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Literature summary extracted from

  • Mishra, A.; Mamidi, A.S.; Rajmani, R.S.; Ray, A.; Roy, R.; Surolia, A.
    An allosteric inhibitor of Mycobacterium tuberculosis ArgJ implications to a novel combinatorial therapy (2018), EMBO Mol. Med., 10, e8038 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
2.3.1.35 drug development the enzyme is a target for inhibition in treatment of Mycobacterium tuberculosis infection, e.g. inhibitor pranlukast (PRK) is highly effective against in vitro and in vivo survival of Mycobacterium tuberculosis and being an FDA-approved drug, it shows a potential for development of advanced combinatorial therapy against tuberculosis Mycobacterium tuberculosis

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.3.1.35 gene argJ, DNA and amino acid sequence determination and analysis, recombinant expression of His-tagged enzyme Mycobacterium tuberculosis

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.3.1.35 ethambutol
-
 Mycobacterium tuberculosis
2.3.1.35 isoniazid
-
 Mycobacterium tuberculosis
2.3.1.35 additional information structure-based inhibitor library screening and identification, overview. Molecular dynamics simulation results decipher a proposed mode of PRK/SRB binding to the allosteric pocket on MtArgJ Mycobacterium tuberculosis
2.3.1.35 pranlukast i.e. PRK, is an allosteric inhibitor of the arginine biosynthetic enzyme ornithine acetyltransferase (MtArgJ) in Mycobacterium tuberculosis. PRK treatment remarkably abates the survival of free as well as macrophage-internalized Mtb, and shows enhanced efficacy in combination with standard-of-care drugs. Notably, PRK also reduces the 5-lipoxygenase (5-LO) signaling in the infected macrophages, thereby surmounting an enhanced response against intracellular pathogen. Further, treatment with PRK alone or with rifampicin leads to significant decrease in Mtb burden and tubercular granulomas in Mycobacterium tuberculosis-infected mice lungs. The allosteric inhibitor of MtArgJ acts as a dual-edged sword, by targeting the intracellular bacteria as well as the bacterial pro-survival signaling in the host. PRK treatment reduces the infection-associated apoptosis in the host. PRK is highly effective against in vitro and in vivo survival of Mtb and being an FDA-approved drug, it shows a potential for development of advanced combinatorial therapy against tuberculosis. The selectivity and specificity of this inhibitor lies in its ability to allosterically modulate the substrate-binding interface, binding structure, overview. PRK also targets the host macrophage leukotriene signaling to limit the intracellular Mtb growth Mycobacterium tuberculosis
2.3.1.35 rifampicin
-
 Mycobacterium tuberculosis
2.3.1.35 sorafenib i.e. SRB, shows marked reduction in Mycobacterium tuberculosis survival in combination with standard-of-care anti-TB drugs Mycobacterium tuberculosis

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
2.3.1.35 0.0918
-
 N2-Acetyl-L-ornithine pH and temperature not specified in the publication Mycobacterium tuberculosis

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.3.1.35 N2-acetyl-L-ornithine + L-glutamate Mycobacterium tuberculosis
-
 L-ornithine + N-acetyl-L-glutamate
-
 ?
2.3.1.35 N2-acetyl-L-ornithine + L-glutamate Mycobacterium tuberculosis H37Rv
-
 L-ornithine + N-acetyl-L-glutamate
-
 ?
2.3.1.35 N2-acetyl-L-ornithine + L-glutamate Mycobacterium tuberculosis ATCC 25618
-
 L-ornithine + N-acetyl-L-glutamate
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.3.1.35 Mycobacterium tuberculosis P9WPZ3
-
-
2.3.1.35 Mycobacterium tuberculosis ATCC 25618 P9WPZ3
-
-
2.3.1.35 Mycobacterium tuberculosis H37Rv P9WPZ3
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
2.3.1.35 proteolytic modification enzyme MtArgJ belongs to the N-terminal nucleophile (Ntn) fold class of enzymes, synthesized as a 404-amino acid long protein, which undergoes an autoproteolysis event between the Ala199 and Thr200. This autoproteolysis generates two fragments of approximately equal size (20-21 kDa), which then associate to form a protomeric unit (AB-heterodimer; A2B2 tetramer-dimer of the heterodimer) Mycobacterium tuberculosis

Purification (Commentary)

EC Number Purification (Comment) Organism
2.3.1.35 recombinant His-tagged enzyme by nickel affinity chromatography Mycobacterium tuberculosis

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.3.1.35 N2-acetyl-L-ornithine + L-glutamate
-
 Mycobacterium tuberculosis L-ornithine + N-acetyl-L-glutamate
-
 ?
2.3.1.35 N2-acetyl-L-ornithine + L-glutamate
-
 Mycobacterium tuberculosis H37Rv L-ornithine + N-acetyl-L-glutamate
-
 ?
2.3.1.35 N2-acetyl-L-ornithine + L-glutamate
-
 Mycobacterium tuberculosis ATCC 25618 L-ornithine + N-acetyl-L-glutamate
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.3.1.35 argJ
-
 Mycobacterium tuberculosis
2.3.1.35 glutamate N-acetyltransferase
-
 Mycobacterium tuberculosis
2.3.1.35 OATase
-
 Mycobacterium tuberculosis
2.3.1.35 ornithine acetyltransferase
-
 Mycobacterium tuberculosis
2.3.1.35 ornithine transacetylase
-
 Mycobacterium tuberculosis

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
2.3.1.35 additional information
-
 additional information allosteric inhibition kinetics Mycobacterium tuberculosis
2.3.1.35 0.139
-
 pranlukast pH and temperature not specified in the publication, versus 1 mM of N2-acetyl-L-ornithine Mycobacterium tuberculosis
2.3.1.35 0.244
-
 sorafenib pH and temperature not specified in the publication, versus 1 mM of N2-acetyl-L-ornithine Mycobacterium tuberculosis

General Information

EC Number General Information Comment Organism
2.3.1.35 evolution the arginine biosynthesis bifunctional protein ArgJ is cleaved via autoproteolysis into the arginine biosynthesis bifunctional protein ArgJ alpha chain and the arginine biosynthesis bifunctional protein ArgJ beta chain, which include the activities of glutamate N-acetyltransferase (EC 2.3.1.35, i.e. ornithine acetyltransferase, OATase, or ornithine transacetylase) and amino-acid acetyltransferase (EC 2.3.1.1, i.e. N-acetylglutamate synthase or AGSase) Mycobacterium tuberculosis
2.3.1.35 malfunction enzyme inhibitor pranlukast (PRK) treatment remarkably abates the survival of free as well as macrophage-internalized Mtb, and shows enhanced efficacy in combination with standard-of-care drugs. Notably, PRK also reduces the 5-lipoxygenase (5-LO) signaling in the infected macrophages, thereby surmounting an enhanced response against intracellular pathogen. Further, treatment with PRK alone or with rifampicin leads to significant decrease in Mycobacterium tuberculosis burden and tubercular granulomas in Mtb-infected mice lungs. PRK-mediated killing of Mycobacterium tuberculosis is rescued upon arginine supplementation Mycobacterium tuberculosis
2.3.1.35 metabolism the enzyme is involved in the arginine biosynthetic pathway Mycobacterium tuberculosis
2.3.1.35 physiological function ArgJ in Mycobacterium tuberculosis is a monofunctional enzyme as it facilitates the transfer of acetyl group to glutamate exclusively from N-acetyl ornithine Mycobacterium tuberculosis