Siderophores
Jimmy
Ngo,
Brian
Smith
and
Robert
Taylor
Biological
Need
Metals
are
necessary
for
life
Metals
are
scarce
in
most
environments
Compe>>on
for
Metals
Siderophores!
What
are
they?
Small
biomolecules
secreted
by
Fungi,
Bacteria,
and
some
grasses
Diversity
of
siderophores,
specic
to
species
Chelate
various
metal
ions,
primarily
Fe3+
(Al,
Cu,
Cr,
Zn,
Mn,
Cd,
Pb
among
other
ligands)
Import
of
siderophore-Fe
complex
increases
availability
of
cytosolic
Fe3+
Know
the
Enemy!
Regula>on
Fe3+
in
some
siderophores
reduced
to
Fe2+
by
various
enzymes
(ferric-chelate
reductase
in
some
bacteria)
Gram-Posi>ve
When
levels
sucient,
Fe2+
binds
Ferric
Uptake
Regulator
(FUR),
FUR-Fe
complex
represses
expression
of
siderophore
synthetase
gene
Gram-Nega>ve
When
levels
sucient,
Fe2+
binds
Dipthera
Toxin
Repressor
(DtxR),
DtxR-Fe
complex
represses
expression
of
siderophore
synthetase
gene
Export
Ac>ve
Transport
eux
pump
Reliance
on
either
ATP
or
proton
gradient
an>port
coupling
Sensi>ve
to
siderophore
structure
will
not
export
siderophore
complexed
to
metal
Func>on!
Siderophores
must
be
stronger
binders
of
Fe
than
compe>ng
host
binders
(Transferrin)
Fe3+
is
a
hard
acid,
prefers
hard
bases
such
as
anionic
or
neutral
oxygen
So
major
groups
in
siderophores
include
catecholates,
hydroxamates,
and
carboxylates
What
is
Chela>on?
The
forma>on
of
two
or
more
separate
bindings
between
a
ligand
and
a
central
atom,
such
as
Fe
As
opposed
to
a
coordina>on
complex,
where
only
one
bond
exists
between
mul>ple
monodentate
ligands
and
a
central
atom
The
Chelate
Eect
A
chelate
complex
is
generally
more
stable
when
compared
to
a
similar
complex
composed
of
mul>ple
monodentate
ligands
Because
of
entropy,
when
a
chelate
ligand
binds
to
the
metal
there
is
either
a
smaller,
or
more
favorable,
change
in
entropy
Cd2+
+
4
MeNH2
Cd(MeNH2)42+
Cd2+
+
2
en
Cd(en)22+
3+
Binding
of
Fe
O`en
siderophores
form
a
hexadentate,
octahedral
complex
with
Fe3+
The
most
eec>ve
are
ones
that
have
three
bidentate
ligands
(Chelate
eect
+
Oxygen)
Desferrioxamine
B
hap://parasitology.med.nyu.edu/people/faculty/allen-clarkson
hap://www.uni-marburg.de/e15/ag-oberthuer/research?language_sync=1
A
Notable
Siderophore
Enterobac>n
Anity:
Ka=1052
M-1
Higher
than
EDTA
Strongest
Known
Import
Eukaryo>c
Exchange
+
Reduc>on
of
Fe3+
at
membrane,
only
Fe2+
taken
up
Prokaryo>c
Uptake
of
en>re
Siderophore-Metal
complex
Mul>ple
ac>ve
transport
pumps
for
cytoplasmic
reloca>on
triggered
by
interac>on
with
TonB
receptor
3+
Release
of
Fe
Fe3+
is
a
hard
metal,
binds
strongly
to
neutral
or
anionic
oxygen,
thus
the
prevalence
of
oxygen
groups
in
siderophores
However
Fe2+
has
a
lower
anity
for
these
groups
and
is
released
from
the
siderophore,
and
the
siderophore
can
be
recycled
Enzymes
such
as
ferric-chelate
reductase
are
used
to
reduce
chelated
Fe3+
to
Fe2+
2
Fe(II)
+
NAD+
2
Fe(III)
+
NADH
+
H+
3+
Release
of
Fe
The
siderophore
Enterobac>n
has
such
a
high
anity
for
iron
that
reducing
the
iron
isnt
sucient
to
release
it
Instead
when
it
enters
the
cell
it
is
cleaved
by
ferrienterobac>n
esterase
Medical
Applica>ons
Rela>vely
new
eld,
important
to
examine
all
possibili>es
for
an>microbial
aaack
An>microbial
Targe>ng:
Regula>on
Pro
-
Manipula>ng
FUR
binding
also
impacts
regula>on
of
FeSOD
and
MnSOD
(puts
addi>onal
pressure
on
cell
for
Fe
while
simultaneously
starving
it
of
Fe)
Con
-
Dicult
Accessibility
An>microbial
Targe>ng:
Export
Pro
Shulng
down
export
would
put
less
Fe
strain
on
host
(no
extracellular
Siderophore
to
chelate
free
metal)
Con
Poten>al
methods
involve
satura>on
of
siderophore
with
non-reducing
metals
(Gallium
tested).
These
metals
can
prove
harmful
to
the
pa>ent.
An>microbial
Targe>ng:
Import
Pros
Most
selec>ve,
current
work
focuses
on
manipula>on
of
import
Inhibit
TonB
receptor,
preven>ng
reimport
(Fe
starva>on)
or
Chelate
siderophores
with
large
molecule,
also
preven>ng
reimport
or
Chelate
siderophores
with
destruc>ve
agent,
intracellular
apopto>c
signal,
that
would
enter
only
targeted
microbe
via
selec>ve
siderophore
binding/import
An>microbial
Targe>ng:
Import
Cons
Cri>cal
to
understand
limita>ons
for
emerging
medical
applica>on
Binding
of
siderophore
with
large
molecule
to
prevent
reimport
could
cause
insolubility
precipitates
in
blood
Intracellular
bombs
must
be
extremely
selec>ve
for
the
siderophore
can
not
have
free
diusion
or
import
into
other
cells!
Addi>onal
Applica>ons
Rapid
chela>on
of
excess
metals
preven>ng
Transferrin
binding
and
iron
overload
(babies
gelng
into
iron
supplements)
