Human N-Acetyltransferase 1 and 2 Differ in Affinity Towards Acetyl-Coenzyme A Cofactor and N-Hydroxy-Arylamine Carcinogens

Hein, David W.; Doll, Mark A.; Habil, Mariam R.

doi:10.3389/fphar.2022.821133

Cited by 5 publications

(5 citation statements)

References 39 publications

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“…Arylamine N-acetyltransferase comprises N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) in humans (Hein et al, 2022). NAT2 is mainly expressed in the liver and the GI tract (Husain et al, 2007), and is responsible for the N-acetylation polymorphism observed in human populations (Weber and Hein, 1985;McDonagh et al, 2014;Agundez and Garcia-Martin, 2018;Mitchell, 2020).…”

Section: N-acetyltransferase Acetylation Polymorphisms and Tb Treatme...mentioning

confidence: 99%

The role of Mycobacterium tuberculosis acetyltransferase and protein acetylation modifications in tuberculosis

Huang¹,

Zhu²,

Pan³

et al. 2023

Front. Cell. Infect. Microbiol.

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Tuberculosis (TB) is a widespread infectious disease caused by Mycobacterium tuberculosis (M. tb), which has been a significant burden for a long time. Post-translational modifications (PTMs) are essential for protein function in both eukaryotic and prokaryotic cells. This review focuses on the contribution of protein acetylation to the function of M. tb and its infected macrophages. The acetylation of M. tb proteins plays a critical role in virulence, drug resistance, regulation of metabolism, and host anti-TB immune response. Similarly, the PTMs of host proteins induced by M. tb are crucial for the development, treatment, and prevention of diseases. Host protein acetylation induced by M. tb is significant in regulating host immunity against TB, which substantially affects the disease’s development. The review summarizes the functions and mechanisms of M. tb acetyltransferase in virulence and drug resistance. It also discusses the role and mechanism of M. tb in regulating host protein acetylation and immune response regulation. Furthermore, the current scenario of isoniazid usage in M. tb therapy treatment is examined. Overall, this review provides valuable information that can serve as a preliminary basis for studying pathogenic research, developing new drugs, exploring in-depth drug resistance mechanisms, and providing precise treatment for TB.

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Section: N-acetyltransferase Acetylation Polymorphisms and Tb Treatme...mentioning

confidence: 99%

The role of Mycobacterium tuberculosis acetyltransferase and protein acetylation modifications in tuberculosis

Huang¹,

Zhu²,

Pan³

et al. 2023

Front. Cell. Infect. Microbiol.

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“…Recently, Hein et al reported a difference in the affinity of acetyl-CoA for NAT1 and NAT2 (Hein et al, 2022). Using various substrates, they quantified the apparent acetyl-CoA Km for both enzymes and then inferred differences in binding affinity.…”

Section: F the Interaction Of The Nats With Acetyl-coamentioning

confidence: 99%

“…The relationship between Km and binding affinity for a double displacement reaction is complex as the Km is dependent on the off-rate of the acetylated substrate (Minchin and Butcher, 2015;Wang et al, 2005). In the study by Hein et al, the off-rates, at least for two substrates (N-hydroxy-aminofluorene and Nhydroxy-animobiphenyl), were much slower for NAT1 than for NAT2 (Hein et al, 2022). However, this does not explain the differences in acetyl-CoA apparent Km, supporting the conclusion that it has a higher affinity for NAT1 than NAT2.…”

Section: F the Interaction Of The Nats With Acetyl-coamentioning

confidence: 99%

The Arylamine N-Acetyltransferases as Therapeutic Targets in Metabolic Diseases Associated with Mitochondrial Dysfunction

Choudhury,

Gill,

McAleese

et al. 2023

Pharmacol Rev

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In humans, there are two arylamine N-acetyltransferase genes that encode functional enzymes (NAT1 and NAT2) as well as one pseudogene, all of which are located together on chromosome 8. While they were first identified by their role in the acetylation of drugs and other xenobiotics, recent studies have shown strong associations for both enzymes in a variety of diseases including cancer, cardiovascular disease, and diabetes. There is growing evidence that this association may be causal. Consistently, NAT1 and NAT2 are shown to be required for healthy mitochondria. This review discusses the current literature on the role of both NAT1 and NAT2 in mitochondrial bioenergetics. It will attempt to relate our understanding of the evolution of the two genes with biological function and then present evidence that several major metabolic diseases are influenced by NAT1 and NAT2. Finally, it will discuss current and future approaches to inhibit or enhance NAT1 and NAT2 activity/expression using small molecule drugs. Significance statementThe arylamine N-acetyltransferases, NAT1 and NAT2, share common features in their associations with mitochondrial bioenergetics. Together, they are potential drug targets for diseases where mitochondrial dysfunction is a hallmark of onset and progression.

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“…DNA adducts not repaired can result in mutations leading to cancer ( Wang et al, 2019 ; NTP, 2021 ). NAT1 catalyzes ABP N-acetyltransferase and N-OH-ABP O-acetyltransferase activities ( Hein et al, 1993 ; Millner et al, 2012 ; Zhou et al, 2013 ; Leggett et al, 2021 ; Leggett et al, 2022 ; Hein et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…NAT1 is selective for acetylation of 4-alkylanilines due to binding to V216, which is replaced by S216 in NAT2 ( Liu et al, 2007 ). NAT1 exhibits higher affinity than NAT2 for the O-acetylation of N-hydroxy-arylamine carcinogens such as N-OH-ABP ( Hein et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

560G>A (rs4986782) (R187Q) Single Nucleotide Polymorphism in Arylamine N-Acetyltransferase 1 Increases Affinity for the Aromatic Amine Carcinogens 4-Aminobiphenyl and N-Hydroxy-4-Aminobiphenyl: Implications for Cancer Risk Assessment

Doll

Hein

2022

Front. Pharmacol.

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Human arylamine N-acetyltransferase 1 (NAT1) catalyzes the N-acetylation of arylamine carcinogens such as 4-aminobiphenyl (ABP), and following N-hydroxylation, the O-acetylation of N-hydroxy-arylamine carcinogens such as N-hydroxy-ABP (N-OH-ABP). Genetic polymorphisms in NAT1 are linked to cancer susceptibility following exposures. The effects of individual single nucleotide polymorphisms (SNPs) in the NAT1 coding exon on Michaelis-Menten kinetic constants was assessed for ABP N-acetyltransferase and N-OH-ABP O-acetyltransferase activity following transfection of human NAT1 into COS-1 cells (SV40-transformed African green monkey kidney cells). NAT1 coding region SNPs 97C > T (rs56318881) (R33stop), 190C > T (rs56379106) (R64W), 559C > T (rs5030839) (R187stop) and 752A > T (rs56172717) (D251V) reduced ABP N- acetyltransferase and N-OH-ABP O-acetyltransferase activity below detection. 21T > G (rs4986992) (synonymous), 402T > C (rs146727732) (synonymous), 445G > A (rs4987076) (V149I), 613A > G (rs72554609) (M205V) and 640T > G (rs4986783) (S241A) did not significantly affect Vmax for ABP N-acetyltransferase or N-OH-ABP O-acetyltransferase. 781G > A (rs72554610) (E261K), and 787A > G (rs72554611) (I263V) slightly reduced ABP N-acetyltransferase and N-OH-ABP O-acetyltransferase activities whereas 560G > A (rs4986782) (R187Q) substantially and significantly reduced them. 560G > A (rs4986782) (R187Q) significantly reduced the apparent Km for ABP and N-OH-ABP a finding that was not observed with any of the other NAT1 SNPs tested. These findings suggest that the role of the 560G > A (rs4986782) (R187Q) SNP cancer risk assessment may be modified by exposure level to aromatic amine carcinogens such as ABP.

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Human N-Acetyltransferase 1 and 2 Differ in Affinity Towards Acetyl-Coenzyme A Cofactor and N-Hydroxy-Arylamine Carcinogens

Cited by 5 publications

References 39 publications

The role of Mycobacterium tuberculosis acetyltransferase and protein acetylation modifications in tuberculosis

The role of Mycobacterium tuberculosis acetyltransferase and protein acetylation modifications in tuberculosis

The Arylamine N-Acetyltransferases as Therapeutic Targets in Metabolic Diseases Associated with Mitochondrial Dysfunction

560G>A (rs4986782) (R187Q) Single Nucleotide Polymorphism in Arylamine N-Acetyltransferase 1 Increases Affinity for the Aromatic Amine Carcinogens 4-Aminobiphenyl and N-Hydroxy-4-Aminobiphenyl: Implications for Cancer Risk Assessment

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