Copper-peptide complex structure and reactivity when found in conserved His-Xaa-His sequences

Article abstract of DOI:10.1021/ja505098v

Oxygen-activating copper proteins may possess His-X_aa-His chelating sequences at their active sites and additionally exhibit imidiazole group δN vs εN tautomeric preferences. As shown here, such variations strongly affect copper ions coordination geometry, redox behavior, and oxidative reactivity. Copper(I) complexes bound to either δ-HGH or ε-HGH tripeptides were synthesized and characterized. Structural investigations using X-ray absorption spectroscopy, density functional theory calculations, and solution conductivity measurements reveal that δ-HGH forms the Cu^I dimer complex [{Cu^I(δ-HGH)}₂]²⁺ (1) while ε-HGH binds Cu^I to give the monomeric complex [Cu^I(ε-HGH)]⁺ (2). Only 2 exhibits any reactivity, forming a strong CO adduct, [Cu^I(ε-HGH)(CO)]⁺, with properties closely matching those of the copper monooxygenase PHM. Also, 2 is reactive toward O₂ or H₂O₂, giving a new type of O₂-adduct or Cu^II-OOH complex, respectively.

Full text of DOI:10.1021/ja505098v

Communication
pubs.acs.org/JACS
Open Access on 08/29/2015
Copper−Peptide Complex Structure and Reactivity When Found in
Conserved His‑X -His Sequences
aa
†
†
†
‡
‡
Ga Young Park, Jung Yoon Lee, Richard A. Himes, Gnana S. Thomas, Ninian J. Blackburn,
,
†
and Kenneth D. Karlin*
†
Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218, United States
‡
Institute of Environmental Health, Oregon Health and Sciences University, Portland, Oregon 97239, United States
*
S Supporting Information
ABSTRACT: Oxygen-activating copper proteins may
possess His-X -His chelating sequences at their active
aa
sites and additionally exhibit imidiazole group δN vs εN
tautomeric preferences. As shown here, such variations
strongly affect copper ion’s coordination geometry, redox
behavior, and oxidative reactivity. Copper(I) complexes
bound to either δ-HGH or ε-HGH tripeptides were
synthesized and characterized. Structural investigations
using X-ray absorption spectroscopy, density functional
theory calculations, and solution conductivity measure-
Figure 1. His-X -His sequences present in the copper active site of (a)
aa
3
5
PHM (PDB entry 1SDW), (b) SOD5 (4N3T), and (c) MCO
8
(1ZPU).
I
ments reveal that δ-HGH forms the Cu dimer complex
facilitates electron transfer, but it binds to three δNHis sites (in
I
2+
I
[
{Cu (δ-HGH)} ] (1) while ε-HGH binds Cu to give
fact where two of the His residues are adjacent in the overall
2
I
+
3
the monomeric complex [Cu (ε-HGH)] (2). Only 2
peptide sequence). These observations raise basic questions
exhibits any reactivity, forming a strong CO adduct,
relevant to PHM active-site structure and function: how do these
specific tautomeric imidazole N atom configurations imposed by
nature control (i) copper coordination number and geometry,
I
+
[
Cu (ε-HGH)(CO)] , with properties closely matching
those of the copper monooxygenase PHM. Also, 2 is
II
I
reactive toward O or H O , giving a new type of O -
(ii) Cu /Cu redox potential, (iii) electronic structure/bonding
and associated spectroscopic properties, and (iv) exogenous
ligand preferences?
2
2
2
2
II
adduct or Cu −OOH complex, respectively.
I
We have previously reported studies of Cu complexes of
11
he study of peptide complexation to copper ions has been
of great interest to (bio)chemists since the most common
modified histidylhistidine (HisHis) peptides where imidazole
N atoms were specifically blocked, allowing study of δ-HH (δN
of both H’s available for metal coordination) or ε-HH (εN of
both H’s available for metal coordination). Significantly, both
T
ligands at copper active sites in proteins are amino acids, most
1
often histidine. A survey of His imidazole group binding to
I
copper proteins involved in redox chemistry, including O2
reactivity, indicates that the His-X -His (X = amino acid)
dipeptides adopt a linear two-coordinate NHis−Cu −NHis
environment. In the present work, we aimed to understand
aa
aa
tripeptide motif is a frequently observed sequence, including, for
why the unique His-Xaa-His sequence is particularly “selected” in
2
,3
4
I
1h
example, His-Thr-His in PHM and DβM, His-Val-His in
7
nature by generating Cu complexes of His-Gly-His tripeptides
5
6
with varying δN versus εN atom availability and investigating
their structural features and chemical properties.
SOD5 and pMMO, and His-Gln-His in APLP2 and LYOX.
Four highly conserved His-X -His sequences exist in a bridging
aa
8
The tripeptides δ-HGH and ε-HGH (Chart 1) were
synthesized by modifications of literature procedures and
fashion in the trinuclear copper ion cluster of MCOs (Figure 1).
Also, a similar motif appears in pentapeptide domains
12
standard solution-phase peptide synthesis techniques. The
(
HLHWH) present in the amyloid precursor protein (APP)
7,9
associated with the development of Alzheimer’s disease.
The imidazole group of histidine ligands can bind to Cu ion
Chart 1
through either the δN or εN site, and tautomeric preferences
10
occur in different classes of copper proteins. The variations
most certainly are critical in determining the functions and
properties of the enzymes because of differences in decisive
steric/electronic effects imparted to the copper ion center, for
example controlling the exact nature of O2 binding and
consequent structure−reactivity and the specificity of substrate
approach. For example, in PHM, O binds at the Cu site, which
2
M
is close to where the substrate docks; Cu is ligated by two εN
Received: May 21, 2014
M
sites of His’s in an HTH sequence. Cu , which is ∼11 Å away,
H
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ja505098v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
N-/C-tripeptide terminal groups were also “protected” using
either fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbon-
yl (Boc), or benzyl groups to avoid any likelihood of terminal-
13
group Cu coordination. δ-HGH and ε-HGH were metalated
I
with [Cu (CH CN) ]ClO in CH Cl . Solid complexes were
3
4
4
2
2
isolated by precipitation and purified by recrystallization from
CH Cl /Et O; their elemental analysis and electrospray
2
2
2
ionization mass spectrometry envelope isotope patterns were
I +
14
consistent with the [ligand−Cu ] cation formulations.
Extended X-ray absorption fine structure (EXAFS) spectros-
copy (Figure 2) of LCu complex solids and accompanying
1
4
I
Figure 3. DFT-optimized geometries (RB3LYP/6-311G**) for (a)
dimer 1 and (b) mononuclear 2 (∠εN−Cu−εN = 160.2°). The
calculations were carried out with the protecting groups on the non-
copper-coordinating N atom and N-/C-termini replaced with H
His
1
4
atoms.
14
(
by 11.5 kJ/mol). The stronger solution experimental evidence
thus points to the dimer formulation; apparently, intramolecular
two-coordination leads to an excessively strained structure. By
I
contrast, structural energy minimization for a Cu −ε-HGH
I
complex leads to a preferred mononuclear formulation, [Cu (ε-
+
HGH)] (2) (Figure 3b), on the basis of electronic energies
I
corrected for zero-point energy; a dimer structure as in 1 is
thermodynamically disfavored by 44.0 kJ/mol. Also, a dimer is
ruled out by solution conductivity measurements showing that
Figure 2. EXAFS and XANES spectroscopic data for (a) [{Cu (δ-
HGH)}2]2 (1) [data (black), fit (red)] and (b) [Cu (ε-HGH)] (2)
data (blue), fit (red)]. Overlapped spectra for comparison are shown in
+
I
+
[
1
4,17
the Supporting Information.
this complex behaves as a 1:1 electrolyte.
Notably, the DFT-
derived structure for complex 2 reveals a significant bending in
1
4
I
I
computational analyses (Figure 3) provide strong evidence
the two-coordinate Cu coordination, with ∠N−Cu −N =
I
that Cu complexes of both δ-HGH and ε-HGH possess two-
160.2°, as suggested by the XANES data and the unexpected
I
I
coordinate N −Cu −N
geometries. Multiple scattering
definitively reveals the patterns known for N −Cu coordina-
tion. For the Cu complex of δ-HGH, the data given in Figure 2a
oxidative reactivity (vide infra); nevertheless, short Cu −N
His
His
Im
bond distances are present that are typical of this coordination
number for Cu and much shorter than those observed in three-
His
I
I
I
display the best fit to two δN -ligand scatterers with Cu−N =
coordinate Cu −N compounds (vide supra).
His
3
I
I
1
.867 Å, indicative of linear two-coordinate Cu , as observed
The features observed here for Cu binding to His-X -His
aa
1
1
I
earlier with the HisHis peptides. These very short Cu −N
peptides contrast greatly with those observed for the previously
11
I
+
bonds are characteristic of this very low coordination, being
studied HisHis peptides, where the [Cu (δ-HH)] complex
I
significantly shorter than those found in three-coordinate Cu −
showed monomeric behavior (DFT and solution conductivity)
1
5
I
+
N compounds.
3
while [Cu (ε-HH)] is a 2:1 solution electrolyte with a dimeric
structure. Just inserting a Gly amino acid between two His
residues leads to significant changes in the Cu coordination
environment. Do these alterations affect other physical/
spectroscopic properties or reactivity patterns?
I
The EXAFS data for the solid complex of Cu with ε-HGH are
extremely similar. The best and only fit was found with two-His
14
I
ligation (Figure 2b) and a Cu −N bond length of 1.878 Å,
His
I
also indicating two-coordinate Cu . The only significant
difference is a small decrease in the intensity of the 8983 eV
pre-edge transition found in the X-ray absorption near-edge
structure (XANES) spectroscopic data, which may suggest some
To address such questions, we first examined the CO binding
I
I
behavior of the new Cu −peptide complexes, as CO is a Cu -
specific ligand (and more generally an O surrogate) and can
2
1
1,16
deviation from a strictly linear geometry.
this deviation seems to directly relate to this Cu compound’s
remarkably different (compared with the δ-HGH Cu complex)
As described below,
provide insights into coordination number and ligand donation
ability. CO adducts of acetone solutions (under Ar) of 1 and 2
were generated by direct CO bubbling. As previously established
I
I
I
+
electrochemical and CO-binding behavior and its reactivity
toward O and H O .
for near-linear two-coordinate [Cu (HisHis)] complexes, CO
binding is very weak, and high-frequency stretching vibrations
2
2
2
−
1
11b,15c,18
Density functional theory (DFT) structural analyses and
supporting solution conductivity measurements lead to differing
formulations for δ-HGH and ε-HGH in comparison with our
previous findings for HisHis dipeptides. The EXAFS data
(νCO = 2110−2112 cm ) of low intensity are observed.
This is also the case here, as the IR spectrum of 1−CO exhibits
+
1
I
ν
= 2103 cm− (Table 1). By contrast, [Cu (ε-HGH)(CO)]
CO
(2−CO) displays a high-intensity absorption at lower frequency
I
−1 14
indicate near-perfect linear two-coordination for Cu in the δ-
(ν = 2092 cm ). This observation suggests that there is a
CO
HGH complex. Solution conductivity data in dimethylforma-
significant geometric-coordinative effect leading to stronger
ligation of CO to Cu and better back-donation from Cu when it
I
I
I
mide (DMF) provide an Onsager plot for a Cu −δ-HGH
complex with a slope in the range expected for 2:1 electrolyte
is bound to the ε-HGH ligand rather than to either the δ-HGH or
I
−1
behavior, thus indicating a dimer formulation, [{Cu (δ-
HisHis system (Table 1). This νCO of 2092 cm for 2−CO in
HGH)}2]2 (1). We note that Figure 3a is a geometry
optimization assuming a dimer formulation. In fact, higher-
level computations and energy comparisons (in vacuum) reveal
that a monomeric formulation and structure are slightly favored
+
fact compares very well with that observed for the enzyme Cu
M
−1
19
−1 20
sites in PHM (2093 cm ) and DβM (2089 cm ), which are
ligated by two histidyl εN atoms of the His-Thr-His active-site
tripeptide sequence (Figure 1a). Thus, 2−CO possesses a
B
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Journal of the American Chemical Society
Communication
I
II
Table 1. Comparison of Properties of Cu −Peptide
newly synthesized cupric complex [Cu (ε-HGH)(H O)]-
2
14
Complexes
(ClO ) , or (ii) the reaction of 2 with 1.5 equiv of H O
4 2 2 2
Figure 4a), a recently reported procedure for generating Cu −
II
(
Cu−N
ν
O /H O
2 2 2
reactivity
His
CO
(cm
a
b
−1
c
complex
(Å)
)
redox behavior
I
2+
[
[
[
[
{Cu (δ-HGH)} ]
1.867
1.878
1.876
1.863
2103
irreversible
no
yes
no
2
I
+
Cu (ε-HGH)]
2092
2110
2112
quasi-reversible
irreversible
I
+
Cu (δ-HH)]
I
2+
{Cu (ε-HH)} ]
irreversible
no
2
a
b
c
Determined by solution conductivity. Measured by XAS. IR
stretching frequency.
chemical environment reasonably mimicking that of the protein
active sites.
II
+
Figure 4. (a) UV−vis spectra of [Cu (ε-HGH)(OOH)] generated by
addition of 1.5 equiv of H O to a 3.5 mM solution of 2 in acetone at 193
Cyclic voltammetry measurements were performed on 1 and 2
in DMF under argon to probe their electrochemical properties.
2
2
II
+
K. (b) EPR spectrum of [Cu (ε-HGH)(OOH)] at 77 K (g = 2.25, g
∥
⊥
14
Complex 1 displays irreversible redox behavior (Table 1), as
= 2.05, A = 192 G, A = 15 G).
∥
⊥
I
expected for a two-coordinate Cu species; the same was shown
24
II
previously for analogous complexes formed from HisHis ligand
OOH species. [Cu (ε-HGH)(OOH)](ClO ) is presently
4
1
1b
systems. On the other hand, 2 shows quasi-reversible redox
characterized by (i) its UV−vis features [λ = 366 nm (ε =
max
+
14
−1
−1
II
behavior (E1/2 ≈ −390 mV vs Fc /Fc). Such chemical effects
2600 M cm ), assignable to a −OOH → Cu ligand-to-metal
I
derived from tautomeric preferences for binding of Cu to these
charge transfer absorption on the basis of the correspondence
2
4,25
HGH tripeptides were further clarified by studies of oxidative
reactivity (vide infra).
with a number of literature examples,
and λmax = 600 nm (ε =
200 M− cm ), a d−d transition band] and (ii) its distinctive
mononuclear-type axial EPR spectrum at 77 K (g = 2.25, g =
1
−1
Complex 1 is unreactive toward O as a solid or in solution
2
∥
⊥
below 0 °C [with only extremely slow oxidation and color change
2.05, A = 192 G, A = 15 G; Figure 4b).
∥ ⊥
21
I
occurring at room temperature (RT)]. This behavior isI
In conclusion, we have generated new Cu complexes with His-
Gly-His tripeptides to probe fundamental aspects of CuI
chemistry with this particular histidine-containing sequence;
analogous to that observed for linear two-coordinate Cu
11b,15a−c
complexes studied previously.
In the context of other
works, as an exception (i.e., the only case where we observe facile
we have also probed the presence of synthetically imposed
I
reactivity with O ), the reaction of 2 with O in acetone results in
tautomeric preferences (δN vs εNIm availability) for Cu . The
2
2
Im
I
2+
the formation of a metastable complex at −80 °C that exhibits
dimer [{Cu (δ-HGH)} ] (1) exhibits favorable near-linear
2
−
1
−1
absorptions at 336 nm (ε = 1110 M cm ) and 606 nm (ε =
1
twofold coordination via intermolecular Cu−δN binding. This
His
10 M− cm ). Frozen-solution electron paramagnetic
1
−1 14
complex is not redox-active and only weakly binds CO.
Furthermore, it does not react with either O or H O (Scheme
resonance (EPR) measurements were silent, indicating that
whatever species is present is diamagnetic but that warming to
RT results in the formation of a paramagnetic mononuclear
2
2
2
I
+
1). However, [Cu (ε-HGH)] (2) shows two-His ligation with
species. The low-temperature UV−vis absorptions are not
Scheme 1
I
characteristic of any well-known O −Cu adduct, such as a
2
II
2
2
superoxo−Cu , peroxo−dicopper(II) (μ-1,2 or μ-η :η ), or
2
2
bis(μ-oxo)dicopper(III) complex. Also, warming the inter-
mediate to RT and testing for peroxide using iodometric
titrations gave a 100% yield of H O based on a stoichiometry of
2
2
1
4
two molar equiv of 2 per H O . This suggests that the reaction
2
2
of 2 with O leads to a peroxide-level species (i.e., two-electron
2
reduction of O ) but with unusual UV−vis features (see above).
2
Further detailed studies are warranted. Following Na EDTA/
2
23
H O/CH Cl demetalation procedures, the organic product
2
2
2
was identified as unreacted starting ligand. Therefore, whatever
I
Cu −O (n = 1, 2, ...) adduct forms at low temperature does not
n
2
affect any ligand oxidation/oxygenation chemistry, as is some-
deviation from linearity. The similarity of our synthetic construct
to the protein is notable: the IR spectrum of the carbonyl adduct
times observed.
II
As Cu −hydroperoxo complexes are of interest as basic
entities derived from Cu /O reactions and have been discussed
2−CO matches that observed for the enzyme PHM Cu −CO
M
I
adduct with its active-site εH-X -εH chelating moiety. Also, 2
2
aa
in the realm of possible enzyme active intermediates capable of
substrate oxidative behavior, we sought to study the present
copper−peptide complexes. 1 is in fact unreactive toward H O ,
displays redox activity and readily reacts with O and H O to
afford the first oxygen-intermediate species to be noted with Cu
ligated to biologically relevant His-containing peptides.
2
2
2
I
2
2
a remarkable observation that further demonstrates the extreme
It is striking that a switch in the imidazole tautomer can
I
I
stability of Cu in a linear two-coordinate nitrogen ligand
radically influence the reactivity of a Cu center. These results, in
I
environment. However, we could generate a green-colored
conjunction with our previous work with Cu -HisHis com-
II
+
11
species (presumed to possess a [Cu (ε-HGH)(OOH)]
formulation) in acetone at −80 °C by (i) addition of H O (10
plexes, highlight the manner in which nature exerts its control
of function. Even slight changes (dipeptide vs tripeptide; δN vs
2
2
Im
II
equiv)/Et N to a mononuclear Cu derivative of ε-HGH, the
εNIm availability) can significantly affect an enzyme metal
3
C
dx.doi.org/10.1021/ja505098v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
center’s structure and reactivity. Thus, our continuing research
will add to an understanding of structure−function relationships
in copper enzymes and the role of His binding motifs in
facilitating Cu−O2 (and even reactive oxygen species)
intermediate formation.
(13) (a) Isidro-Llobet, A.; Alvarez, M.; Albericio, F. Chem. Rev. 2009,
09, 2455. (b) A reviewer asked about our choice of blocking groups,
1
e.g., the use of Fmoc and trityl for blocking εN imidazole positions in the
δ peptide. Fmoc was preferred over Boc and trityl was preferred over
benzyl because Boc and benzyl protection was more expensive, gave
lower yields in synthesis, and afforded final peptides exhibiting poor
solubility in organic solvents. Examination of molecular models
indicated that the nature of the protecting group should not influence
ASSOCIATED CONTENT
■
I
Cu binding.
*
S
Supporting Information
(
(
14) See the Supporting Information.
15) (a) Sanyal, I.; Strange, R. R.; Blackburn, N. J.; Karlin, K. D. J. Am.
Synthetic and analytical details; UV−vis, IR, and EPR spectra;
cyclic voltammograms; and Onsager plots. This material is
available free of charge via the Internet at http://pubs.acs.org.
Chem. Soc. 1991, 113, 4692. (b) Sanyal, I.; Karlin, K. D.; Strange, R. W.;
Blackburn, N. J. J. Am. Chem. Soc. 1993, 115, 11259. (c) Sorrell, T. N.;
Jameson, D. L. J. Am. Chem. Soc. 1983, 105, 6013. (d) Tan, G. O.;
Hodgson, K. O.; Hedman, B.; Clark, G. R.; Garrity, M. L.; Sorrell, T. N.
Acta Crystallogr. 1990, C46, 1773. (e) Okkersen, H.; Groeneve, W.;
Reedijk, J. Recl. Trav. Chim. Pays-Bas 1973, 92, 945. (f) Lewin, A. H.;
Cohen, I. A.; Michl, R. J. J. Inorg. Nucl. Chem. 1974, 36, 1951. (g) Agnus,
Y.; Louis, R.; Weiss, R. J. Chem. Soc., Chem. Commun. 1980, 867.
(h) Engelhardt, L. M.; Pakawatchai, C.; White, A. H.; Healy, P. C. J.
Chem. Soc., Dalton Trans. 1985, 117. (i) Munakata, M.; Kitagawa, S.;
Shimono, H.; Masuda, H. Inorg. Chim. Acta 1989, 158, 217.
j) Habiyakare, A.; Lucken, E. A. C.; Bernardinelli, G. J. Chem. Soc.,
Dalton Trans. 1991, 2269.
(16) (a) Kau, L.-S.; Spira-Solomon, A. J.; Penner-Hahn, J. E.; Hodgson,
K. O.; Solomon, E. I. J. Am. Chem. Soc. 1987, 109, 6433. (b) Blackburn,
N. J.; Strange, R. W.; Reedijk, J.; Volbeda, A.; Farooq, A.; Karlin, K. D.;
Zubieta, J. Inorg. Chem. 1989, 28, 1349.
AUTHOR INFORMATION
■
Corresponding Author
karlin@jhu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
The authors acknowledge support of this research from the
National Institutes of Health (R01 GM28962 to K.D.K. and R01
NS027583 to N.J.B.).
REFERENCES
■
(17) Geary, W. J. Coord. Chem. Rev. 1971, 7, 81.
(
1) (a) Sigel, H.; Martin, R. B. Chem. Rev. 1982, 82, 385. (b) Daugherty,
R. G.; Wasowicz, T.; Gibney, B. R.; DeRose, V. J. Inorg. Chem. 2002, 41,
(18) (a) Voo, J. K.; Lam, K. C.; Rheingold, A. L.; Riordan, C. G. J.
Chem. Soc., Dalton Trans. 2001, 1803. (b) Casella, L.; Gullotti, M.;
Pallanza, G.; Ligoni, L. J. Am. Chem. Soc. 1988, 110, 4221. (c) Pasquali,
M.; Floriani, C.; Chiesivilla, A.; Guastini, C. Inorg. Chem. 1980, 19, 3847.
2
623. (c) Deschamps, P.; Kulkarni, P. P.; Gautam-Basak, M.; Sarkar, B.
Coord. Chem. Rev. 2005, 249, 895. (d) Kozlowski, H.; Kowalik-
Jankowska, T.; Jezowska-Bojczuk, M. Coord. Chem. Rev. 2005, 249,
(
d) Chou, C. C.; Su, C. C.; Yeh, A. Inorg. Chem. 2005, 44, 6122.
2
323. (e) Rockcliffe, D. A.; Cammers, A.; Murali, A.; Russell, W. K.;
(
(
19) Jaron, S.; Blackburn, N. J. Biochemistry 1999, 38, 15086.
20) Blackburn, N. J.; Pettingill, T. M.; Seagraves, K. S.; Shigeta, R. T. J.
DeRose, V. J. Inorg. Chem. 2006, 45, 472. (f) Shimazaki, Y.; Takani, M.;
Yamauchi, O. Dalton Trans. 2009, 7854. (g) Tay, W. M.; Hanafy, A. I.;
Angerhofer, A.; Ming, L.-J. Bioorg. Med. Chem. Lett. 2009, 19, 6709.
Biol. Chem. 1990, 265, 15383.
I
(
21) Essentially all Cu complexes with nitrogenous ligands oxidize to
(
2
h) Timari, S.; Kallay, C.; Osz, K.; Sovago, I.; Varnagy, K. Dalton Trans.
009, 1962.
2) Abbreviations: PHM = peptidylglycine α-hydroxylating mono-
II
Cu forms in an aerobic environment over hours or days or longer.
Under such conditions, the complexes formed are not O adducts and
2
(
are not relevant to the chemistry of species formed in fast reactions.
oxygenase; DβM = dopamine β-monooxygenase; SOD5 = superoxide
dismutase; pMMO = particulate methane monooxygenase; APLP2 = Aβ
precursor-like protein 2; LYOX = lysyl oxidase; MCO = multicopper
oxidase.
(22) (a) Mirica, L. M.; Ottenwaelder, X.; Stack, T. D. P. Chem. Rev.
2
004, 104, 1013. (b) Lewis, E. A.; Tolman, W. B. Chem. Rev. 2004, 104,
1
047. (c) Hatcher, L. Q.; Karlin, K. D. J. Biol. Inorg. Chem. 2004, 9, 669.
(
23) Maiti, D.; Narducci Sarjeant, A. A.; Karlin, K. D. Inorg. Chem.
008, 47, 8736.
24) Kim, S.; Saracini, C.; Siegler, M. A.; Drichko, N.; Karlin, K. D.
Inorg. Chem. 2012, 51, 12603.
25) (a) Wada, A.; Harata, M.; Hasegawa, K.; Jitsukawa, K.; Masuda,
H.; Mukai, M.; Kitagawa, T.; Einaga, H. Angew. Chem. Int. Ed. 1998, 37,
98. (b) Yamaguchi, S.; Wada, A.; Nagatomo, S.; Kitagawa, T.;
(
3) Prigge, S. T.; Kolhekar, A.; Eipper, B. A.; Mains, R. E.; Amzel, M.
Science 1997, 278, 1300.
4) Prigge, S. T.; Mains, R. E.; Eipper, B. A.; Amzel, L. M. Cell. Mol. Life
Sci. 2000, 57, 1236.
5) Gleason, J. E.; Galaleldeen, A.; Peterson, R. L.; Taylor, A. B.;
2
(
(
(
(
Holloway, S. P.; Waninger-Saroni, J.; Cormack, B. P.; Cabelli, D. E.;
Hart, P. J.; Culotta, V. C. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 5866.
7
Jitsukawa, K.; Masuda, H. Chem. Lett. 2004, 33, 1556. (c) Mizuno, M.;
Honda, K.; Cho, J.; Furutachi, H.; Tosha, T.; Matsumoto, T.; Fujinami,
S.; Kitagawa, T.; Suzuki, M. Angew. Chem. Int. Ed. 2006, 45, 6911.
(
(
6) Lieberman, R. L.; Rosenzweig, A. C. Nature 2005, 434, 177.
7) Hesse, L.; Beher, D.; Masters, C. L.; Multhaup, G. FEBS Lett. 1994,
3
49, 109.
8) Taylor, A. B.; Stoj, C. S.; Ziegler, L.; Kosman, D. J.; Hart, P. J. Proc.
Natl. Acad. Sci. U.S.A. 2005, 102, 15459.
(
d) Maiti, D.; Narducci Sarjeant, A. A.; Karlin, K. D. J. Am. Chem. Soc.
007, 129, 6720. (e) Yamaguchi, S.; Nagatomo, S.; Kitagawa, T.;
Funahashi, Y.; Ozawa, T.; Jitsukawa, K.; Masuda, H. Inorg. Chem. 2003,
(
2
(
(
9) Brown, D. R. Dalton Trans. 2009, 4069.
10) (a) Karlin, K. D.; Zhu, Z.-Y.; Karlin, S. J. Biol. Inorg. Chem. 1998, 3,
4
2, 6968. (f) Yamaguchi, S.; Masuda, H. Sci. Technol. Adv. Mater. 2005, 6,
3
4. (g) Fujii, T.; Naito, A.; Yamaguchi, S.; Wada, A.; Funahashi, Y.;
1
1
72. (b) Karlin, S.; Zhu, Z.-Y.; Karlin, K. D. Proc. Natl. Acad. Sci. U.S.A.
997, 94, 14225.
Jitsukawa, K.; Nagatomo, S.; Kitagawa, T.; Masuda, H. Chem. Commun.
2
003, 2700.
(
11) (a) Himes, R. A.; Park, G. Y.; Sutha Siluvai, G. S.; Blackburn, N. J.;
Karlin, K. D. Angew. Chem. Int. Ed. 2008, 47, 9084. (b) Himes, R. A.;
Park, G. Y.; Barry, A. N.; Blackburn, N. J.; Karlin, K. D. J. Am. Chem. Soc.
2
(
007, 129, 5352.
12) (a) Kovalainen, J. T.; Christiaans, J. A. M.; Kotisaari, S.; Laitinen, J.
T.; Mannisto, P. T.; Tuomisto, L.; Gynther, J. J. Med. Chem. 1999, 42,
193. (b) Harding, S. J.; Jones, J. H.; Sabirov, A. N.; Samukov, V. V. J.
1
Pept. Sci. 1999, 5, 368. (c) Jones, J. H.; Rathbone, D. L.; Wyatt, P. B.
Synthesis 1987, 1110.
D
dx.doi.org/10.1021/ja505098v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX