10.1002/anie.202005915
Angewandte Chemie International Edition
COMMUNICATION
[2]
[3]
[4]
A. Husain, X. Y. Zhang, M. A. Doll, J. C. States, D. F. Barker, D. W.
Hein, Drug Metab. Dispos. 2007, 35, 721-727.
E. M. McDonagh, S. Boukouvala, E. Aklillu, D. W. Hein, R. B. Altman,
T. E. Klein, Pharmacogenet. Genomics 2014, 24, 409-425.
a) D. M. Grant, N. C. Hughes, S. A. Janezic, G. H. Goodfellow, H. J.
Chen, A. Gaedigk, V. L. Yu, R. Grewal, Mutat. Res. 1997, 376, 61-70;
b) D. W. Hein, Mutat. Res. 2002, 506-507, 65-77.
[5]
[6]
[7]
C. Genomes Project, A. Auton, L. D. Brooks, R. M. Durbin, E. P.
Garrison, H. M. Kang, J. O. Korbel, J. L. Marchini, S. McCarthy, G. A.
McVean, G. R. Abecasis, Nature 2015, 526, 68-74.
M. Kinzig-Schippers, D. Tomalik-Scharte, A. Jetter, B. Scheidel, V.
Jakob, M. Rodamer, I. Cascorbi, O. Doroshyenko, F. Sorgel, U. Fuhr,
Antimicrob. Agents Chemother. 2005, 49, 1733-1738.
J. R. Palamanda, D. Hickman, A. Ward, E. Sim, M. Romkes-Sparks, J.
D. Unadkat, Drug Metab. Dispos. 1995, 23, 473-477.
[8]
[9]
J. A. G. Agundez, Curr. Drug Metab. 2008, 9, 520-531.
a) M. Matejcic, M. Vogelsang, Y. B. Wang, I. M. Parker, BMC Cancer
2015, 15; b) X. J. Ying, P. Dong, B. Shen, J. Wang, S. Wang, G. Wang,
J. Cancer Res. Clin. Oncol. 2011, 137, 1661-1667.
[10]
[11]
a) V. Rendo, et al., Nat Commun 2020, 11, 1308; b) C. H. Johnson, J.
Ivanisevic, G. Siuzdak, Nat. Rev. Mol. Cell Biol. 2016, 17, 451-459.
a) D. Globisch, D. Pearson, A. Hienzsch, T. Brückl, M. Wagner, I.
Thoma, P. Thumbs, V. Reiter, A. C. Kneuttinger, M. Müller, S. A.
Sieber, T. Carell, Angew. Chem. Int. Ed. 2011, 50, 9739-9742; b) D.
Globisch, A. Y. Moreno, M. S. Hixon, A. A. K. Nunes, J. R. Denery, S.
Specht, A. Hoerauf, K. D. Janda, Proc. Natl. Acad. Sci. U. S. A. 2013,
110, 4218-4223; c) T. Brückl, D. Globisch, M. Wagner, M. Müller, T.
Carell, Angew. Chem. Int. Ed. 2009, 48, 7932-7934.
[12]
[13]
a) M. Kawakita, K. Hiramatsu, J. Biochem. 2006, 139, 315-322; b) K.
Hiramatsu, M. Sugimoto, S. Kamei, M. Hoshino, K. Kinoshita, K.
Iwasaki, M. Kawakita, J. Biochem. 1995, 117, 107-112; c) Y. Umemori,
Y. Ohe, K. Kuribayashi, N. Tsuji, T. Nishidate, H. Kameshima, K. Hirata,
N. Watanabe, Clin. Chim. Acta 2010, 411, 1894-1899.
a) N. Rioux, L. H. Mitchell, P. Tiller, K. Plant, J. Shaw, K. Frost, S.
Ribich, M. P. Moyer, R. A. Copeland, R. Chesworth, N. J. Waters, Drug
Metab. Dispos. 2015, 43, 936-943; b) M. R. Meyer, A. Robert, H. H.
Maurer, Toxicol. Lett. 2014, 227, 124-128.
L. Liu, A. Von Vett, N. X. Zhang, K. J. Walters, C. R. Wagner, P. E.
Hanna, Chem. Res. Toxicol. 2007, 20, 1300-1308.
N. Garg, L. P. Conway, C. Ballet, M. S. P. Correia, F. K. S. Olsson, M.
Vujasinovic, J. M. Lohr, D. Globisch, Angew. Chem. Int. Ed. 2018, 57,
13805-13809.
Figure 5. Acetylation experiments of commonly prescribed drugs (a)
amlodipine (7), (b) duloxetine (8), (c) nebivolol (9), and (d) salbutamol (11) after
incubation with recombinant enzymes for 24h at 37°C.
2016, the drugs acetylated by NAT2 in this study were prescribed
over 124 million times in the USA alone.[23] Furthermore, 21% of
the 200 most prescribed drugs in the USA contain aliphatic
amines, representing almost 900 million prescriptions. Differential
metabolism of drugs according to NAT2 genotype therefore has
the potential to affect a major part of the population. These
findings suggest that knowledge of the patient’s NAT2 genotype
can aid in optimizing drug dosage to maximize efficacy and
minimize side effects.
[14]
[15]
[16]
a) L. Miller-Fleming, V. Olin-Sandoval, K. Campbell, M. Ralser, J. Mol.
Biol. 2015, 427, 3389-3406; b) T. J. Erb, B. S. Evans, K. Cho, B. P.
Warlick, J. Sriram, B. M. Wood, H. J. Imker, J. V. Sweedler, F. R.
Tabita, J. A. Gerlt, Nat. Chem. Biol. 2012, 8, 926-932.
[17]
[18]
S. Mandal, A. Mandal, H. E. Johansson, A. V. Orjalo, M. H. Park, Proc.
Natl. Acad. Sci. U. S. A. 2013, 110, 2169-2174.
a) F. Madeo, T. Eisenberg, F. Pietrocola, G. Kroemer, Science 2018,
359; b) F. Pietrocola, F. Castoldi, O. Kepp, D. Carmona-Gutierrez, F.
Madeo, G. Kroemer, Autophagy 2019, 15, 362-365; c) T. Eisenberg,
et al., Nat. Med. 2016, 22, 1428-1438.
a) V. K. Gupta, et al., Nat. Neurosci. 2013, 16, 1453-1460; b) A. F.
Fernandez, et al., Nature 2018, 558, 136-140.
F. Madeo, D. Carmona-Gutierrez, O. Kepp, G. Kroemer, Aging (Albany
N. Y.) 2018, 10, 2209-2211.
a) R. A. Casero, Jr., T. Murray Stewart, A. E. Pegg, Nat. Rev. Cancer
2018, 18, 681-695; b) N. Minois, D. Carmona-Gutierrez, F. Madeo,
Aging (Albany N. Y.) 2011, 3, 716-732; c) A. E. Pegg, Chem. Res.
Toxicol. 2013, 26, 1782-1800; d) Y. Ou, S. J. Wang, D. Li, B. Chu, W.
Gu, Proc. Natl. Acad. Sci. U. S. A. 2016, 113, E6806-E6812.
a) M. K. Ma, M. H. Woo, H. L. McLeod, Am. J. Health Syst. Pharm.
2002, 59, 2061-2069; b) C. J. Omiecinski, J. P. Vanden Heuvel, G. H.
Perdew, J. M. Peters, Toxicol. Sci. 2011, 120, S49-75.
In summary, cell-based and in vitro assays revealed acetylation
of several endogenous metabolites and major drugs that have not
previously been described as substrates of this enzyme. This
previously unknown enzymatic activity extends NAT2 acetylation
beyond aromatic xenobiotics to the modification of aliphatic
amine-containing endogenous metabolites and drugs, implying
that ~10% of commonly prescribed drugs can be metabolized by
NAT2. We therefore postulate that NAT2 acetylator phenotype
affects the efficacy and clearance of commonly used drugs with
non-aromatic amines and propose that the catalytic activity of
NAT2 should be re-classified to encompass acetylation of both
aryl- and alkylamines.
[19]
[20]
[21]
[22]
[23]
drugs-of-2019/, ClinCalc, 2018.
Acknowledgements: This study was funded by the Swedish
Research Council (VR 2016-04423), Carl Tryggers Foundation
(CTS 2018:820) and start-up grant from SciLifeLab to DG; VR
2016-01890 and the Cancer Foundation (CAN 2018/772) to TS.
We also thank the Västerbotten Intervention Programme, the
MONICA study and the County Council of Västerbotten for
providing NSHDS data and samples. Acknowledged are also the
contribution from Biobank Sweden (VR 2017-00650) and Natallia
Rameika for support with human samples.
Keywords: N-acetyltransferase
•
polyamines
•
mass
spectrometry • metabolomics • drug metabolism
[1]
S. R. Hanson, M. D. Best, C.-H. Wong, Angew. Chem. Int. Ed. 2004,
43, 5736-5763.
4
This article is protected by copyright. All rights reserved.