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Literature summary for 2.3.1.35 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
Search for more literature for 2.3.1.35

Application

Application Comment Organism
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)

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

Inhibitors

Inhibitors Comment Organism Structure
ethambutol
-
 Mycobacterium tuberculosis
isoniazid
-
 Mycobacterium tuberculosis
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
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
rifampicin
-
 Mycobacterium tuberculosis
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]

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

Natural Substrates/ Products (Substrates)

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

Organism

Organism UniProt Comment Textmining
Mycobacterium tuberculosis P9WPZ3
-
-
Mycobacterium tuberculosis ATCC 25618 P9WPZ3
-
-
Mycobacterium tuberculosis H37Rv P9WPZ3
-
-

Posttranslational Modification

Posttranslational Modification Comment Organism
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)

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

Substrates and Products (Substrate)

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

Synonyms

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

Ki Value [mM]

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

General Information

General Information Comment Organism
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
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
metabolism the enzyme is involved in the arginine biosynthetic pathway Mycobacterium tuberculosis
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