The Molecular Structure of Ornithine Acetyltransferase from Mycobacterium tuberculosis Bound to Ornithine, a Competitive Inhibitor

Sankaranarayanan, R.; Cherney, M.M.; Garen, Craig R.; Garen, Grace; Niu, Cuijuan; Yuan, Marshall; James, Michael N.G.

doi:10.1016/j.jmb.2010.02.018

Cited by 19 publications

(17 citation statements)

References 40 publications

(56 reference statements)

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“…Mt ArgJ belongs to the N‐terminal nucleophile (Ntn) fold class of enzymes, synthesized as a 404‐amino acid long protein, which undergoes an auto‐proteolysis event between the Ala199 and Thr200. This auto‐proteolysis 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; Sankaranarayanan et al , ). The affinity‐purified His‐tagged Mt ArgJ thus yields three distinct bands on SDS–PAGE, one full‐length and two cleaved products (20 and 21 kDa each; Fig B; Marc et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…Mycobacterium tuberculosis argJ gene is encoded by the ORF Rv1653 and belongs to the N‐terminal nucleophile fold family of enzymes (Cole et al , ; Xu et al , ). The crystal structure of Mt ArgJ in native form and in complex with Ornithine has been determined at 1.7 and 2.4 Å, respectively (Sankaranarayanan et al , ). ArgJ in Mtb is a mono‐functional enzyme as it facilitates the transfer of acetyl group to glutamate exclusively from N‐acetyl Ornithine.…”

Section: Introductionmentioning

confidence: 99%

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An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy

et al. 2018

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The existing treatment regime against tuberculosis is not adequate, and novel therapeutic interventions are required to target Mycobacterium tuberculosis (Mtb) pathogenesis. We report Pranlukast (PRK) as a novel allosteric inhibitor of Mtb's arginine biosynthetic enzyme, Ornithine acetyltransferase (MtArgJ). 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 Mtb‐infected mice lungs. Taken together, this study demonstrates a novel allosteric inhibitor of MtArgJ, which acts as a dual‐edged sword, by targeting the intracellular bacteria as well as the bacterial pro‐survival signaling 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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy

et al. 2018

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“…BapA hydrolyzes ␤-oligopeptides and mixed ␤/␣-oligopeptides with a ␤-amino acid residue at the N terminus (20). OAT is involved in the arginine biosynthetic pathway because it catalyzes the transfer of an acetyl group from N-acetylornithine to glutamate (21,22). In contrast, NylC p2 hydrolyzes Ahx cyclic and linear oligomers (degree of polymerization Ͼ3) but has no detectable activity with the 66 peptides tested (supplemental Table S4), including D,L-Ala-Gly-Gly (14,15).…”

Section: Subunit Structure and Function Relationship With Other N-tn mentioning

confidence: 99%

Three-dimensional Structure of Nylon Hydrolase and Mechanism of Nylon-6 Hydrolysis

Negoro

Shibata

Tanaka

et al. 2012

Journal of Biological Chemistry

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Background: Biodegradation of polyamides is important from the industrial and environmental point of view. Results: We identified the catalytic residue of nylon hydrolase as Thr-267 and enhanced the protein thermostability by 36°C (T m ϭ 88°C) by introducing mutations at the subunit interfaces of tetramer structure. Conclusion:We revealed the mechanism of nylon-6 hydrolysis. Significance: We established an approach to biodegrade polymeric nylon-6.

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“…Recently, we solved the 1.7 Å structure of native Mtb OAT (PDB code 3IT4), which reveals the conserved fold of the N-terminal nucleophile family of enzymes 69 . Additionally, we reported the first 2.4 Å binary complex of Mtb OAT bound to ornithine (ORN, PDB code 3IT6) 69 , a competitive inhibitor against the cognate substrate, L-glutamate. The monomer of Mtb OAT, which consists of 404 amino acid residues, splits into two halves forming a two-domain architecture; Domain I (residues 1-284) and Domain II (residues 285-404).…”

Section: Structure Of Ornithine Acetyltransferase (Oat) From Mtbmentioning

confidence: 99%

The TB Structural Genomics Consortium: A decade of progress

et al. 2011

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Summary The TB Structural Genomics Consortium is a worldwide organization of collaborators whose mission is the comprehensive structural determination and analyses of Mycobacterium tuberculosis proteins to ultimately aid in tuberculosis diagnosis and treatment. Congruent to the overall vision, Consortium members have additionally established an integrated facilities core to streamline M. tuberculosis structural biology and developed bioinformatics resources for data mining. This review aims to share the latest Consortium developments with the TB community, including recent structures of proteins that play significant roles within M. tuberculosis. Atomic resolution details may unravel mechanistic insights and reveal unique and novel protein features, as well as important protein-protein and protein-ligand interactions, which ultimately leads to a better understanding of M. tuberculosis biology and may be exploited for rational, structure-based therapeutics design.

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The Molecular Structure of Ornithine Acetyltransferase from Mycobacterium tuberculosis Bound to Ornithine, a Competitive Inhibitor

Cited by 19 publications

References 40 publications

An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy

An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy

Three-dimensional Structure of Nylon Hydrolase and Mechanism of Nylon-6 Hydrolysis

The TB Structural Genomics Consortium: A decade of progress

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