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The Key Roles of Mycobacterium tuberculosis FadD23 C-terminal Domain in Catalytic Mechanisms

Sulfolipid-1 (SL-1) is located in the Mycobacterium tuberculosis (M. tb) cell wall, and is essential for pathogen virulence and intracellular growth. Multiple proteins (e.g., Pks2, FadD23, PapA1, and MmpL8) in the SL-1 synthesis pathway can be treated as drug targets, but, to date, their structures...

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Autores principales: Yan, Mengrong, Cao, Lin, Zhao, Li, Zhou, Weihong, Liu, Xiang, Zhang, Wei, Rao, Zihe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9989471/
https://www.ncbi.nlm.nih.gov/pubmed/36896429
http://dx.doi.org/10.3389/fmicb.2023.1090534
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author Yan, Mengrong
Cao, Lin
Zhao, Li
Zhou, Weihong
Liu, Xiang
Zhang, Wei
Rao, Zihe
author_facet Yan, Mengrong
Cao, Lin
Zhao, Li
Zhou, Weihong
Liu, Xiang
Zhang, Wei
Rao, Zihe
author_sort Yan, Mengrong
collection PubMed
description Sulfolipid-1 (SL-1) is located in the Mycobacterium tuberculosis (M. tb) cell wall, and is essential for pathogen virulence and intracellular growth. Multiple proteins (e.g., Pks2, FadD23, PapA1, and MmpL8) in the SL-1 synthesis pathway can be treated as drug targets, but, to date, their structures have not been solved. The crystal structures of FadD23 bound to ATP or hexadecanoyl adenylate was determined in this study. We have also investigated long-chain saturated fatty acids as biological substrates of FadD23 through structural, biological, and chemical analyses. The mutation at the active site of FadD23 greatly influences enzymatic activity. Meanwhile, the FadD23 N-terminal domain alone cannot bind palmitic acid without C-terminal domain facilitation since it is almost inactive after removing the C-terminal domain. FadD23 is the first protein in the SL-1 synthesis pathway whose structure has been solved. These results reveal the importance of the C-terminal domain in the catalytic mechanism.
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spelling pubmed-99894712023-03-08 The Key Roles of Mycobacterium tuberculosis FadD23 C-terminal Domain in Catalytic Mechanisms Yan, Mengrong Cao, Lin Zhao, Li Zhou, Weihong Liu, Xiang Zhang, Wei Rao, Zihe Front Microbiol Microbiology Sulfolipid-1 (SL-1) is located in the Mycobacterium tuberculosis (M. tb) cell wall, and is essential for pathogen virulence and intracellular growth. Multiple proteins (e.g., Pks2, FadD23, PapA1, and MmpL8) in the SL-1 synthesis pathway can be treated as drug targets, but, to date, their structures have not been solved. The crystal structures of FadD23 bound to ATP or hexadecanoyl adenylate was determined in this study. We have also investigated long-chain saturated fatty acids as biological substrates of FadD23 through structural, biological, and chemical analyses. The mutation at the active site of FadD23 greatly influences enzymatic activity. Meanwhile, the FadD23 N-terminal domain alone cannot bind palmitic acid without C-terminal domain facilitation since it is almost inactive after removing the C-terminal domain. FadD23 is the first protein in the SL-1 synthesis pathway whose structure has been solved. These results reveal the importance of the C-terminal domain in the catalytic mechanism. Frontiers Media S.A. 2023-02-21 /pmc/articles/PMC9989471/ /pubmed/36896429 http://dx.doi.org/10.3389/fmicb.2023.1090534 Text en Copyright © 2023 Yan, Cao, Zhao, Zhou, Liu, Zhang and Rao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Yan, Mengrong
Cao, Lin
Zhao, Li
Zhou, Weihong
Liu, Xiang
Zhang, Wei
Rao, Zihe
The Key Roles of Mycobacterium tuberculosis FadD23 C-terminal Domain in Catalytic Mechanisms
title The Key Roles of Mycobacterium tuberculosis FadD23 C-terminal Domain in Catalytic Mechanisms
title_full The Key Roles of Mycobacterium tuberculosis FadD23 C-terminal Domain in Catalytic Mechanisms
title_fullStr The Key Roles of Mycobacterium tuberculosis FadD23 C-terminal Domain in Catalytic Mechanisms
title_full_unstemmed The Key Roles of Mycobacterium tuberculosis FadD23 C-terminal Domain in Catalytic Mechanisms
title_short The Key Roles of Mycobacterium tuberculosis FadD23 C-terminal Domain in Catalytic Mechanisms
title_sort key roles of mycobacterium tuberculosis fadd23 c-terminal domain in catalytic mechanisms
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9989471/
https://www.ncbi.nlm.nih.gov/pubmed/36896429
http://dx.doi.org/10.3389/fmicb.2023.1090534
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