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16S rRNA Methyltransferases as Novel Drug Targets Against Tuberculosis

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Abstract

Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis (M.tb) whose natural history traces back to 70,000 years. TB remains a major global health burden. Methylation is a type of post-replication, post-transcriptional and post-translational epi-genetic modification involved in transcription, translation, replication, tissue specific expression, embryonic development, genomic imprinting, genome stability and chromatin structure, protein protein interactions and signal transduction indicating its indispensable role in survival of a pathogen like M.tb. The pathogens use this epigenetic mechanism to develop resistance against certain drug molecules and survive the lethality. Drug resistance has become a major challenge to tackle and also a major concern raised by WHO. Methyltransferases are enzymes that catalyze the methylation of various substrates. None of the current TB targets belong to methyltransferases which provides therapeutic opportunities to develop novel drugs through studying methyltransferases as potential novel targets against TB. Targeting 16S rRNA methyltransferases serves two purposes simultaneously: a) translation inhibition and b) simultaneous elimination of the ability to methylate its substrates hence stopping the emergence of drug resistance strains. There are ~ 40 different rRNA methyltransferases and 13 different 16S rRNA specific methyltransferases which are unexplored and provide a huge opportunity for treatment of TB.

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Abbreviations

SAM:

S-adenosyl-L-methionine

ATP:

Adenosine triphosphate

BRENDA:

A comprehensive enzyme information system

EC:

Enzyme Commission

DMTs:

DNA Methyltransferases

CpG dinucleotides:

Cytosine-phosphate-guanine sites

Dam:

DNA adenine Methyltransferase

MDR:

Multi-drug-resistant

XDR:

Extensively-drug-resistant

PTC:

Peptidyl transferase center

DC:

Decoding center

PET:

Peptide exit tunnel

PDB:

Protein data bank

Dcm:

DNA cytosine Methyltransferase

PMTs:

Protein Methyltransferases

PRMTs:

Protein arginine methyltransferases

PKMTs:

Protein lysine(K) Methyl Transferases

NTMTs:

N-Terminal Methyl Transferases

CTMTs:

Carboxy Terminal Methyl Transferases

SET:

Su(var)3-9, Enhancer-of-zeste and Trithorax

RMTs:

RNA Methyltransferases

tRNA:

Transfer RNA

mRNA:

Messenger RNA

rRNA:

Ribosomal RNA

tmRNA:

Transfer-messenger RNA

snRNA:

Small nuclear RNA

snoRNA:

Small nucleolar RNA

SCOP:

Structural Classification of Proteins

CATH:

Class Architecture Topology Homologous superfamily

CASTp 3.0:

Computed atlas of surface topography of proteins

rRMTs:

rRNA Methyltransferases

16srRMT:

16S rRNA Methyltransferases

Rsm[A,B,C,D,E,F,G,H,I,J]:

Ribosomal RNA small subunit methyltransferase[A,B,C,D,E,F,G,H,I,J]

SSU:

Small ribosomal subunit

LSU:

Large ribosomal subunit

M.tb :

Mycobacterium tuberculosis

Tth:

Thermus thermophilus

Eco:

Escherichia coli

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Acknowledgements

We thank ICMR (Indian Council of Medical Research) for providing funding for this ongoing project (Grant No. ICMR: ISRM 12(07)/2019). We would also like to take this opportunity to thank Dr. Yusupov MM (Laboratory of Structural Biology, Institute of Fundamental Medicine and Biology, Kazan Federal University), for allowing us to use the colored representation of the domains of 16S / 18S rRNA figures from his published article with a few modifications.

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  1. V. L. S. Prasad Burra

    Present address: Centre for Advanced Research and Innovation in Structural Biology of Diseases, K L E F (Deemed To Be) University, Vaddeswaram, Andhra Pradesh, 522 502, India

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  1. Centre for Advanced Research and Innovation in Structural Biology of Diseases, K L E F (Deemed To Be) University, Vaddeswaram, Andhra Pradesh, 522 502, India

    Salaikumaran M. R. & Veena P. Badiger

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BVLS took the initiative, providing the scope and template of the work, monitored the progress, reviewed, wrote, analyzed the data and corrected till the manuscript reached its submission stage. VB and SMR wrote the manuscript, collected, processed the required sequence and structure data and drew figures.

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Salaikumaran, M.R., Badiger, V.P. & Burra, V.L.S.P. 16S rRNA Methyltransferases as Novel Drug Targets Against Tuberculosis. Protein J 41, 97–130 (2022). https://doi.org/10.1007/s10930-021-10029-2

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