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Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa)
Low-molecular-weight protein tyrosine phosphatases (LMW-PTPs) are involved in promoting the intracellular survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis. These PTPs directly alter host signalling pathways to evade the hostile environment of macrophages and avoid...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526854/ https://www.ncbi.nlm.nih.gov/pubmed/37754203 http://dx.doi.org/10.3390/biotech12030059 |
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author | Sulyman, Abdulhakeem O. Fulcher, Jessie Crossley, Samuel Fatokun, Amos A. Olorunniji, Femi J. |
author_facet | Sulyman, Abdulhakeem O. Fulcher, Jessie Crossley, Samuel Fatokun, Amos A. Olorunniji, Femi J. |
author_sort | Sulyman, Abdulhakeem O. |
collection | PubMed |
description | Low-molecular-weight protein tyrosine phosphatases (LMW-PTPs) are involved in promoting the intracellular survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis. These PTPs directly alter host signalling pathways to evade the hostile environment of macrophages and avoid host clearance. Among these, protein tyrosine phosphatase A (Mt-PTPa) is implicated in phagosome acidification failure, thereby inhibiting phagosome maturation to promote Mycobacterium tuberculosis (Mtb) survival. In this study, we explored Mt-PTPa as a potential drug target for treating Mtb. We started by screening a library of 502 pure natural compounds against the activities of Mt-PTPa in vitro, with a threshold of 50% inhibition of activity via a <500 µM concentration of the candidate drugs. The initial screen identified epigallocatechin, myricetin, rosmarinic acid, and shikonin as hits. Among these, the naphthoquinone, shikonin (5, 8-dihydroxy-2-[(1R)-1-hydroxy-4-methyl-3-pentenyl]-1,4-naphthoquinone), showed the strongest inhibition (IC(50) 33 µM). Further tests showed that juglone (5-hydroxy-1,4-naphthalenedione), another naphthoquinone, displayed similar potent inhibition of Mt-PTPa to shikonin. Kinetic analysis of the inhibition patterns suggests a non-competitive inhibition mechanism for both compounds, with inhibitor constants (Ki) of 8.5 µM and 12.5 µM for shikonin and juglone, respectively. Our findings are consistent with earlier studies suggesting that Mt-PTPa is susceptible to specific allosteric modulation via a non-competitive or mixed inhibition mechanism. |
format | Online Article Text |
id | pubmed-10526854 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-105268542023-09-28 Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa) Sulyman, Abdulhakeem O. Fulcher, Jessie Crossley, Samuel Fatokun, Amos A. Olorunniji, Femi J. BioTech (Basel) Article Low-molecular-weight protein tyrosine phosphatases (LMW-PTPs) are involved in promoting the intracellular survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis. These PTPs directly alter host signalling pathways to evade the hostile environment of macrophages and avoid host clearance. Among these, protein tyrosine phosphatase A (Mt-PTPa) is implicated in phagosome acidification failure, thereby inhibiting phagosome maturation to promote Mycobacterium tuberculosis (Mtb) survival. In this study, we explored Mt-PTPa as a potential drug target for treating Mtb. We started by screening a library of 502 pure natural compounds against the activities of Mt-PTPa in vitro, with a threshold of 50% inhibition of activity via a <500 µM concentration of the candidate drugs. The initial screen identified epigallocatechin, myricetin, rosmarinic acid, and shikonin as hits. Among these, the naphthoquinone, shikonin (5, 8-dihydroxy-2-[(1R)-1-hydroxy-4-methyl-3-pentenyl]-1,4-naphthoquinone), showed the strongest inhibition (IC(50) 33 µM). Further tests showed that juglone (5-hydroxy-1,4-naphthalenedione), another naphthoquinone, displayed similar potent inhibition of Mt-PTPa to shikonin. Kinetic analysis of the inhibition patterns suggests a non-competitive inhibition mechanism for both compounds, with inhibitor constants (Ki) of 8.5 µM and 12.5 µM for shikonin and juglone, respectively. Our findings are consistent with earlier studies suggesting that Mt-PTPa is susceptible to specific allosteric modulation via a non-competitive or mixed inhibition mechanism. MDPI 2023-09-20 /pmc/articles/PMC10526854/ /pubmed/37754203 http://dx.doi.org/10.3390/biotech12030059 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sulyman, Abdulhakeem O. Fulcher, Jessie Crossley, Samuel Fatokun, Amos A. Olorunniji, Femi J. Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa) |
title | Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa) |
title_full | Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa) |
title_fullStr | Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa) |
title_full_unstemmed | Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa) |
title_short | Shikonin and Juglone Inhibit Mycobacterium tuberculosis Low-Molecular-Weight Protein Tyrosine Phosphatase a (Mt-PTPa) |
title_sort | shikonin and juglone inhibit mycobacterium tuberculosis low-molecular-weight protein tyrosine phosphatase a (mt-ptpa) |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526854/ https://www.ncbi.nlm.nih.gov/pubmed/37754203 http://dx.doi.org/10.3390/biotech12030059 |
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