Proteomic Atomics Reveals a Distinctive Uracil‐5‐Methyltransferase

Abstract

Carbon (C), hydrogen (H), nitrogen (N), oxygen (O), and sulfur (S) atoms intrigue as they are the foundation for amino acid (AA) composition and the folding and functions of proteins and thus define and control the survival of a cell, the smallest unit of life. Here, we calculated the proteomic atom distribution in > 1500 randomly selected species across the entire current phylogenetic tree and identified uracil-5-methyltransferase (U5MTase) of the protozoan parasite Plasmodium falciparum (Pf, strain Pf3D7), with a distinct atom and AA distribution pattern. We determined its apicoplast location and in silico 3D protein structure to refocus attention exclusively on U5MTase with tremendous potential for therapeutic intervention in malaria. Around 300 million clinical cases of malaria occur each year in tropical and subtropical regions of the world, resulting in over one million deaths annually, placing malaria among the most serious infectious diseases. Genomic and proteomic research of the clades of parasites containing Pf is progressing slowly and the functions of most of the~5300 genes are still unknown. We applied a 'bottom-up' comparative proteomic atomics analysis across the phylogenetic tree to visualize a protein molecule on its actual basis -i. e., its atomic level. We identified a protruding Pf3D7-specific U5MTase, determined its 3D protein structure, and identified potential inhibitory drug molecules through in silico drug screening that might serve as possible remedies for the treatment of malaria. Besides, this atomic-based proteome map provides a unique approach for the identification of parasite-specific proteins that could be considered as novel therapeutic targets.

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing

“…The crystallographic three-dimensional (3D) protein structure of the FAM72A protein (from Protein Data Bank (PDB) data [ 30 ]) and UNG2 protein (Gene ID: 7374, isoform-2: NP_550433.1, 313 AAs; 1AKZ_A PDB model; DOI: 10.2210/pdb1akz/pdb [ 31 ]) were retrieved from the PDB [ 32 ] with a resolution of 1.55 Å. Compound structures were downloaded from the PubChem database [ 33 ] as described previously [ 30 , 34 , 35 ].…”

“…The UNG2 3D peptide sequence was based on the UNG2 protein sequence (Gene ID: 7374, isoform-2: NP_550433.1, 313 AAs; Uniprot-ID: P13051) and the 1AKZ_A PDB model (DOI: 10.2210/pdb1akz/pdb) [ 31 ] was selected as the template. The obtained template for the N-terminal UNG2 3D peptide structure model (AA 1-313) was then forwarded for UNG2 3D peptide structure modeling with I-TASSER [ 36 , 37 ] and Modeller v9.20 [ 38 , 39 ] software, and Chimera software was used as a graphical interface as described previously [ 34 , 35 , 39 ]. For comparison, we also applied the UNG2 protein sequence to the state-of-the-art machine learning method, AlphaFold (( ), accessed on 3 November 2021) [ 40 , 41 ].…”

“…The UNG2 AA composition was calculated to identify and justify the AA residues promoting structured or unstructured regions in the UNG2 protein. Modeled structures were visualized using Chimera software as the graphical interface to check the core, rim, and buried regions, as described previously [ 30 , 34 , 35 ].…”

“…The FAM72A monomer was exported as a PDB file, whereas the UNG2 peptide was submitted as a FASTA-formatted AA sequence (AA 1–45), and MODPEP and MDOCK were applied for the fine adjustments of FAM72A-UNG2 interactions [ 44 ]. Modeled structures were visualized using Chimera software as a graphical interface, as described previously [ 30 , 34 , 35 ].…”

“…The protein carbon distribution (CARd) analysis was performed to validate the specific FAM72A-UNG2 interaction sites using our recently described algorithm [ 35 , 47 ].…”