Mycobacterium tuberculosis Protein Tyrosine Phosphatase PtpB Structure Reveals a Diverged Fold and a Buried Active Site

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Protein tyrosine phosphatase 1B (PTP1B) is a validated target for the treatment of type 2 diabetes and obesity. The discovery of selective inhibitors with drug-like properties has proven to be challenging because there are [about]80 PTP family members that share a similar and positively charged active site. To overcome these challenges, we have pursued two novel approaches for the covalent inactivation of PTP1B. Exo-affinity labeling agents exploit covalent reactions with amino acids outside the enzyme active site to gain both affinity and selectivity. We prepared several affinity labeling agents using a 12-step convergent synthesis. Enzyme assays revealed that some of these agents are capable of inactivating the enzyme by covalent modification. In another project, we prepared a low molecular weight mimic of the oxidized form of PTP1B that is generated in cells, during insulin signaling events. Seeking molecules capable of covalent capture of oxidized PTP1B, we treated this chemical model with several carbon nucleophiles, such as 1,3-diketones and sulfone-stabilized carbon anions. These carbon nucleophiles readily reacted with the model compound, under mild conditions to give stable adducts. Inactivation experiments revealed that 1,3-diketones are capable of inactivating the oxidized PTP1B at micromolar concentrations.

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ATP synthase, an essential enzyme in growth and multiplication is modulated by protein tyrosine phosphatase in Mycobacterium tuberculosis H37Ra

Biochimie ◽

10.1016/j.biochi.2019.07.023 ◽

2019 ◽

Vol 165 ◽

pp. 156-160 ◽

Cited By ~ 1

Author(s):

Aditi Chatterjee ◽

Sapna Pandey ◽

Ekta Dhamija ◽

Swati Jaiswal ◽

Shivraj M. Yabaji ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Atp Synthase ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Protein Tyrosine ◽

Essential Enzyme

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Sydowiols A–C: Mycobacterium tuberculosis protein tyrosine phosphatase inhibitors from an East China Sea marine-derived fungus, Aspergillus sydowii

Tetrahedron Letters ◽

10.1016/j.tetlet.2013.08.137 ◽

2013 ◽

Vol 54 (45) ◽

pp. 6081-6083 ◽

Cited By ~ 20

Author(s):

Xinru Liu ◽

Fuhang Song ◽

Li Ma ◽

Caixia Chen ◽

Xue Xiao ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

East China Sea ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

East China ◽

Aspergillus Sydowii ◽

Phosphatase Inhibitors ◽

Protein Tyrosine ◽

China Sea

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Crystal Structure of Low-Molecular-Weight Protein Tyrosine Phosphatase from Mycobacterium tuberculosis at 1.9-Å Resolution

Journal of Bacteriology ◽

10.1128/jb.187.6.2175-2181.2005 ◽

2005 ◽

Vol 187 (6) ◽

pp. 2175-2181 ◽

Cited By ~ 53

Author(s):

Chaithanya Madhurantakam ◽

Eerappa Rajakumara ◽

Pooja Anjali Mazumdar ◽

Baisakhee Saha ◽

Devrani Mitra ◽

...

Keyword(s):

Protein Tyrosine Phosphatase ◽

Active Site ◽

Tyrosine Phosphatase ◽

Chloride Ion ◽

Low Molecular Weight ◽

Molecular Weight Protein ◽

Substrate Specificities ◽

Protein Tyrosine ◽

Weight Protein ◽

Low Molecular Weight Protein

ABSTRACT The low-molecular-weight protein tyrosine phosphatase (LMWPTPase) belongs to a distinctive class of phosphotyrosine phosphatases widely distributed among prokaryotes and eukaryotes. We report here the crystal structure of LMWPTPase of microbial origin, the first of its kind from Mycobacterium tuberculosis. The structure was determined to be two crystal forms at 1.9- and 2.5-Å resolutions. These structural forms are compared with those of the LMWPTPases of eukaryotes. Though the overall structure resembles that of the eukaryotic LMWPTPases, there are significant changes around the active site and the protein tyrosine phosphatase (PTP) loop. The variable loop forming the wall of the crevice leading to the active site is conformationally unchanged from that of mammalian LMWPTPase; however, differences are observed in the residues involved, suggesting that they have a role in influencing different substrate specificities. The single amino acid substitution (Leu12Thr [underlined below]) in the consensus sequence of the PTP loop, C T GNICRS, has a major role in the stabilization of the PTP loop, unlike what occurs in mammalian LMWPTPases. A chloride ion and a glycerol molecule were modeled in the active site where the chloride ion interacts in a manner similar to that of phosphate with the main chain nitrogens of the PTP loop. This structural study, in addition to identifying specific mycobacterial features, may also form the basis for exploring the mechanism of the substrate specificities of bacterial LMWPTPases.

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