Structural insights into the substrate binding mechanism of novel ArgA from Mycobacterium tuberculosis

Das, Uddipan; Singh, Ekta; Dharavath, Sudhaker; Subhramanyam, Udaya Kumar Tiruttani; Pal, Ranjan; Vijayan, Ramachandran; Menon, Saji; Kumar, Saroj; Gourinath, S.; Srinivasan, Alagiri

doi:10.1016/j.ijbiomac.2018.12.163

Cited by 5 publications

(4 citation statements)

References 27 publications

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“…superfamily [56]. ArgA is regulated by negative feedback through the binding of L-Arg to the active site [57].…”

Section: Arga Inhibitorsmentioning

confidence: 99%

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Amino Acid Biosynthesis Inhibitors in Tuberculosis Drug Discovery

Guida,

Tammaro,

Quaranta

et al. 2024

Pharmaceutics

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According to the latest World Health Organization (WHO) report, an estimated 10.6 million people were diagnosed with tuberculosis (TB) in 2022, and 1.30 million died. A major concern is the emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains, fueled by the length of anti-TB treatment and HIV comorbidity. Innovative anti-TB agents acting with new modes of action are the only solution to counteract the spread of resistant infections. To escape starvation and survive inside macrophages, Mtb has evolved to become independent of the host by synthesizing its own amino acids. Therefore, targeting amino acid biosynthesis could subvert the ability of the mycobacterium to evade the host immune system, providing innovative avenues for drug discovery. The aim of this review is to give an overview of the most recent progress in the discovery of amino acid biosynthesis inhibitors. Among the hits discovered over the past five years, tryptophan (Trp) inhibitors stand out as the most advanced and have significantly contributed to demonstrating the feasibility of this approach for future TB drug discovery. Future efforts should be directed at prioritizing the chemical optimization of these hits to enrich the TB drug pipeline with high-quality leads.

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“…superfamily [56]. ArgA is regulated by negative feedback through the binding of L-Arg to the active site [57].…”

Section: Arga Inhibitorsmentioning

confidence: 99%

“…It is classified as an N -acetylglutamate synthase (NAGS) and belongs to the GCN5-related N -acetyl transferase superfamily [ 56 ]. ArgA is regulated by negative feedback through the binding of L -Arg to the active site [ 57 ].…”

Section: Inhibitors Of Amino Acid Biosynthesismentioning

confidence: 99%

Amino Acid Biosynthesis Inhibitors in Tuberculosis Drug Discovery

Guida,

Tammaro,

Quaranta

et al. 2024

Pharmaceutics

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“…Comparison of characteristic features of 3D-crystal structures of NAGS from different microorganisms like M. tuberculosis and N. gonorrhea provided insights into conformational arrangements needed for inhibition and regulation of enzyme activity and function. Both NAGS M. tuberculosis (PDB ID: 6ADD, 5YO2 [ 80 ] and NAGSN. Gonorrhea (PDB ID: 2R98 [ 81 ] crystal structures exists as dimer stacked together to form hexamer arrangement that is necessary for feedback inhibition by arginine.…”

Section: Structural Characteristics Of Enzymes Targeted By Amino Acid...mentioning

confidence: 99%

“…Sequence alignment for NAGS sequences retrieved from different organisms; Reproduced from Refs. [ 46 , 80 , 81 ] …”

Section: Structural Characteristics Of Enzymes Targeted By Amino Acid...mentioning

confidence: 99%

Insight into de-regulation of amino acid feedback inhibition: a focus on structure analysis method

Naz,

Liu,

Farooq

et al. 2023

Microb Cell Fact

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Regulation of amino acid’s biosynthetic pathway is of significant importance to maintain homeostasis and cell functions. Amino acids regulate their biosynthetic pathway by end-product feedback inhibition of enzymes catalyzing committed steps of a pathway. Discovery of new feedback resistant enzyme variants to enhance industrial production of amino acids is a key objective in industrial biotechnology. Deregulation of feedback inhibition has been achieved for various enzymes using in vitro and in silico mutagenesis techniques. As enzyme’s function, its substrate binding capacity, catalysis activity, regulation and stability are dependent on its structural characteristics, here, we provide detailed structural analysis of all feedback sensitive enzyme targets in amino acid biosynthetic pathways. Current review summarizes information regarding structural characteristics of various enzyme targets and effect of mutations on their structures and functions especially in terms of deregulation of feedback inhibition. Furthermore, applicability of various experimental as well as computational mutagenesis techniques to accomplish feedback resistance has also been discussed in detail to have an insight into various aspects of research work reported in this particular field of study.

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