Biochemical, structural, and functional studies reveal that MAB_4324c from Mycobacterium abscessus is an active tandem repeat N-acetyltransferase

Husam M.A.B. Alsarraf; Kien Lam Ung; Matt D. Johansen; Juliette Dimon; Vincent Olieric; Laurent Kremer; Mickaël Blaise

doi:10.1002/1873-3468.14360

Biochemical, structural, and functional studies reveal that MAB_4324c from Mycobacterium abscessus is an active tandem repeat N-acetyltransferase

Husam M.A.B. Alsarraf, Kien Lam Ung, Matt D. Johansen, Juliette Dimon, Vincent Olieric, Laurent Kremer, Mickaël Blaise^*

^*Corresponding author for this work

Department of Molecular Biology and Genetics - Plant Molecular Biology

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

Mycobacterium abscessus is a pathogenic non-tuberculous mycobacterium that possesses an intrinsic drug resistance profile. Several N-acetyltransferases mediate drug resistance and/or participate in M. abscessus virulence. Mining the M. abscessus genome has revealed genes encoding additional N-acetyltransferases whose functions remain uncharacterized, among them MAB_4324c. Here, we showed that the purified MAB_4324c protein is a N-acetyltransferase able to acetylate small polyamine substrates. The crystal structure of MAB_4324c was solved at high resolution in complex with its cofactor, revealing the presence of two GCN5-related N-acetyltransferase domains and a cryptic binding site for NADPH. Genetic studies demonstrate that MAB_4324c is not essential for in vitro growth of M. abscessus; however, overexpression of the protein enhanced the uptake and survival of M. abscessus in THP-1 macrophages.

Original language	English
Journal	FEBS Letters
Volume	596
Issue	12
Pages (from-to)	1516-1532
Number of pages	17
ISSN	0014-5793
DOIs	https://doi.org/10.1002/1873-3468.14360
Publication status	Published - Jun 2022

Keywords

GCN5
infection
intracellular survival
macrophage
Mycobacterium abscessus
N-acetyltransferase
X-ray structure

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FEBS Letters - 2022 - Alsarraf - Biochemical structural and functional studies reveal that MAB 4324c from MycobacteriumFinal published version, 2.18 MBLicence: CC BY-NC-ND

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title = "Biochemical, structural, and functional studies reveal that MAB_4324c from Mycobacterium abscessus is an active tandem repeat N-acetyltransferase",

abstract = "Mycobacterium abscessus is a pathogenic non-tuberculous mycobacterium that possesses an intrinsic drug resistance profile. Several N-acetyltransferases mediate drug resistance and/or participate in M. abscessus virulence. Mining the M. abscessus genome has revealed genes encoding additional N-acetyltransferases whose functions remain uncharacterized, among them MAB_4324c. Here, we showed that the purified MAB_4324c protein is a N-acetyltransferase able to acetylate small polyamine substrates. The crystal structure of MAB_4324c was solved at high resolution in complex with its cofactor, revealing the presence of two GCN5-related N-acetyltransferase domains and a cryptic binding site for NADPH. Genetic studies demonstrate that MAB_4324c is not essential for in vitro growth of M. abscessus; however, overexpression of the protein enhanced the uptake and survival of M. abscessus in THP-1 macrophages.",

keywords = "GCN5, infection, intracellular survival, macrophage, Mycobacterium abscessus, N-acetyltransferase, X-ray structure",

author = "Alsarraf, {Husam M.A.B.} and Ung, {Kien Lam} and Johansen, {Matt D.} and Juliette Dimon and Vincent Olieric and Laurent Kremer and Micka{\"e}l Blaise",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.",

year = "2022",

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doi = "10.1002/1873-3468.14360",

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Biochemical, structural, and functional studies reveal that MAB_4324c from Mycobacterium abscessus is an active tandem repeat N-acetyltransferase. / Alsarraf, Husam M.A.B.; Ung, Kien Lam; Johansen, Matt D. et al.
In: FEBS Letters, Vol. 596, No. 12, 06.2022, p. 1516-1532.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Biochemical, structural, and functional studies reveal that MAB_4324c from Mycobacterium abscessus is an active tandem repeat N-acetyltransferase

AU - Alsarraf, Husam M.A.B.

AU - Ung, Kien Lam

AU - Johansen, Matt D.

AU - Dimon, Juliette

AU - Olieric, Vincent

AU - Kremer, Laurent

AU - Blaise, Mickaël

PY - 2022/6

Y1 - 2022/6

N2 - Mycobacterium abscessus is a pathogenic non-tuberculous mycobacterium that possesses an intrinsic drug resistance profile. Several N-acetyltransferases mediate drug resistance and/or participate in M. abscessus virulence. Mining the M. abscessus genome has revealed genes encoding additional N-acetyltransferases whose functions remain uncharacterized, among them MAB_4324c. Here, we showed that the purified MAB_4324c protein is a N-acetyltransferase able to acetylate small polyamine substrates. The crystal structure of MAB_4324c was solved at high resolution in complex with its cofactor, revealing the presence of two GCN5-related N-acetyltransferase domains and a cryptic binding site for NADPH. Genetic studies demonstrate that MAB_4324c is not essential for in vitro growth of M. abscessus; however, overexpression of the protein enhanced the uptake and survival of M. abscessus in THP-1 macrophages.

AB - Mycobacterium abscessus is a pathogenic non-tuberculous mycobacterium that possesses an intrinsic drug resistance profile. Several N-acetyltransferases mediate drug resistance and/or participate in M. abscessus virulence. Mining the M. abscessus genome has revealed genes encoding additional N-acetyltransferases whose functions remain uncharacterized, among them MAB_4324c. Here, we showed that the purified MAB_4324c protein is a N-acetyltransferase able to acetylate small polyamine substrates. The crystal structure of MAB_4324c was solved at high resolution in complex with its cofactor, revealing the presence of two GCN5-related N-acetyltransferase domains and a cryptic binding site for NADPH. Genetic studies demonstrate that MAB_4324c is not essential for in vitro growth of M. abscessus; however, overexpression of the protein enhanced the uptake and survival of M. abscessus in THP-1 macrophages.

KW - GCN5

KW - infection

KW - intracellular survival

KW - macrophage

KW - Mycobacterium abscessus

KW - N-acetyltransferase

KW - X-ray structure

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Biochemical, structural, and functional studies reveal that MAB_4324c from Mycobacterium abscessus is an active tandem repeat N-acetyltransferase

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