Chemistry Reference
In-Depth Information
side.reactions.
35
.Finally,.ferroportin.is.an.iron.export.protein.that.regulates.the.low.
of.iron.out.of.the.cell.
35
.While.there.may.be.more.biomolecules.involved,.these.few.
are.known.to.have.a.signiicant.impact.on.the.free.iron.concentration.in.the.cell,.and.
mutations.or.mis-folding.of.these.proteins.could.certainly.result.in.excess.free.iron.
34
Excess.free.iron.present.in.the.cell.can.have.a.signiicant.impact.on.the.intracel-
lular.chemistry.of.neuronal.cells.and.is.assumed.to.play.a.role.in.many.of.the.cur-
rent.theories.of.Parkinson's.disease,.such.as.UPS.pathway.inhibition.or.malfunction,.
oxidative.stress,.α-synuclein.aggregation,.and.Lewy.body.formation.
34
.Experimental.
evidence. has. shown. that. iron. chelators. actually. reduce. proteasome. inhibition,. or.
rather.that.excess.free.iron.can.inhibit.the.UPS.pathway.
36
.As.discussed.earlier,.inhi-
bition.of.this.pathway.can.have.a.deleterious.effect.on.the.cell.
The. presence. of. Fe
3+
. and. other. metal. ions. such. as. Al
3+
,. Co
3+
,. Mn
2+
,. Ca
2+
,. and.
Cu
2+
.in.solution.is.also.associated.with.an.increase.in.α-synuclein.aggregation.
4
.The.
Fenton.reaction,.shown.earlier,.increases.the.concentration.of.Fe
3+
.within.the.cell..
Previous.simulations.using.Car-Parrinello.molecular.dynamics.(CPMD).have.shown.
that. Fe
3+
. initiates. water. dissociation. and. forms. Eigen. (H
3
O
+
). and. Zundel. (H
5
O
+
).
complexes..The.formation.of.these.complexes.may.have.an.effect.on.the.mechanism.
of.the.Fenton.reaction.as.well.as.on.the.pH.and.chemical.reactivity.of.the.solution.
around.it,.which.(as.discussed.earlier).affects.α-synuclein.aggregation..It.has.been.
proposed. that. α-synuclein. is. also. a. metal-binding. protein. and. that. this. binding. in.
turn.affects.the.protein.structure.and.aggregation.rates.
37
.However,.little.is.known.
about. the. mechanism. of. this. binding. and. current. experimental. techniques. are. not.
capable.of.measuring.the.interaction.of.iron.and.α-synuclein.at.a.molecular.level.
A.popular.current.theory.not.only.in.Parkinson's.disease,.but.also.in.Alzheimer's.
and. other. neurodegenerative. disorders,. is. the. early. aggregation. and. monomer.
hypothesis.
31
. As. already. discussed,. one. of. the. hallmarks. of. Parkinson's. disease. is.
the.formation.of.synuclein.aggregates..Familial.forms.of.Parkinson's.disease.involve.
mutations.in.α-synuclein.that.result.in.a.higher.propensity.for.aggregation..The.early.
aggregation.and.monomer.hypothesis.focuses.on.inhibiting.aggregation.at.the.earli-
est.stage.possible.so.as.to.prevent.the.development.of.the.disease.before.aggregates.
form..The.formation.of.aggregates.is.theorized.to.be.the.result.of.decreasing.solubil-
ity.of.the.α-synuclein.monomers,.resulting.in.the.formation.of.partially.folded.inter-
mediates. that. are. hypothesized. to. lead. to. the. formation. of. the. observed. insoluble.
amorphous.aggregates.and.ibrils.
31,38
While.some.of.the.factors.discussed.earlier.have.been.shown.experimentally.to.
increase.the.rate.of.aggregation,.one.aspect.of.protein.folding.and.interaction.that.
is.not.often.investigated.is.the.effect.of.hydration.on.protein.structure.and.folding.
mechanism.
39
.The.presence.of.water.can.have.a.signiicant.effect.on.the.structure.of.
proteins. by. interfering. with. and. preventing. some. intramolecular. interactions.. The.
absence. of. or. decrease. in. the. number. of. water. molecules. present. can. also. have. a.
considerable.effect.on.protein.structure.by.allowing.intramolecular.interactions.not.
normally.seen,.resulting.in.mis-folded.proteins.or.partially.folded.intermediates.that.
lead.to.an.increased.rate.of.aggregation..Without.fully.understanding.the.impact.of.
water,.the.structure.and.dynamics.of.a.protein.in.vivo.cannot.be.fully.understood.
Speciically,.solvent.effects.cannot.be.ignored.in.predicting.the.structure.of.a.bio-
molecule.and.its.conformation.since.approximately.60%.of.the.human.body.consists.
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