The nitrosoamphetamine metabolite is accommodated in the active site of human hemoglobin: Spectroscopy and crystal structure

Powell, Samantha M.; Thomas, Leonard M.; Richter-Addo, George B.

doi:10.1016/j.jinorgbio.2020.111262

Title: The nitrosoamphetamine metabolite is accommodated in the active site of human hemoglobin: Spectroscopy and crystal structure

Journal Article · Tue Sep 29 00:00:00 UTC 2020 · Journal of Inorganic Biochemistry

DOI: https://doi.org/10.1016/j.jinorgbio.2020.111262 · OSTI ID:1777113

Powell, Samantha M. ^[1]; Thomas, Leonard M. ^[1]; Richter-Addo, George B. ^[1]

Univ. of Oklahoma, Norman, OK (United States)

Amphetamine-based (Amph) drugs are metabolized in humans to their hydroxylamine (AmphNHOH) and nitroso (AmphNO) derivatives. The latter metabolites are known to bind to the Fe centers of cytochrome P450 and other heme enzymes to inhibit their activities. Although these AmphNHOH/AmphNO metabolites are present in vivo, their interactions with the blood protein hemoglobin (Hb) and the muscle protein (Mb) have been largely discounted due to a perception that the relatively small heme active sites of Hb and Mb will not be able to accommodate the large AmphNO group. Here, we report the 2.15 Å resolution X-ray crystal structure of the AmphNO adduct of adult human hemoglobin as the Hb [α-Fe^III(H₂O)][β-Fe^II(AmphNO)] derivative. We show that the binding of AmphNO to the β subunit is enabled by an E helix movement and stabilization of ligand binding by H-bonding with the distal His63 residue. We also observe an AmphNHOH group in the Xe2 pocket in close proximity to the α heme site in this derivative. Additionally, UV–vis spectroscopy was used to characterize this and related wt and mutant Mb adducts. Importantly, our X-ray crystal structure of this Hb-nitrosoamphetamine complex represents the first crystal structure of a wild-type heme protein adduct of any amphetamine metabolite. Our results provide a framework for further studies of AmphNHOH/AmphNO interactions with Hb and Mb as viable processes that potentially contribute to the overall biological inorganic chemistry of amphetamine drugs.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF); USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1777113

Report Number(s):: PNNL-SA--155174

Journal Information:: Journal of Inorganic Biochemistry, Journal Name: Journal of Inorganic Biochemistry Vol. 213; ISSN 0162-0134

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (43)

Pattern of cavities in globins: The case of human hemoglobin Savino, Carmelinda; Miele, Adriana E.; Draghi, Federica Biopolymers, Vol. 91, Issue 12 https://doi.org/10.1002/bip.21201	journal	December 2009
Crystal structures of ferrous horse heart myoglobin complexed with nitric oxide and nitrosoethane Copeland, Daniel M.; West, Ann H.; Richter-Addo, George B. Proteins: Structure, Function, and Genetics, Vol. 53, Issue 2 https://doi.org/10.1002/prot.10495	journal	September 2003
Formation of Iron(II)–Nitrosoalkane Complexes: A New Activity of Microperoxidase 8 Ricoux, Remy; Boucher, Jean-Luc; Mansuy, Daniel Biochemical and Biophysical Research Communications, Vol. 278, Issue 1 https://doi.org/10.1006/bbrc.2000.3785	journal	November 2000
Comparisons of the formation of cytochrome P-450 complexes absorbing at 455 nm in rabbit and rat microsomes James, Robert C.; Franklin, Michael R. Biochemical Pharmacology, Vol. 24, Issue 8 https://doi.org/10.1016/0006-2952(75)90150-1	journal	April 1975
The nature of the “455 nm absorbing complex” formed during the cytochrome P450 dependent oxidative metabolism of amphetamine Mansuy, D.; Beaune, P.; Chottard, J. C. Biochemical Pharmacology, Vol. 25, Issue 5 https://doi.org/10.1016/0006-2952(76)90398-1	journal	March 1976
Interaction of aliphatic N-hydroxylamines with microsomal cytochrome P450: Nature of the different derived complexes and inhibitory effects on monoxygenases activities Mansuy, Daniel; Rouer, Evelyne; Bacot, Charles Biochemical Pharmacology, Vol. 27, Issue 8 https://doi.org/10.1016/0006-2952(78)90456-2	journal	January 1978
Cytochrome P450 product complexes and glutathione consumption produced in isolated hepatocytes by norbenzphetamine and its N-oxidized congeners Hirata, Masaharu; Lindeke, Björn; Orrenius, Sten Biochemical Pharmacology, Vol. 28, Issue 4 https://doi.org/10.1016/0006-2952(79)90239-9	journal	January 1979
Cytochrome P-455 complex formation in the metabolism of phenylalkylamines—V Lindere, Björn; Paulsen, Ulla; Von Bahr, Christer Biochemical Pharmacology, Vol. 30, Issue 4 https://doi.org/10.1016/0006-2952(81)90072-1	journal	February 1981
Particular ability of cytochromes P450 3A to form inhibitory P450-iron-metabolite complexes upon metabolic oxidation of aminodrugs Bensoussan, C.; Delaforge, M.; Mansuy, D. Biochemical Pharmacology, Vol. 49, Issue 5 https://doi.org/10.1016/0006-2952(94)00477-4	journal	March 1995
The role of N-hydroxyamphetamine in the metabolic deamination of amphetamine Wrigth, Jeremy; Cho, Arthur K.; Gal, Joseph Life Sciences, Vol. 20, Issue 3 https://doi.org/10.1016/0024-3205(77)90389-7	journal	February 1977
Competition with Xenon Elicits Ligand Migration and Escape Pathways in Myoglobin Tetreau, Catherine; Blouquit, Yves; Novikov, Eugene Biophysical Journal, Vol. 86, Issue 1 https://doi.org/10.1016/S0006-3495(04)74120-X	journal	January 2004
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
The isomerization of nitrosomethane to formaldoxime Gowenlock, B. G.; Batt, L. Journal of Molecular Structure: THEOCHEM, Vol. 454, Issue 1 https://doi.org/10.1016/S0166-1280(98)00315-7	journal	December 1998
Internal cavities and ligand passageways in human hemoglobin characterized by molecular dynamics simulations Mouawad, Liliane; Maréchal, Jean-Didier; Perahia, David Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1724, Issue 3 https://doi.org/10.1016/j.bbagen.2005.05.014	journal	August 2005
Hemoglobin–ligand binding: Understanding Hb function and allostery on atomic level Safo, Martin K.; Ahmed, Mostafa H.; Ghatge, Mohini S. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1814, Issue 6 https://doi.org/10.1016/j.bbapap.2011.02.013	journal	June 2011
The structural dynamics of myoglobin Brunori, M.; Bourgeois, D.; Vallone, B. Journal of Structural Biology, Vol. 147, Issue 3 https://doi.org/10.1016/j.jsb.2004.04.008	journal	September 2004
Nitrosoamphetamine binding to myoglobin and hemoglobin: Crystal structure of the H64A myoglobin-nitrosoamphetamine adduct Wang, Bing; Powell, Samantha M.; Guan, Ye Nitric Oxide, Vol. 67 https://doi.org/10.1016/j.niox.2017.04.012	journal	July 2017
Ligand Migration and Cavities within Scapharca Dimeric HbI: Studies by Time-Resolved Crystallo- graphy, Xe Binding, and Computational Analysis Knapp, James E.; Pahl, Reinhard; Cohen, Jordi Structure, Vol. 17, Issue 11 https://doi.org/10.1016/j.str.2009.09.004	journal	November 2009
Formation of prostaglandin synthase-iron-nitrosoalkane inhibitory complexes upon in situ oxidation of N-substituted hydroxylamines Mahy, J. P.; Mansuy, D. Biochemistry, Vol. 30, Issue 17 https://doi.org/10.1021/bi00231a009	journal	April 1991
Cavities in proteins: structure of a metmyoglobin xenon complex solved to 1.9 .ANG. Tilton, Robert F.; Kuntz, Irwin D.; Petsko, Gregory A. Biochemistry, Vol. 23, Issue 13 https://doi.org/10.1021/bi00308a002	journal	June 1984
Mechanism of oxidation of N-hydroxyphentermine by superoxide Fukuto, Jon M.; Di Stefano, Emma W.; Burstyn, Judith N. Biochemistry, Vol. 24, Issue 15 https://doi.org/10.1021/bi00336a052	journal	July 1985
Direct formation of complexes between cytochrome P-450 and nitrosoarenes Fukuto, Jon M.; Brady, John F.; Burstyn, Judith N. Biochemistry, Vol. 25, Issue 9 https://doi.org/10.1021/bi00357a065	journal	May 1986
Formation of Nitric Oxide Synthase−Iron(II) Nitrosoalkane Complexes: Severe Restriction of Access to the Iron(II) Site in the Presence of Tetrahydrobiopterin Renodon, Axelle; Boucher, Jean-Luc; Wu, Chaoqun Biochemistry, Vol. 37, Issue 18 https://doi.org/10.1021/bi972297s	journal	May 1998
Nitrosoalkane complexes of iron-porphyrins: analogy between the bonding properties of nitrosoalkanes and dioxygen Mansuy, Daniel; Battioni, Pierrette; Chottard, Jean Claude Journal of the American Chemical Society, Vol. 105, Issue 3 https://doi.org/10.1021/ja00341a027	journal	February 1983
Reduction of .alpha.,.beta.-unsaturated nitro compounds with boron hydrides: a new route to N-substituted hydroxylamines Mourad, M. Soubei; Varma, Rajender S.; Kabalka, George W. The Journal of Organic Chemistry, Vol. 50, Issue 1 https://doi.org/10.1021/jo00201a030	journal	January 1985
Comparative studies of N-hydroxylation and N-demethylation by microsomal cytochrome P-450 Burstyn, Judith N.; Iskandar, Marco; Brady, John F. Chemical Research in Toxicology, Vol. 4, Issue 1 https://doi.org/10.1021/tx00019a009	journal	January 1991
Degradation of human hemoglobin by organic C-nitroso compounds Yi, Jun; Ye, Guan; Thomas, Leonard M. Chemical Communications, Vol. 49, Issue 95 https://doi.org/10.1039/c3cc46174b	journal	January 2013
A mechanistic study of the decomposition of phenylhydroxylamine to azoxybenzene and aniline and its catalysis by iron(II) and iron(III) ions stabilised by ethylenediaminetetra-acetic acid Mulvey, Denise; Waters, William A. Journal of the Chemical Society, Perkin Transactions 2, Issue 14 https://doi.org/10.1039/p29770001868	journal	January 1977
High-level expression of sperm whale myoglobin in Escherichia coli. Springer, B. A.; Sligar, S. G. Proceedings of the National Academy of Sciences, Vol. 84, Issue 24 https://doi.org/10.1073/pnas.84.24.8961	journal	December 1987
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
A phased translation function Read, R. J.; Schierbeek, A. J. Journal of Applied Crystallography, Vol. 21, Issue 5 https://doi.org/10.1107/S002188988800562X	journal	October 1988
electronic Ligand Builder and Optimization Workbench ( eLBOW ): a tool for ligand coordinate and restraint generation Moriarty, Nigel W.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 10 https://doi.org/10.1107/S0907444909029436	journal	September 2009
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
An editor for the generation and customization of geometry restraints Moriarty, Nigel W.; Draizen, Eli J.; Adams, Paul D. Acta Crystallographica Section D Structural Biology, Vol. 73, Issue 2 https://doi.org/10.1107/S2059798316016570	journal	February 2017
Deprenyl is metabolized to methamphetamine and amphetamine in man. Reynolds, Gp; Elsworth, Jd; Blau, K. British Journal of Clinical Pharmacology, Vol. 6, Issue 6 https://doi.org/10.1111/j.1365-2125.1978.tb00883.x	journal	December 1978
Stereoselectivity in the human metabolism of methamphetamine Li, Linghui; Everhart, Tom; Jacob III, Peyton British Journal of Clinical Pharmacology, Vol. 69, Issue 2 https://doi.org/10.1111/j.1365-2125.2009.03576.x	journal	February 2010
Nitrosoalkanes as Fe(II) Ligands in the 455-nm-Absorbing Cytochrome P-450 Complexes Formed from Nitroalkanes in Reducing Conditions Mansuy, Daniel; Gans, Pierre; Chottard, Jean-Claude European Journal of Biochemistry, Vol. 76, Issue 2 https://doi.org/10.1111/j.1432-1033.1977.tb11631.x	journal	June 1977
Nitrosoalkanes as Fe(II) Ligands in the Hemoglobin and Myoglobin Complexes Formed from Nitroalkanes in Reducing Conditions Mansuy, Daniel; Chottard, Jean Claude; Chottard, Genevieve European Journal of Biochemistry, Vol. 76, Issue 2 https://doi.org/10.1111/j.1432-1033.1977.tb11632.x	journal	June 1977
New activities of a catalytic antibody with a peroxidase activity: Formation of Fe(II)-RNO complexes and stereoselective oxidation of sulfides Ricoux, Rémy; Lukowska, Edyta; Pezzotti, Fabio European Journal of Biochemistry, Vol. 271, Issue 7 https://doi.org/10.1111/j.1432-1033.2004.04032.x	journal	March 2004
Metabolic incorporation of oxygen into primary and secondary aliphatic amines and the consequences in carbon-nitrogen bond cleavage Beckett, A. H.; Bélanger, P. M. Journal of Pharmacy and Pharmacology, Vol. 27, Issue 7 https://doi.org/10.1111/j.2042-7158.1975.tb09505.x	journal	July 1975
Complexes of Metabolites of Amphetamines with Hepatic Cytochrome P-450 Franklin, Michael R. Xenobiotica, Vol. 4, Issue 3 https://doi.org/10.3109/00498257409049353	journal	January 1974

Similar Records

The use of protein adducts to investigate the disposition of reactive metabolites of benzene

Journal Article · Sun Dec 01 04:00:00 UTC 1996 · Environmental Health Perspectives · OSTI ID:472165

Rappaport, S M; McDonald, T A; Yeowell-O`Connell, K

The Streptococcus pyogenes Shr protein captures human hemoglobin using two structurally unique binding domains

Journal Article · Tue Oct 09 00:00:00 UTC 2018 · Journal of Biological Chemistry · OSTI ID:1560082

Macdonald, Ramsay; Cascio, Duilio; Collazo, Michael J.; +2 more

Protein adducts of benzoquinone and benzene oxide: A study of the reactive metabolites of benzene

Thesis/Dissertation · Sat Jan 01 04:00:00 UTC 1994 · OSTI ID:68639

McDonald, T A

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
amphetamine
hemoglobin
iron
myoglobin
nitroso
x-ray structure

Title: The nitrosoamphetamine metabolite is accommodated in the active site of human hemoglobin: Spectroscopy and crystal structure

Citation Formats

References (43)

Similar Records

Related Subjects