T3D0117 - Manganese

1. Major prion protein

May play a role in neuronal development and synaptic plasticity. May be required for neuronal myelin sheath maintenance. May play a role in iron uptake and iron homeostasis. Soluble oligomers are toxic to cultured neuroblastoma cells and induce apoptosis (in vitro). Association with GPC1 (via its heparan sulfate chains) targets PRNP to lipid rafts. Also provides Cu(2+) or ZN(2+) for the ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate side chains (By similarity).

Manganese binds to the prion protein, altering its conformation, displacing copper, and altering the redox chemistry of the metal-protein complex. These changes are similar to those associated with prion disease. (R443)

P04156

PRNP

SNPJam Report

• R443 — Brazier MW, Davies P, Player E, Marken F, Viles JH, Brown DR: Manganese binding to the prion protein. J Biol Chem. 2008 May 9;283(19):12831-9. Epub 2008 Mar 10. [18332141 ]

2. Putative testis-specific prion protein

Manganese binds to the prion protein, altering its conformation, displacing copper, and altering the redox chemistry of the metal-protein complex. These changes are similar to those associated with prion disease. (R443)

Q86SH4

PRNT

SNPJam Report

• R443 — Brazier MW, Davies P, Player E, Marken F, Viles JH, Brown DR: Manganese binding to the prion protein. J Biol Chem. 2008 May 9;283(19):12831-9. Epub 2008 Mar 10. [18332141 ]

3. Aconitate hydratase, mitochondrial

Catalyzes the isomerization of citrate to isocitrate via cis-aconitate (By similarity).

Manganese interferes with amino acid metabolism by inhibiting aconitase, resulting in an increase in citrate levels. It is also believed that this direct disruption of the catalytic [4Fe-4S] cluster of aconitase by manganese produces iron regulary protein 1, resulting in alterations in cellular iron homeostasis. (R444)

Q99798

ACO2

SNPJam Report

• R444 — Crooks DR, Ghosh MC, Braun-Sommargren M, Rouault TA, Smith DR: Manganese targets m-aconitase and activates iron regulatory protein 2 in AF5 GABAergic cells. J Neurosci Res. 2007 Jun;85(8):1797-809. [17469137 ]

4. Cytoplasmic aconitate hydratase

Iron sensor. Binds a 4Fe-4S cluster and functions as aconitase when cellular iron levels are high. Functions as mRNA binding protein that regulates uptake, sequestration and utilization of iron when cellular iron levels are low. Binds to iron-responsive elements (IRES) in target mRNA species when iron levels are low. Binding of a 4Fe-4S cluster precludes RNA binding. Catalyzes the isomerization of citrate to isocitrate via cis-aconitate (By similarity).

Manganese interferes with amino acid metabolism by inhibiting aconitase, resulting in an increase in citrate levels. It is also believed that this direct disruption of the catalytic [4Fe-4S] cluster of aconitase by manganese produces iron regulary protein 1, resulting in alterations in cellular iron homeostasis. (R444)

P21399

ACO1

SNPJam Report

• R444 — Crooks DR, Ghosh MC, Braun-Sommargren M, Rouault TA, Smith DR: Manganese targets m-aconitase and activates iron regulatory protein 2 in AF5 GABAergic cells. J Neurosci Res. 2007 Jun;85(8):1797-809. [17469137 ]

5. Iron-responsive element-binding protein 2

Binds to iron-responsive elements (IRES), which are stem-loop structures found in the 5'-UTR of ferritin, and delta aminolevulinic acid synthase mRNAs, and in the 3'-UTR of transferrin receptor mRNA. Binding to the IRE element in ferritin results in the repression of its mRNA translation. Binding of the protein to the transferrin receptor mRNA inhibits the degradation of this otherwise rapidly degraded mRNA

Manganese alters cellular iron homeostasis by stabilizing iron regulatory protein 2. This may occur by manganese competing directly for an iron-binding site on the iron binding protein, disrupting the cellular mechanisms responsible for its iron-dependent degradation. (R444)

P48200

IREB2

SNPJam Report

• R444 — Crooks DR, Ghosh MC, Braun-Sommargren M, Rouault TA, Smith DR: Manganese targets m-aconitase and activates iron regulatory protein 2 in AF5 GABAergic cells. J Neurosci Res. 2007 Jun;85(8):1797-809. [17469137 ]