ALAN v.51 n.1 supl.1 Caracas mar. 2001
The chemistry of ferrous bis-glycinate chelate
Albion Laboratories, Inc., Clearfield, Utah U .S.A.
A
few years later, in 1920, Morgan and Drew applied the term "chelate" to
the molecular structure postulated by Werner (8). In order to form a
chelate, it was recognized that the ligand must have two points of
attachment to the metal ion. It was this caliper-like mode of attachment
that led to the use of the Greek word "chele", meaning lobster claw, to
describe how the ligand was attached to the metal ion. When the claw,
or ligand, held the cation, the metal was restricted in its ability to
enter into other chemical reactions. Once chelated, the metal's chemical
and physical characteristics changed (9). The metal chelates are
coordination compounds in contrast to metal salts where the cation is
bound by electrostatic attraction. In a chelate, the ligand donates
electrons to the cation. More than one donor atom must come from the
ligand so that a heterocyclic ring is formed with the metal being part
of that ring. Comprehension of the structure and characteristics of
metal chelates has had far reaching consequences in medicine, biology,
chemistry, environmental chemistry, and, particularly, nutrition, due to
the stability of the metallic molecule formed.
Complexation of a metal by water in an octahedral geometry as described by Werner
The first of these criteria
requires that the ligand must possess two functional groups, each
capable of donating electrons to bond with the metal ion (11). The
elements in the ligand that commonly function as donors are the more
electronegative ones in the right hand side of the periodic table,
primarily in Group V (12,13). The most important of these ligands
contain N or O or both (14). The donor atoms may form a part of either
an acidic or a basic functional group. Additionally, approximately 65%
of the various types of amino acid sirle
chains contain potential metal binding sites such as the sulfuydryls and
hydroxyls binding groups. The common backbone of the naturally
occurring amino acids contain the α-carboxyl and α-amino groups each of
which can bind metal ions (11). In an
aqueous environment the α-amino acid exists in the zwitterionic state
with both the α-carboxyl and the α-amino groups ionized with opposite
charges. Both reactive groups can thus participate in the chelation of
the metal ion. The carboxyl group contains an electron that can
be shared with the metal ion through a covalent bond. While the amino
group has a pair of electrons that can be donated to the metal ion to
form a coordinate covalent bond. The amino acid ligand is considered to
be bidentate. The amino moiety meets the criteria of Lewis base when
joined to the metal in accordance to current chemistry theory.
There
are three classes of bidentate ligands: (1) two basic groups, (2) one
acidic and one basic group, and (3) two acidic groups. Amino acids fall
into the second category of bidentate ligands. Using glycine (NH2CH2COOH) as an example, in water at a pH of between 3 and 9, this ligand exists as the zwitterion, H3N+CH2COO-.
The amino acid has lost a proton from the COOH group and is thus
capable of chelating a metal ion and forming a five member ring through
donation of one or more electrons to the metal (15).
A
second prerequisite for chelation to occur requires that the functional
groups of the ligand be located so that a ring structure can be formed
with the metal atom being the closing member of the ring (12). Logically
if the ligand has two donor atoms that must attach to a single metal
ion, then a ring structure must be formed. Due to the nature of the
elemental constituents of the ring members, this ring, by definition,
must be heterocyclic. The formation of a ferrous bis-glycinate chelate
is shown in Figure 2 and illustrates this concept.
Each heterocyclic ring in Figure 2
contains two bonds which extend between the ferrous ion and the glycine
ligand in each ring. The first bond between the cation and the anionic,
or polar portion, of the ligand is covalent in nature because they
share one electron from the carboxyl group and one electron from the
ferrous ion. This is the bond between the oxygen from the COO- group, and the Fe++.
The second bond is a coordinate covalent bond. In this case, the iron
behaves as Lewis acid, and the glycine as a Lewis base. The donation of
both electrons from the same atom in the amino group of the ligand to
the metal ion establishes the coordinate covalent bond. This donation of
electrons will go to the lowest energy orbital of the iron ion that is
unfilled, which in this case is a p-orbital (15,16).
The
size of the ligand will also affect the stereochemistry of the chelate.
While one ligand may be able to attach itself to a metal ion without
problem, the addition of a second or third may be prevented by a clash
between the first ligand and parts of the second or third when the
latter ligands attempt to position themselves properly for attachment
(12). In the case of the ferrous bis-glycinate chelate formed from the
reaction in Figure 2,
only the amino acid backbone is involved in the bonding of the ligand
to the ferrous ion. This results in the amino acid backbone assuming a
configuration that sterically allows it to function as a ligand without
straining the bonds within the amino acid.
Using
x-ray diffraction spectrometry, it has been determined that when the
two glycine ligands are chelated to the ferrous ion, the ligands orient
themselves in the least sterically hindered conformation possible. The
covalent and coordinate covalent bonds are tied to the metal at uniform
tetrahedral angles (11,21,22). Figure 3
illustrates a ferrous bis-glycinate chelate molecule drawn from a
computer generated model that employed thermodynamic algorithms 10
determine the most thermodynamically stable configuration. This figure
is consistent with the models previously developed by Pettit and Hefford
describing the steric orientation of amino acid ligand in this class of
bidentate chelates and with x-ray diffraction studies of known chelates
(22,23).
The fourth requirement for
chelation to occur is that the potential reaction between the metal ion
and ligands must be energetically possible. As noted by Werner, the
charge on a metal ion influences its coordination number. If this charge
is low, then only a few lone pairs of electrons from a small number of
ligands could prevent the bonding of greater numbers of ligands. Where
the bonding between the metal and the ligand is primarily covalent, as
in the case of an amino acid chelate, the coordination number of the
metal is determined by the number of bonding orbitals available on the
metal for combination with the ligand orbitals (19). In the case of the
ferrous ion, it is satisfied by a bonding of two glycine ligands as
demonstrated in Figure 2.
If a molar ratio (ligand to iron) of one glycine molecule or less is
employed in the reaction, the ferrous ion has the capability of being
bonded to some other ligand which may ultimately displace or interfere
with chelation by the original glycine ligand. Thus in most situations a
ferrous bis-glycinate chelate is relatively stable since the charges on
both the ion and ligands are balanced and the molar ratio of ligand to
metal is stoichiometrically correcto However in the presence of a strong
oxidizer or reducer, the valency of the metal may change.
FIGURE 3
Ferrous
bis-glycinate chelate drawn to correctly depict the tetrahedral
relationship of the bonds of O, N, C and the metal and the resulting
perpendicular orientation of the two ligand ring structures. The figure
is based on x-ray diffraction spectrometry of pure metal – bis-glucinate
chelate crystals
Not all chelates of iron have equal bioavailability.
Chelation does not guarantee mineral absorption from the gut or its
subsequent metabolism if absorbed (24). After comparing various iron
chelates (EDTA, fructose, citric acid) to ferrous sulfate, Bates, et al.
concluded, "Chelation does not, in itself, ensure efficient uptake [of
iron]. . . " (25). Rubin et al. reported that an EDTA chelate of iron
may bypass the normal absorptive mechanism in the intestines and be
absorbed by diffusion, but due to its high stability constant most of
that EDTA chelated iron later appears in the urine unmetabolized
(26,27). Because some FeEDTA is absorbed intact through the intestine
but subsequently deposited in the urine, Kratzer and Vohra report this
form of iron cannot be effectively used in the treatment of anemia (28).
In order for mineral absorption and metabolism to occur, the chelate
must be nutritionally functional. There are several criteria that must
be met for a chelate to be classified as a nutritionally functional
chelate.
The first of these requirements is
that the iron chelate must have a low molecular weight. In 1970, it was
suggested that in order for an iron amino acid chelate to cross cell (
membranes intact it must have a molecular weight of less , than 1500
daltons (29). Subsequently, others have reported that small molecular
weight chelates facilitate the transfer of iron from serum to tissues
(30). Kratzer and Vohra reported ( that in order for a ligand from a
chelate to promote metal absorption (which goes beyond simply protecting
the metal t ion in the gastrointestinal tract), it must have a
molecular weight of under 1000 daltons. They have added that the higher
molecular weight metalloproteins, such as ferritin or hemosiderin
facilitate storage of the absorbed iron but suggested that these
proteinaceous ligands are too large for intact transport of the iron
molecule across cell membranes. For the transfer to occur the iron must
be removed from the protein complex and bonded to another ligand that
has a lower molecular weight (28).
It is
relatively easy to calculate the molecular weight of a ferrous
bis-g1ycinate chelate. The iron atom has an atomic weight of about 56
daltons. Each glycine ligand has a molecular weight of 75 daltons. Thus
using the formula illustrated in Figure 2,
the ferrous bis-glycinate chelate has molecular weight of about 204
daltons. This molecular weight has been confirmed in the laboratory
(31). This in turn confirms that the molecular weight of the ferrous
bis-glycinate chelate is well below the maximum molecular weight of 800
daltons established by AAFCO for a molecule to be classified as an amino
acid chelate and well below the postulated absorptive limits
(10,29,30).
The second requirement for a
nutritionally functional chelate relates to its stability constant. If
fue chelate is to be classified as nutritionally functional, it must
have a stability constant that is higher than the potential formation
constants of the ligands in the intestinal chyme. This higher stability
constant of the amino acid chelate prevents the molecule from being
destroyed in the gut and allows the chelate to cross the intestinal cell
membrane intact with the metal. Once absorbed into the mucosal cell, a
nutritionally functional chelate must have a stability constant which is
lower than those ligands in the storage systems of the mucosal cells
and the transport systems that deliver the iron to target tissues (29).
In this way, the chelate can be metabolized (degraded into the ligands
and metal) after absorption across the mucosal cell membrane, and still
participate in the regulatory pathways of the metal.
The
Lewis basic strength of the ligand will also affect stability. The
greater Lewis basicity of the ligand, the more stable the resulting
chelate molecule (32). Glycine is an weak Lewis base, overall. This
moderates the stability of the bis- glycinate chelate, and while it is
more stable than the food ligands, it has a lower stability constant
than the iron storage and transport ligands in the body. In a study in
which 59FeSO4 and 55Fe bis-glycinate
chelate were mixed in a cornmeal porridge and fed to 10 volunteers at
breakfast, the absorption of the iron from the chelate was significantly
(p<0.00 1) higher (5.3 times) than was iron absorption from the
sulfate. There was no exchange of the radiolabelled irons from the
ferrous bis-glycinate chelate and ferrous sulfate in the intestinal pool
before absorption demonstrating that this bis- glycinate chelate was
not affected by food ligands and was absorbed intact into the mucosal
cells (33). Once absorbed into the mucosal tissue there is significant
(p<0.05) hydrolyzation of the iron amino acid chelate into its
individual components: iron and amino acids with the rates of transfer
to the serosa from the mucosal tissue being different for each component
(34).
Multidentate ligands, if not
stearically hindered, form more stable chelates than do monodentate
ligands (32). Glycine is a bidentate ligand, and as shown in Figure 3, when the ferrous ion is chelated with two glycine ligands there is no stearic hindrance to either
ligand (35). The stability constant is also affected by the π-bonding
strength of the central metal atom (32). It has been shown that, among
the transition metal ions, copper has the highest stability. Iron is
relatively low: Zn2+ < Cu2+ > Ni2+ > Co2+ > Fe2+ > Mn2+ (36).
It is estimated that a nutritionally functional chelate must have a stability constant of between 107 and 108,
in order for that chelate to survive the environment of the stomach and
intestine and still be hydrolyzed within the mucosal cells or other
tissues (38). An absorbed iron chelate, if it is functional, must have a
bonding constant which is lower than that of transferrin (39). The iron
bis-g1ycinate chelate meets the criteria of having the ideal stability
constant for a nutritionally functional chelate. It has a stability
constant of approximately 107.5 at pH 7 (37).
REFERENCES
1. Werner A. Beitrag zur Konstitution Anaorganischer Verbindunge, Z, Anorg U Allgem Chem 1893;3:267. [ Links ]
3. Werner A & Z Vilmos. Beitrag zur Konstitution Anaorganischer Verbindunge, A anorg U Allegem Chem 1899;21: 153. [ Links ]
5. Werner A. Zer Kenntnis des Asymmetrischen Kobaltatoms V. Ber Deut Chem Ges, 1911;45:121. [ Links ]
6. Werner A. Über spiegelbild-isomerie bei chromverbindungen. III. Ber Deut Chem Ges, 1912;45:3065. [ Links ]
7.
Werner A. Zur Kenntnis des Asymmetrischen Kobaltatoms XII. Uber
Optische Aktivitat bei Kohlenstoffreien Verbindugen. Ber Deut Chem Ges,
1914;47:3087. [ Links ]
8.
Morgan G. & H Drew. Research on residual affinity and co-
ordination. II. Acetylacetones of selenium and tellurium. J Chem Soc,
1920;117:1456. [ Links ]
9. Bell CF. Principles and Application of Metal Chelation. Oxford, Clarendon Press, 1977, p. 3. [ Links ]
10.
Bachman PM. (Ed.) Official Publication 2000. Oxford, IN, American
Association of Feed Control Officials, 2000, p. 257. [ Links ]
11.
Glusker JP. Structural Aspects of Metal Liganding to Functional Groups
in Proteins. In Anfinsen, CB, JT Edsall, FM Richards & DS Eisenberg,
(Eds.) Advances in Protein Chemistry. San Diego, CA, Academic
Press,1991, V.42, p. 4. [ Links ]
13. Bell CF. Principles and Application of Metal Chelation. Oxford, Clarendon Press, 1977, p. 9. [ Links ]
14.
Van Uitert LG & WC Femelius. Coordination compounds. IX. Solution
stabilities of the chelate compounds of a number of organic ligands. J
Am Chem Soc 1954;76:375. [ Links ]
15. Bell CF. Principles and Application of Metal Chelation. Oxford, Clarendon Press, 1977, p. 11-18. [ Links ]
16.
Bailar JC, T Moeller, J Kleinberg, CO Guss, ME Castellion & C Metz.
Chemistry. Orlando, FL, Academic Press, 1984, p. 246-253.Ahrens, LH.
Ionization Potentials: Some Variations, Implications, and Applications.
Oxford, UK, Pergamon Press, 1983. [ Links ]
17.
Ahrens RD. Ionization potentials: Some Variations, Implications, and
Applications. Oxford, U.K. Pergamon Press. 1983. [ Links ]
18. Shannon RD & CT. Prewitt. Effective ionic radil in oxides and flourides. Acta Crystallogr 1969;25:925-46. [ Links ]
19. Bell CF. Principles and Application of Metal Chelation. Oxford, Clarendon Press, 1977, p. 33-35. [ Links ]
20.
Howard JB & DC Rees. Perspectives on Non-Heme Iron Protein
Chemistry. In C.B. Anfinsen, J. T. Edsall, F.M. Richards & D.S.
Eisenberg, (Eds.) Advances in Protein Chemistry. San Diego, CA, Academic
Press, 1991, V.42, p.206. [ Links ]
21.
Dalley NK. X-ray diffraction of iron amino acid chelate, Albion
Laboratories, Inc., Unpublished Research Report, 1978. [ Links ]
22.
Dalley NK. X-ray diffraction crystallography of Albion Zinc Amino Acid
Chelate. Albion Laboratories, Inc., Unpublished Research Report, 1991.
[ Links ]
23.
Pettit LD & RJW Hefford. Steroselectivity in the metal complexes of
amino acids and dipeptides. In: Metal Ions in Biological Systems. H.
Sigel (Ed.) NY, Marcel Deker, 1979; V.9 p. 173-212. [ Links ]
24. Ashmead H, D Ashmead & N Jensen. Chelation does not guarantee mineral metabolism. J App Nutr 26:5-21, 1974. [ Links ]
25.
Bates GW, J Boyer, JC Hegenauer & P Saltman. Facilitation of iron
absorption by ferric fructose. Am J Clin Nutr, 1972;25:983. [ Links ]
26.
Rubin M., J Houlihan & JV Princiotto. Chelation and Iron Metabolism
I; Relative iron binding of chelating agents and siderophilin in serum.
Proc Soc Exp Biol and Med 1960;103:663. [ Links ]
27.
Rubin M & JV Princiotto. Synthetic amino acid chelating agents and
iron metabolism. Ann NY Acad Sci 1960;88:450. [ Links ]
28. Kratzer FH & P Vohra. Chelates in Nutrition. Boca Raton, FL, CRC Press, 1986, p. 42-44. [ Links ]
29.
Hofner W. Eisen und manganhaltige Verbindungen im Blutungassafit von
Helianthus annuus, Physiol Plant, 1970;23:673-677. [ Links ]
30.
Tiffin LO. Translocation of micronutrients in plants. In:
Micronutrients in Agriculture. RC Dinauer (Ed.) Madison, WI, Soil
Science Society of America, Inc., 1972, p. 207. [ Links ]
31.
Johnson B. Molecular weights of several commercial chelates. Albion
Laboratories, Inc. Unpublished research, 1974. [ Links ]
32. Kratzer FH & P Vohra. Chelates in Nutrition. Boca Raton, FL, CRC Press, 1986; p. 25-27. [ Links ]
33.
Allen LH. Properties of iron amino acid chelate as iron fortificants
for maize. In: Proceedings International Conference on Human Nutrition.
Salt Lake City, UT, Albion Laboratories, Inc., 1998, p. 96-108.
[ Links ]
34.
Ashmead HD, DJ Graff & HH Ashmead. Intestinal Absorption of Metal
Ions and Chelates. Springfield, IL, Charles C Thomas, 1985, p. 205-212.
[ Links ]
35.
Jeppsen RB. Organic minerals and their bioavailability on the basis of
chemistry. In: Proceedings International Animal Conference. Salt Lake
City, UT, Albion Laboratories, Inc., 1997, p. 8. [ Links ]
37. Kragten J. Atlas of Metal-ligand Equilibria in Aqueous Solution. Chichester, Ellis Horwood, 1978. [ Links ]
38. Ashmead SD. Metabolism of zinc amino acid chelate: A preliminary study. Masters Thesis, University of Utah, 1994. [ Links ]
39.
Williams RJP. An introduction to the nature of iron transport and
storage. In: Iron Transport and Storage. P Ponka, HM Schulman & RC
Woodworth. (Eds.) Boca Raton, FL, CRC Press, 1990, p.1-15. [ Links ]
40.
Reeds PJ & PR Beckett. Protein and amino acids. In: Present
Knowledge in Nutrition. EF Ziegler & U Filer (Eds.) Washington, DC,
ILSI 1996, p. 67-68. [ Links ]
41.
Jaksie T, F Jahoor, PJ Reeds & W Heird. The determination of amino
acid synthesis in human neonates with a glucose stable isotope. Surg
Forum 1993;44:642-686. [ Links ]
42.
Jackson AA, JCL Shaw, A Barber & M Golden. Nitrogen metabolism in
pre-term infants red human donor breast milk: The possible essentiality
of glycine. Ped Res 1981; 15: 1454- 1461. [ Links ]
43.
Davis T, HV Nguyen, R Garcia-Bravo. The amino acid composition of human
milk is not unique. J Nutr 1994;124:1128-1134. [ Links ]
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