Synthesis, Structure, and Molecular Dynamics of Gallium
Complexes of Schizokinen and the Amphiphilic
Evgeny A. Fadeev, Minkui Luo, and John T. Groves*
Contribution from the Department of Chemistry, Princeton UniVersity,
Princeton, New Jersey 08544
Received March 31, 2004; E-mail: email@example.com
Abstract: A new general synthesis of the citrate-based siderophores acinetoferrin (Af) and schizokinen
(Sz) and their analogues is described. The molecular structure of gallium schizokinen, GaSz, was determined
by combined1H NMR, Hartree-Fock ab initio calculations, DFT, and empirical modeling of vicinal proton
NMR spin-spin couplings. The metal-coordination geometry of GaSz was determined from NOE contacts
to be cis-cis with respect to the two chelating hydroxamates. One diaminopropane adopts a single chairlike
conformation while another is a mixture of two ring pucker arrangements. Both amide hydrogens are
internally hydrogen bonded to metal-ligating oxygen atoms. The acyl methyl groups are directed away
from each other with an average planar angle of ca. 130°. The kinetics of GaSz racemization were followed
by selective, double spin-echo inversion-recovery1H NMR spectroscopy over the temperature range of
10-45 °C. The racemization proceeds by a multistep mechanism that is proton independent between pD
5 and 12 (k0 ) 1.47 (0.15 s-1)) and acid catalyzed below pD 4 (k1 ) 2.25 (0.15) × 104M-1s-1). The
activation parameters found for the two sequential steps of the proton independent pathway were ∆Hq)
25 ( 3 kcal M-1, ∆Sq) 25 ( 7 cal M-1K-1and ∆Hq) 17.1 ( 0.2 kcal M-1, ∆Sq) 0.3 ( 2.7 cal M-1K-1.
The first step of the proton-independent mechanism was assigned to the dissociation of the carboxyl group.
The second step was assigned to complex racemization. The proton-assisted step was assigned to a
complete dissociation of the R-hydroxy carboxyl group at pD < 4. The ab initio modeling of gallium
acinetoferrin, GaAf, and analogues derived from the structure of GaSz has shown that the pendant trans-
octenoyl fragments are oriented in opposite directions with the average planar angle of ca. 130°. This
arrangement prevents GaAf from adopting a phospholipid-like structural motif. Significantly, iron siderophore
complex FeAf was found to be disruptive to phospholipid vesicles and is considerably more hydrophilic
than Af, with an eight-fold smaller partition coefficient.
Siderophores are a class of low molecular weight organic
compounds that are produced by microorganisms in response
to iron deficiency. These compounds are capable of highly
selective chelation and delivery of inorganic iron1,2to bacterial
cells via specific, receptor-mediated membrane transport mech-
anisms.3Siderophore-mediated iron uptake is an important
determinant of bacterial growth3and there is suggestive evidence
that iron proteins and siderophores are involved in cell signaling
cascades and quorum sensing.4-6Amphiphiles are a significant
and widely distributed subset of siderophores,7having been
found in pathogens,8-11terrestrial symbionts,12and marine
microorganisms.13-15Mycobactins, lipophilic siderophores of
Mycobacter smegmatis, have shown beneficial activity for the
treatment of arteriosclerosis,16breast cancer,17and postischemic
reperfusion injury.18A synthetic, amphiphilic analogue of
desferoxamine has been reported to inhibit malaria19,20and
another lipophilic tripeptide ornithine-based hydroxamate
(1) Albrecht-Gary, A. M.; Crumbliss, A. L. Met. Ions Biol. Syst. 1998, 35,
(2) Boukhalfa, H.; Crumbliss, A. L. Biometals 2002, 15, 325-339.
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(8) Lane, S. J.; Marshall, P. S.; Upton, R. J.; Ratledge, C. Biometals 1998, 11,
(9) Okujo, N.; Sakakibara, Y.; Yoshida, T.; Yamamoto, S. Biometals 1994, 7,
(10) Snow, G. A. Biochem. J. 1965, 97, 166-175.
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(12) Persmark, M.; Pittman, P.; Buyer, J. S.; Schwyn, B.; Gill, P. R.; Neilands,
J. B. J. Am. Chem. Soc. 1993, 115, 3950-3956.
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Chem. 2001, 76, 175-187.
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Haygood, M. G.; Butler, A. Science 2000, 287, 1245-1247.
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A. D.; Horwitz, M. A.; Burchenal, J. E. B.; Horwitz, L. D. Circulation
2001, 104, 2222-2227.
(17) Pahl, P. M. B.; Horwitz, M. A.; Horwitz, K. B.; Horwitz, L. D. Breast
Cancer Res. Treat. 2001, 69, 69-79.
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Fennessey, P. V.; Horwitz, M. A. Proc. Natl. Acad. Sci. U.S.A. 1998, 95,
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1991, 40, 584-590.
Published on Web 09/01/2004
10.1021/ja048145j CCC: $27.50 © 2004 American Chemical Society
J. AM. CHEM. SOC. 2004, 126, 12065-12075 9 12065
chelator was found to effectively promote growth of Mycobacter
smegmatis.21Strategies for the design of antibiotic “Trojan
Horse” siderophore conjugates have been described.22The
ubiquity of amphiphilic siderophores, the mechanisms of their
exploitation by pathogens, and their promising pharmacological
activities focus attention on the structures and functions of these
little-studied natural products.
Our interest in amphiphiles23and membrane assemblies24-27
has led us to examine the citrate-based siderophore acinetoferrin
(Af) of Acinetobacter haemoliticus, an antibiotic-resistant
bacterium that causes an increasing number of difficult-to-treat
infections.28This bacterium produces two siderophores: acineto-
ferrin9(principally) and smaller amounts of acinetobactin.29,30
Acinetoferrin belongs to a class of citrate-based siderophores
(Figure 1) in which the terminal carboxyl groups of citric acid
are peptide-coupled to two hydroxamate-bearing appendages.
Other citrate-based siderophores are aerobactin,31arthrobactin,32
nannochelin,33petrobactin,34-36rhizobactin 1021,12and schizok-
Acinetoferrin is a unique member of this family, having two
lipophilic side chains resembling a phospholipid structural motif.
The amphiphilic nature of this siderophore and its unusual
structure are suggestive of a special mechanism of action,
wherein its interactions with cell membranes play an essential
role. While the coordination chemistry of ferric schizokinen
FeSz40and ferric aerobactin41have been investigated spectro-
scopically, no molecular structures of this class of citrate-based
siderophores have been reported.
Here we present an efficient and general synthesis of Af, Sz,
and their analogues. We also describe the three-dimensional
structure of the Ga3+complexes of Sz and Af derived from1H
NMR data, Hartree-Fock ab initio, and DFT molecular
modeling. The coordination geometries of the GaAf and GaSz
hydroxamate groups are unambiguously determined to be cis-
cis. The two enantiomers of GaAf and GaSz are shown by1H
NMR to equilibrate readily. A sequential, two-step mechanism
of racemization has been discerned from the kinetics of this
process. The solution structure of FeAf and the conformational
analysis of the FeAf aliphatic tails have been inferred from the
GaSz geometry. The resulting conformation of FeAf suggests
a special mode of interaction of the metal-Af complex with the
cell phospholipid membranes that is dictated by a change in
the arrangement of the lipophilic side chains upon metal binding.
Synthesis of Siderophores. Synthesis of schizokinen42and
acinetoferrin43were reported previously. We developed a general
method (Figure 2) allowing synthetic access to both compounds
and their 2-E-butenoyl and 2-E-dodecenoyl homologues without
major changes in the procedure. The key feature of this approach
is the coupling of 2-tert-butyl-1,3-di-N-(hydroxy)succinimidyl
citrate,421, with 1-N-benzoyloxy-1,3-diaminopropane dihydro-
chloride 2. Compound 2 was conveniently obtained from
propane43upon treatment with dry HCl.
Attachment of the acyl fragments to 3 was achieved in high
yield via the appropriate acyl chloride. The resulting fully
protected siderophores, 4a-d, were amenable to purification
by column chromatography under conditions dictated by the
terminal acyl chain length. This strategy has the advantage of
retaining the protected hydroxamate groups until the molecular
scaffold was fully assembled, thus lessening the iron contamina-
tion acquired from the glassware and silica that is an inherent
difficulty with these compounds.43
The benzoyl protecting groups of 4a-d were removed under
basic conditions and the resulting crude products were separated
on a short column packed with a specially prepared, iron-free
silica.43Final cleavage of the tert-butyl esters 5a-c was effected
with 95:5 TFA:H2O at 25 °C. We found that dry TFA led to
some dehydration of the citrate hydroxyl. The free siderophores
6a (Sz) and 6c were purified by gel filtration with sephadex
G-10. Compounds 6b (Af) and 6d were sufficiently lipophilic
to be separated from the residual TFA by the chloroform/water
Stoichiometry and Overall Structure of the Iron Af and
Gallium Sz Complexes. The iron complexes Fe-6(a-d) were
prepared by metalation of 6(a-d) with ferric ammonium citrate.
Polyacrylamide gel electrophoresis showed that Fe-6(a-d) were
(20) Harpstrite, S. E.; Beatty, A. A.; Collins, S. D.; Oksman, A.; Goldberg, D.
E.; Sharma, V. Inorg. Chem. 2003, 42, 2294-2300.
(21) Lin, Y. M.; Miller, M. J.; Mollmann, U. Biometals 2001, 14, 153-157.
(22) Murray, A. P.; Miller, M. J. J. Org. Chem. 2003, 68, 191-194.
(23) Xu, G. F.; Martinez, J. S.; Groves, J. T.; Butler, A. J. Am. Chem. Soc.
2002, 124, 13408-13415.
(24) Lahiri, J.; Fate, G. D.; Ungashe, S. B.; Groves, J. T. J. Am. Chem. Soc.
1996, 118, 2347-2358.
(25) Groves, J. T.; Fate, G. D.; Lahiri, J. J. Am. Chem. Soc. 1994, 116, 5477-
(26) Groves, J. T.; Neumann, R. J. Am. Chem. Soc. 1989, 111, 2900-2909.
(27) Groves, J. T.; Neumann, R. J. Am. Chem. Soc. 1987, 109, 5045-5047.
(28) Rudant, E.; Courvalin, P.; Lambert, T. Antimicrob. Agents Chemother. 1997,
(29) Yamamoto, S.; Okujo, N.; Sakakibara, Y. Arch. Microbiol. 1994, 162, 249-
(30) Dorsey, C. W.; Tolmasky, M. E.; Crosa, J. H.; Actis, L. A. Microbiology
2003, 149, 1227-1238.
(31) Gibson, F.; Magrath, D. I. Biochim. Biophys. Acta 1969, 192, 175-184.
(32) Schafft, M.; Diekmann, H. Arch. Microbiol. 1978, 117, 203-207.
(33) Kunze, B.; Trowitzschkienast, W.; Hofle, G.; Reichenbach, H. J. Antibiot.
1992, 45, 147-150.
(34) Barbeau, K.; Zhang, G.; Live, D. H.; Butler, A. J. Am. Chem. Soc. 2002,
(35) Bergeron, R. J.; Huang, G. F.; Smith, R. E.; Bharti, N.; McManis, J. S.;
Butler, A. Tetrahedron 2003, 59, 2007-2014.
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2004, 69, 3530-3537.
(37) Akers, H. A. Appl. EnViron. Microbiol. 1983, 45, 1704-1706.
(38) Simpson, F. B.; Neilands, J. B. J. Phycol. 1976, 12, 44-48.
(39) Trick, C. G.; Kerry, A. Curr. Microbiol. 1992, 24, 241-245.
(40) Plowman, J. E.; Loehr, T. M.; Goldman, S. J.; Sanders-Loehr, J. J. Inorg.
Biochem. 1984, 20, 183-197.
(41) Harris, W. R.; Carrano, C. J.; Raymond, K. N. J. Am. Chem. Soc. 1979,
(42) Milewska, M. J.; Chimiak, A.; Glowacky, Z. J. Prakt. Chem./Chem.-Ztg.
1987, 329, 447-456.
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Figure 1. Structure of acinetoferrin, Af (R ) trans-1-heptenyl) and Sz (R
A R T I C L E S
Fadeev et al.
12066 J. AM. CHEM. SOC.9VOL. 126, NO. 38, 2004
negatively charged at neutral pH. Orange colored bands (λmax
) 400-426 nm) of the complex molecules were observed to
move toward the anode. Negative ion electrospray mass
spectrometry of FeAf and GaSz (Figures S1 and S2) complexes
showed one major peak at m/z 636 and 485, respectively,
corresponding to a 1:1 metal-siderophore complex bearing one
negative charge. A NMR titration of Sz with GaBr3 (Figure
S3) also indicated a 1:1 metal-to-ligand stoichiometry in
agreement with the conclusions of Plowman et al.40for the FeSz
complex. Therefore, the ligands must saturate the Ga3+and Fe3+
octahedral coordination and the R-hydroxy acid as well as the
two hydroxamates are deprotonated.
NMR Spectroscopy of GaSz. The1H NMR spectra of GaSz
(Figure 3) and GaAf (Figure S16) were very similar, indicating
very similar structures. Among the spectral similarities are the
ordering and shape of the1H signals from the citrate and 1,3-
diaminopropane methylene groups, and the presence of the two
NOE cross-peaks between one methylene proton adjacent to
the each hydroxamate and the vinyl (GaAf) or methyl (GaSz)
protons of the terminal alkyl side chains. The GaSz spectrum
was more amenable to detailed analysis as it was better resolved
and not complicated by the presence of signals from the trans-
octenoyl fragments of GaAf.
The1H NMR spectrum of the Na[GaSz] in D2O (Figure 3)
displayed remarkably well-defined multiplets in the range of δ
1.4-4.3 for the methylene and methyl protons and at δ 7.5 and
9.3 for the amide protons. There were additional broad
resonances more pronounced at higher pH (>6) that were not
assigned to a particular structure and probably account for a
partially hydrolyzed complex.
The1H peaks of the terminal methyl groups and all the
methylene hydrogen atoms, excluding those on the citrate
moiety, were assigned to one of the N-n-diaminopropane
branches on the ligand on the basis of the bond connectivity
revealed by COSY and distance via NOESY spectra. Thus,
resonances 1-7 in Figure 3 belong to one diaminopropane chain
(designated chain I), and resonances 1′-7′ to the other chain
(chain II). Resonances from the methylene groups neighboring
the hydroxamate residues (2, 2′, 4, and 4′) were distinguished
by the presence of the NOE correlation peaks between the
resonances 2 and 2′ with the corresponding terminal methyl
protons. Hydrogen atoms on the methylene groups connected
to the amide nitrogens were identified by observing crosspeaks
in the COSY spectrum with WET water resonance suppression.
The1H resonance chemical shift assignments for GaSz and
the spin-spin coupling values are shown in Table 1. The
observed spin-coupling pattern for chain I is consistent with a
single conformation with well-defined, staggered relationship
of the central methylene (resonances 6 and 7) with the two
neighboring methylene groups (resonances 2-5). Resonance 7
clearly originates from a proton bearing two trans-diaxial
relationships with its neighbors. Also, there is an additional NOE
signal (not observed for the chain II) between the two hydrogen
atoms (resonances 4 and 5) separated by three carbon atoms.
The protons in chain II, by contrast, display more average-sized
vicinal splittings. Also, the chemical shift dispersion within
geminal proton pairs is smaller in the chain II.
That every proton in the molecule has a distinctive chemical
shift indicated that the GaSz complex is chiral. The 1D1H NMR
spectra of GaSz and GaAf did not show signs of exchange
broadening at room temperature but NOE spectra (Figures S15
and S16) showed slow exchange of chain I and chain II
resonances, indicating that the chains interchanged their identi-
ties by the racemization.44The racemization kinetics were
followed by a Double Pulsed Field Gradient Spin-Echo
(DPFGSE) NOESY-1D experiment45that has a great advantage
over 2D NOESY measurements for small molecules due to the
higher accuracy and speed. The kinetic data yielded accurate
racemization rate constants and activation parameters (see the
section below) allowing an insight into the racemization
Another interesting feature of the GaSz NMR data is the low-
field values of the amide hydrogen chemical shifts (resonances
1 and 1′) at δ 9.43 and 7.5, suggesting the presence of
intramolecular hydrogen bonds.46To investigate properties of
(44) Perrin, C. L.; Dwyer, T. J. Chem. ReV. 1989, 90, 935-967.
(45) Stott, K.; Keeler, J.; Van, Q. N.; Shaka, A. J. J. Magn. Reson. 1997, 125,
(46) Becker, E. Hydrogen bonding. In Encyclopedia of Nuclear Magnetic
Resonance; John Wiley: New York, 1996; Vol. 4, p 4212.
Figure 2. General synthesis of the acinetoferrin siderophore family: (a) 3
equiv of TEA, CH3CN; (b) 2 equiv of acyl chloride, CH2Cl2, reflux, 1 h;
(c) 2 equiv of 5 N aqueous NaOH, CH3OH, 0 °C, 10 min; (d) TFA/H2O
19:1, 1 h. R: -CH3- 4-6a; trans-(CH)2(CH2)4CH3- 4-6b; trans-
(CH)2CH3- 4-6c; trans-(CH)2(CH2)8CH3- 4-6d.
Structures of Ga3+Siderophore Complexes
A R T I C L E S
J. AM. CHEM. SOC. 9 VOL. 126, NO. 38, 2004 12067
these hydrogen bonds, we studied dependencies of amide
resonance chemical shifts on pD. The chemical shift of
resonance 1′ was slightly sensitive to solution pD in the alkaline
region (pD ∼ 11); in contrast resonance 1 did not change until
the complete hydrolysis at pD ∼ 12.
12068 J. AM. CHEM. SOC.9VOL. 126, NO. 38, 2004
Kinetics of GaSz Racemization. The racemization rate was
determined from DPFGSE NOESY-1D spectra as a function
of pD at 15 °C and 25 °C (Figure 8). There were two regimes
of racemization, depending on acidity. At pD > 5 its rate was
nearly constant, krac≈ 1.4 s-1, and the ∆Gqprofile vs T (Figure
in D2O. Spin-spin connectivities, the corresponding coupling magnitudes, and the NOE contacts are indicated. Spin-spin coupling assignments for chain
I are grouped above the spectral line and for chain II, below.
1H NMR spectrum of aqueous Na[GaSz], pH ) 7, T ) 25 °C: (a) WET-1D1H spectrum of the amide region in 10% D2O; (b) 1D1H spectrum
1H NMR Peak Assignments of Ga Schizokinen Complex, GaSza
spin−spin couplings, Hz
spin−spin couplings, Hz
2' 3'4' 5'6'7'
aSpectra taken in D2O at pD ) 7.5. *NOE contact with terminal methyl hydrogens. **Weak NOE signal.
A R T I C L E S
Fadeev et al.
7) obtained from the measured rated constants clearly showed
biphasic behavior. At T < 28 °C, ∆Hqwas 25 ( 3 kcal M-1
and ∆Sqwas 25 ( 7 cal M-1K-1. Above 28 °C the activation
parameters sharply changed: ∆Hqbecame 17.1 ( 0.2 kcal M-1
and ∆Sqdropped to a value of 0.3 ( 2.7 cal M-1K-1. At pD
< 4 the racemization sharply accelerated (Figure 8) and was
first-order in [D]+, where the rate constant krac could be
represented as krac) k1[D]++ k0, with k1) (2.25 ( 0.15) 104
M-1s-1, k0) 1.47 ( 0.15 s-1, R2) 0.9924.
Molecular Modeling of the Structures of GaSz and GaAf.
The geometry of the GaAf structure was approached by
molecular modeling in several steps. Ab initio Hartree-Fock
and DFT-optimized GaSz structures were examined for compat-
ibility with the experimental vicinal spin-spin coupling values,
the NOE contacts, and the dynamic features observed in the
NMR spectra. Candidate structures for the core fragment of
GaAf were chosen in cis-cis and cis-trans coordination
geometries and with various 11-membered chelation ring pucker
arrangements. The best geometries yielded a complete chemical
shift assignment of the GaSz1H NMR spectrum shown in Figure
5. Finally, the favorable GaAf terminal alkyl chain orientations
(Figure 6) were determined by analyzing the torsional energy
profiles for the GaSz models extended with one terminal trans-
1-propenyl and the trans-1-heptenyl tail.
GaSz Model Construction. We considered two GaSz con-
figurations. The cis-cis configuration (Figure 4a),wherein both
hydroxamate NO fragments are cis with respect to the ligand
carboxyl group, appearing to be more relaxed in comparison to
the cis-trans configuration (Figure 4b), in which the hydrox-
amate NO fragment on the right part of molecule is trans- with
respect to the carboxyl group. A third, trans-cis configuration,
was unstable in ab initio computations.
Models of GaSz with different 11-membered chelate ring-
pucker conformations within both cis-cis and cis-trans
geometries were built by changing orientations of the amide
groups and the central methylene units on the two N-n-
propylacetamido chains. The orientations of those groups were
designated as R (“up”) or ? (“down”).47As a reference, the
molecular orientation was as shown in Figures 4 and 5.
Ab Initio Hartree-Fock and DFT Modeling. Calculation
Strategy. The Hartree-Fock ab initio and DFT methods were
explored for the modeling of GaSz structures. Geometry
optimizations with B3LYP/6-31G(d) essentially reproduced the
literature X-ray structure geometrical parameters of gallium
hydroxamate complexes.48-52By contrast, some of those
parameters in the RHF/6-31G(d) gas-phase geometry-optimized
structures deviated slightly from those known from literature.48-52
In particular, the hydroxamate C-O bond length in the RHF/
6-31G(d) structures (1.24 Å) was ∼0.03 Å shorter than is
typical. However, the relative conformational energies were
practically the same when obtained for both ab initio RHF/6-
31G(d) and DFT B3LYP/6-31G(d) methods.53We conclude that
a slight inacuracy in the geometry predictions for the gallium
(47) The four-symbol combinations (RRRR, RRR?, Rγ?R, etc.) were used to
define the various ring-pucker conformations of GaSz. The label characters
reflect orientations of the four groups labeled as i-iV in Figure S25b: left-
hand side methylene (i), left-hand side carbonyl (ii), right-hand side carbonyl
(iii), and right-hand side methylene (iV) groups, in that order. An additional
amide group conformation, "γ", was introduced after we obtained the
optimized structures. In that conformation the amide proton was hydrogen-
bonded to the uncoordinated citrate central carboxyl oxygen, instead of
one of the metal-bound oxygen atoms, as it was in all "R“ and ”?"
(48) Keys, A.; Barbarich, T. J.; Bott, S. G.; Barron, A. R. J. Chem. Soc., Dalton
Trans. 2000w, 577-588.
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1996, 35, 1084-1086.
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D. L. J. Chem. Soc., Dalton Trans. 1991, 231-239.
(51) Borgias, B. A.; Barclay, S. J.; Raymond, K. N. J. Coord. Chem. 1986, 15,
(52) Dhungana, S.; White, P. S.; Crumbliss, A. L. J. Am. Chem. Soc. 2003,
(53) The relative GaSz conformation energies were almost the same when
calculated with RHF/6-31G(d)//RHF/6-31G(d), RHF/6-31G(d)//B3LYP/6-
31G(d), and B3LYP/6-31G(d)//B3LYP/6-31G(d) method combinations for
the geometry optimization and the single point energy calculation
Figure 4. GaSz configurations, (a) cis-cis and (b) cis-trans.
Figure 5. Structures of the two dominant GaSz conformations and1H NMR
resonance assignments. Arrows show the groups with different ring-pucker
arrangements in structures RRRR and RR??.
Figure 6. GaAf structure in RR?? conformation of the core fragment and
in one of the minimum-energy octenoyl tail conformations. Dashed lines
denote the NH‚‚‚O hydrogen bonds.
Structures of Ga3+Siderophore Complexes
A R T I C L E S
J. AM. CHEM. SOC. 9 VOL. 126, NO. 38, 2004 12069