 Enzyme

Rushikesh Patel  1 , Ajay Kumar Raj  1 , Kiran Bharat Lokhande  2 , Mazen A Almasri  3 , Khalid J Alzahrani  4 , Asma Saleh Almeslet  5 , K Venkateswara Swamy  6 , Gargi S Sarode  7 , Sachin C Sarode  7 , Shankargouda Patil  8 , Nilesh Kumar Sharma  1
Affiliations

Detection of Nail Oncometabolite SAICAR in Oral Cancer Patients and Its Molecular Interactions with PKM2 Enzyme

Rushikesh Patel et al. Int J Environ Res Public Health. .

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.

Keywords: SAICAR; in silico studies; metabolite biomarkers; oral cancer; pyruvate kinase M2.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
An oncometabolite SAICAR is detected in nails of oral cancer patients. A positive ESI extracted ion chromatogram (EIC) of SAICAR was detected during LC-HRMS of nail lysates purified with the help of a novel VTGE tool.
Figure 2
Figure 2
An oncometabolite SAICAR (CHEBI ID: 18319) shows strong molecular binding with pyruvate kinase M2 (PKM2) enzyme (PDB ID: 4G1N). Molecular docking and interaction of SAICAR with PKM2 were visualized with the help of Discovery Studio Visualizer. (A) Molecular docking affinity estimated by AutoDock Vina. (B) Three-dimensional view of interaction between SAICAR and PKM2 with binding residues, bond distances, and types of bonds. (C) The docked molecular structure between SAICAR and PKM2 is visualized in a 3D image depicting H-bond interactions (acceptor in green and donor in pink color) (D) Two-dimensional image of docked molecular structure between SAICAR and PKM2 derived from Discovery Studio Visualizer.
Figure 3
Figure 3
An oncometabolite SAICAR displays stable complex with PKM2. PKM2–SAICAR root mean square deviation (RMSD) plot for 10ns of time frame showing the stability of the complex between SAICAR depicts strong and specific binding to PKM2.
Figure 4
Figure 4
SAICAR shows specific contacts within the activation site of PKM2. (A) PKM2 and SAICAR interaction plot on the interaction between amino acid residues and ligand remained during 10 ns simulation. On the Y-axis, the interaction fraction shows the time of established interaction between key amino acid and ligand through different types of bonds such as hydrogen bonds, hydrophobic, ionic, and water bridges. (B) Schematic diagram on the interaction of the ligand with amino acid residues, which has remained for more than 30% of interaction time of the simulation. Here, various color combinations are used to represent the extent and nature of ligands to enzyme atomic interactions including ionic, hydrophobic, polar, water, and solvent exposure.
Figure 5
Figure 5
vNN-ADMET predicts SAICAR as a substrate of drug transporter P-gp and no adverse cell toxicity.
Figure 6
Figure 6
A proposed model on the role of SAICAR oncometabolite as a nail metabolite biomarker and predicted as a key metabolite in growth and proliferation by binding to PKM2.
See this image and copyright information in PMC

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References

    1. Wang Q., Gao P., Wang X., Duan Y. Investigation and identification of potential biomarkers in human saliva for the early diagnosis of oral squamous cell carcinoma. Clin. Chim. Acta. 2014;427:79–85. doi: 10.1016/j.cca.2013.10.004. - DOI - PubMed
    1. Farah C.S., Bhatia N., Lalla Y., Vu A., John K., Gupta V., Baeten J., Johnson A., Kademani D. Advances in Early Detection and Diagnostic Adjuncts in Oral Cavity Cancer. In: Kuriakose M.A., editor. Contemporary Oral Oncology: Biology, Epidemiology, Etiology, and Prevention. Springer International Publishing; Cham, Switzerland: 2017. pp. 355–421.
    1. Sankaranarayanan R., Somanathan T., Thomas G., Ramadas K. Screening for Oral Cancer. In: Kuriakose M.A., editor. Contemporary Oral Oncology: Biology, Epidemiology, Etiology, and Prevention. Springer International Publishing; Cham, Switzerland: 2017. pp. 423–444.
    1. Rai V., Mukherjee R., Ghosh A.K., Routray A., Chakraborty C. “Omics” in oral cancer: New approaches for biomarker discovery. Arch. Oral Biol. 2018;87:15–34. doi: 10.1016/j.archoralbio.2017.12.003. - DOI - PubMed
    1. Santosh A.B.R., Jones T., Harvey J. A review on oral cancer biomarkers: Understanding the past and learning from the present. J. Cancer Res. Ther. 2016;12:486–492. doi: 10.4103/0973-1482.176414. - DOI - PubMed

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