Inorg. Chem. 2006, 45, 8003−8005
Self-Assembly of the 2-His-1-carboxylate Facial Triad in Mononuclear
Iron(II) and Zinc(II) Models of Metalloenzyme Active Sites
Seth J. Friese, Benjamin E. Kucera, Lawrence Que, Jr.,* and William B. Tolman*
Department of Chemistry and Center for Metals in Biocatalysis, UniVersity of Minnesota,
207 Pleasant Street SE, Minneapolis, Minnesota 55455
Received August 17, 2006
A synthetic strategy involving the use of sterically hindered N-donor
and terphenylcarboxylate ligands has been used to prepare
complexes of iron(II) and zinc(II) that feature N2(carboxylate)
donors. X-ray crystallographic and NMR data show that the 2-His-
1-carboxylate facial triad found in metalloenzyme active sites is
closely modeled by the mononuclear complexes. In addition, by
virtue of the flexibility of the ligands used, the geometries and
coordination environments of the complexes display carboxylate
binding mode differences such as those seen in the enzymes.
A ubiquitous structural motif in metalloenzyme active sites
features facial coordination of a pair of histidine imidazoles
and a carboxylate ligand from Asp or Glu to a divalent metal
ion (referred to as the “2-His-1-carboxylate facial triad”).1
Representative examples from the large class with iron(II)
centers2 and those in zinc(II) enzymes, such as thermolysin3a
and carboxypeptidase,3b are sketched in Figure 1. Although
structural comparisons of the various active sites reveal
certain similarities, there are subtle differences in the
carboxylate binding mode. Such “carboxylate shifts”4 that
have been proposed to be important in nonheme dimetal
enzyme function may also play a role in catalysis by the
mononuclear sites with the 2-His-1-carboxylate facial triad.
Efforts to date to prepare synthetic models of this motif
have focused on using “preorganized” tridentate chelates such
as bis(pyrazolyl- or imidazolyl)acetates or -propionates and
analogues.1d,5 However, because of the tethering of the
carboxylate in these ligands, variability and flexibility of the
Figure 1. Illustrative examples of metalloenzyme active sites with the
2-His-1-carboxylate motif: (a) phenylalanine hydroxylase binary enzyme-
tetrahydrobiopterin complex (1J8U);2a (b) phenylalanine hydroxylase ternary
enzyme-tetrahydrobiopterin-substrate complex (1KW0);2b (c) carbox-
ypeptidase (1YME);3b (d) thermolysin (3TMN).3a
binding modes found in the enzymes are difficult to achieve.
A synthetic strategy that has met with considerable success
for generating active site models of nonheme diiron active
sites involves the use of terphenylcarboxylate ligands, which
through steric and hydrophobic effects limit metal coordina-
tion numbers and enable isolation of reactive intermediates.6
Herein we report the use of a related approach in which
sterically hindered carboxylate and N-donor ligands are
combined to assemble mononuclear complexes of iron(II)
and zinc(II). Structural data show that they replicate the
geometry and ligand donor set of the 2-His-1-carboxylate
* To whom correspondence should be addressed. E-mail: que@
chem.umn.edu (L.Q.), tolman@chem.umn.edu (W.B.T.).
(1) (a) Koehntop, K. D.; Emerson, J. P.; Que, L., Jr. J. Biol. Inorg. Chem.
2005, 10, 87-93. (b) Abu-Omar, M. M.; Loaiza, A.; Hontzeas, N.
Chem. ReV. 2005, 105, 2227-2252. (c) Costas, M.; Mehn, M. P.;
Jensen, M. P.; Que, L., Jr. Chem. ReV. 2004, 104, 939-986. (d) Parkin,
G. Chem. ReV. 2004, 104, 699-768.
(5) (a) Beck, A.; Weibert, B.; Burzlaff, N. Eur. J. Inorg. Chem. 2001,
2001, 521-527. (b) Beck, A.; Barth, A.; Hubner, E.; Burzlaff, N.
Inorg. Chem. 2003, 42, 7182-7188. (c) Hegelmann, I.; Beck, A.;
Eichhorn, C.; Weibert, B.; Burzlaff, N. Eur. J. Inorg. Chem. 2003, 2,
339-347. (d) Bruijnincx, P. C. A.; Lutz, M.; Spek, A. L.; van Faassen,
E. E.; Weckhuysen, B. M.; van Koten, G.; Klein Gebbink, R. J. M.
Eur. J. Inorg. Chem. 2005, 779-787.
(6) (a) Que, L., Jr.; Tolman, W. B. J. Chem. Soc., Dalton Trans. 2002,
653-660. (b) Tshuva, E. Y.; Lippard, S. J. Chem. ReV. 2004, 104,
987-1012.
(2) (a) Andersen, O. A.; Flatmark, T.; Hough, E. J. Mol. Biol. 2001, 314,
279-291. (b) Andersen, O. A.; Flatmark, T.; Hough, E. J. Mol. Biol.
2002, 320, 1095-1108.
(3) (a) Holden, H. M.; Matthews, B. W. J. Biol. Chem. 1988, 263, 3256-
3260. (b) Greenblatt, H. M.; Feinberg, H.; Tucker, P. A.; Shoham, G.
Acta Crystallogr., Sect. D 1998, 54, 289-305.
(4) Rardin, R. L.; Tolman, W. B.; Lippard, S. J. New J. Chem. 1991, 15,
417-430.
10.1021/ic061564s CCC: $33.50
Published on Web 09/09/2006
© 2006 American Chemical Society
Inorganic Chemistry, Vol. 45, No. 20, 2006 8003