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Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase

Mycobacterium tuberculosis modulates expression of various metabolism-related genes to adapt in the adverse host environment. The gene coding for M. tuberculosis S-adenosylhomocysteine hydrolase (Mtb-SahH) is essential for optimal growth and the protein product is involved in intermediary metabolism...

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Autores principales: Singhal, Anshika, Arora, Gunjan, Sajid, Andaleeb, Maji, Abhijit, Bhat, Ajay, Virmani, Richa, Upadhyay, Sandeep, Nandicoori, Vinay K., Sengupta, Shantanu, Singh, Yogendra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719076/
https://www.ncbi.nlm.nih.gov/pubmed/23877358
http://dx.doi.org/10.1038/srep02264
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author Singhal, Anshika
Arora, Gunjan
Sajid, Andaleeb
Maji, Abhijit
Bhat, Ajay
Virmani, Richa
Upadhyay, Sandeep
Nandicoori, Vinay K.
Sengupta, Shantanu
Singh, Yogendra
author_facet Singhal, Anshika
Arora, Gunjan
Sajid, Andaleeb
Maji, Abhijit
Bhat, Ajay
Virmani, Richa
Upadhyay, Sandeep
Nandicoori, Vinay K.
Sengupta, Shantanu
Singh, Yogendra
author_sort Singhal, Anshika
collection PubMed
description Mycobacterium tuberculosis modulates expression of various metabolism-related genes to adapt in the adverse host environment. The gene coding for M. tuberculosis S-adenosylhomocysteine hydrolase (Mtb-SahH) is essential for optimal growth and the protein product is involved in intermediary metabolism. However, the relevance of SahH in mycobacterial physiology is unknown. In this study, we analyze the role of Mtb-SahH in regulating homocysteine concentration in surrogate host Mycobacterium smegmatis. Mtb-SahH catalyzes reversible hydrolysis of S-adenosylhomocysteine to homocysteine and adenosine and we demonstrate that the conserved His363 residue is critical for bi-directional catalysis. Mtb-SahH is regulated by serine/threonine phosphorylation of multiple residues by M. tuberculosis PknB. Major phosphorylation events occur at contiguous residues Thr219, Thr220 and Thr221, which make pivotal contacts with cofactor NAD(+). Consequently, phosphorylation negatively modulates affinity of enzyme towards NAD(+) as well as SAH-synthesis. Thr219, Thr220 and Thr221 are essential for enzyme activity, and therefore, responsible for SahH-mediated regulation of homocysteine.
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spelling pubmed-37190762013-07-23 Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase Singhal, Anshika Arora, Gunjan Sajid, Andaleeb Maji, Abhijit Bhat, Ajay Virmani, Richa Upadhyay, Sandeep Nandicoori, Vinay K. Sengupta, Shantanu Singh, Yogendra Sci Rep Article Mycobacterium tuberculosis modulates expression of various metabolism-related genes to adapt in the adverse host environment. The gene coding for M. tuberculosis S-adenosylhomocysteine hydrolase (Mtb-SahH) is essential for optimal growth and the protein product is involved in intermediary metabolism. However, the relevance of SahH in mycobacterial physiology is unknown. In this study, we analyze the role of Mtb-SahH in regulating homocysteine concentration in surrogate host Mycobacterium smegmatis. Mtb-SahH catalyzes reversible hydrolysis of S-adenosylhomocysteine to homocysteine and adenosine and we demonstrate that the conserved His363 residue is critical for bi-directional catalysis. Mtb-SahH is regulated by serine/threonine phosphorylation of multiple residues by M. tuberculosis PknB. Major phosphorylation events occur at contiguous residues Thr219, Thr220 and Thr221, which make pivotal contacts with cofactor NAD(+). Consequently, phosphorylation negatively modulates affinity of enzyme towards NAD(+) as well as SAH-synthesis. Thr219, Thr220 and Thr221 are essential for enzyme activity, and therefore, responsible for SahH-mediated regulation of homocysteine. Nature Publishing Group 2013-07-23 /pmc/articles/PMC3719076/ /pubmed/23877358 http://dx.doi.org/10.1038/srep02264 Text en Copyright © 2013, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Article
Singhal, Anshika
Arora, Gunjan
Sajid, Andaleeb
Maji, Abhijit
Bhat, Ajay
Virmani, Richa
Upadhyay, Sandeep
Nandicoori, Vinay K.
Sengupta, Shantanu
Singh, Yogendra
Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase
title Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase
title_full Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase
title_fullStr Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase
title_full_unstemmed Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase
title_short Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase
title_sort regulation of homocysteine metabolism by mycobacterium tuberculosis s-adenosylhomocysteine hydrolase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719076/
https://www.ncbi.nlm.nih.gov/pubmed/23877358
http://dx.doi.org/10.1038/srep02264
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