Chemistry Reference
In-Depth Information
1.3.1.4 Ionophores and Siderophores
Ionophores [155] are small peptides or other kinds of molecules excreted by microorgan-
isms which can selectively bind and transport alkali or alkaline earth metal ions across
cell membranes and artificial lipid bilayers, whereas siderophores [156] selectively bind
and transport Fe
3þ
[75]. These molecules can: (a) disturb the ionic balance across mem-
brane, such as nactins, lasalocid, and valinomycin, (b) create pores on membranes, such
as gramicidins, and (c) compete for iron in the environment, such as ferrichromes. The
potential imbalance across the cell membrane may slow down cell growth or cause cell
death. Consequently, the metal ions in metalloionophores serve as “magic bullets” to
cause a potential imbalance and engender antibiotic activities. The mechanism of this
type of antibiotic activity has been adopted in the design of channel-forming antibacterial
agents [157].
Ionophores and siderophores exhibit significant conformational changes upon metal
binding [155], from extended conformations to compact folded forms as in the case of
nactins (e.g., nonactin, tetranactin, and dinactin) and valinomycin [158,159]. The metallo-
forms then bind specific receptors on the cell surface and result in the transport of metal
ions into the cell. Depending on the target metal ions, the structures of the metalloforms
may vary dramatically. In the case of enniatin cyclic (
L
-N-methyl-valine-
D
-hydroxy-
isovalerate)
3
, the parent ionophore has a structure very similar to its K
þ
complex, yet
quite distinct from its Rb
þ
complex [160]. This family of antibiotics contain an O-rich
metal-binding environment, including ether groups, the carbonyl group of esters and
amides, and carboxylates preferably for binding with alkali and alkaline earth metal ions
in different metal:ligand ratios attributed to the structures, the size of their metal-binding
site, the ionic radii of the metal ions, and/or the hydration energy of the cations [75].
The gramicidins family is a peptide ionophore family produced by
Bacillus brevis
[161], of which gramicidin A is the major component. Its primary structure contains six
D
-form amino acids, that is, formyl-Val-Gly-Ala-(
D
-Leu
4
)-Ala-(
D
-Val
6
)-Val-(
D
-Val
8
)-Trp-
(
D
-Leu
10
)-Trp-(
D
-Leu
12
)-Trp-(
D
-Leu
14
)-Trp-ethanolamine (and Trp
11
!
Phe in gramici-
din B and Trp
11
Tyr in gramicidin C). This family exhibits an antibiotic mechanism
different from those cation-binding ionophores described above by inserting into the lipid
bilayer as a dimer and folding into a unique b-double-stranded helix [162] to create a pore
of
!
4A
(Figure 1.13) with selectivity in the order H
þ
>
NH
4
þ
>
Cs
þ
>
Rb
þ
>
K
þ
>
Na
þ
N(CH
3
)
4
þ
in 0.1M salt [163]. However, it does not show permeability to the
divalent metal ions Mg
2þ
,Ca
2þ
,Ba
2þ
, and Zn
2þ
, which bind to the entrance of the chan-
nel and prevent the transport of monovalent cations [164]. Similar configurations are
observed for the peptide backbone in both solution and solid state [165] (Figure 1.13)
with hydrophobic amino acid side chains facing outward for better interaction with the
lipid bilayer [165-170]. However, the structures in solution determined by NMR spectros-
copy exhibit a higher degree of irregularity, such as the shape of the channel. The binding
of monovalent metal ions does not seem to cause a significant conformational change in
gramicidins. The insertion of gramicidins into membranes does not rely on the binding of
metal ions as in the case of the ionophores described above, thus it does not create a fur-
ther energy barrier for metal binding and transport.
The extremely small solubility product
K
sp
of
Li
þ
>
>
10
38
for Fe(OH)
3
under aerobic phys-
iological conditions makes soluble Fe
3þ
in aqueous solutions very scarce. To overcome
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