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UseCase5 MPTP
Example of cellular transport and selective accumulation
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is a neurotoxin resulting in Parkinson like symptoms. The effect is caused through targeting of the dopaminergic neurons in the substantia nigra.
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a lipophilic compound capable of crossing the blood brain barrier and absorbed by glial cells. In astrocytes, MPTP is converted by monoamine oxidase to MPDP, which then autooxodizses to MPP+ -{Boelsterli 2003}-. MPP+ accumulates in dopaminergic neurons due to selective uptake by the Dopamine transporter (DAT) resulting in cell death -{Boelsterli 2003}-. MPP+ toxicity due to ability to bind to and inhibit complex 1 activity in mitochondria -{Boelsterli 2003}-. There is a high concentration of dopanimergic neurons in the substantia nigra, cell death causes Parkinsons like symptoms.
note: rats are not sensitive due to the poor expression of monoamine oxidase. Mechanism combines previous examples of mitochondrial complex 1 inhibition.
Representational
Biochemical Cell type specification Chemical derivatives Expression(language requirements) Biological dispositions Functional (Question and Answers) Q. “What mechanism involves inhibition of mitochondrial complex 1?” A. “mechanism of dopaminergic neuron injury by MPTP” Query:‘mechanistic toxicology process specification’ that ‘results in’ some ‘mitochondrial complex 1 inhibition’ Q. “What are the results of this mechanism?” A. “inhibition of mitochondrial electron transport complex 1, and damage to the substantia nigra” Query:‘process’ that ‘is result of’ some ‘mechanism of selective dopaminergic neuron death by MPTP’ Q. “What proteins are involves in this mechanism?” A. “monoamine oxidase” Query: protein that ‘is agent in’ some (process that ‘is part of’ some ‘mechanism of dopaminergic neuron injury by MPTP’) Q. “What derivatives of MPTP are involved in this mechanism?” A. MPDP and MPP+ Query:‘chemical entity’ that ‘derives from’ some MPTP Q. “Does part of this mechanism take place in glial cells?” A. “THe enzymatic conversion of MPTP to MPDP and autooxidation of MPDP to MPP+” Query: process that ‘is located in’ some ‘glial cell’ and ‘is part of’ some ‘mechanism of dopaminergic neuron injury by MPTP’ Q. “Which enzymes are agents in the conversion of MPTP to MPDP?” A. “monoamine oxidase” Query:protein that ‘is agent in’ some (‘process’ that ‘has target’ some MPTP and ‘has product’ some ‘MPDP’) Q. “Which process results in damage to the substantia nigra?” A. “mitochondrial complex 1 inhibition in dopaminergic neuron” Q. “What complex does MPP+ form in this mechanism?” A.“MPP+ forms a complex with mitochondrial electron complex 1” Query:‘molecular complex’ that ‘has part’ some MPP+ Q. “what process forms this complex?” A.“MPP+ Mitochondrial electron complex 1 complex formation” Query:‘process and ’has product’ some (‘molecular complex’ that ‘has part’ some MPP+)‘ Q. “Does MPTP derive into a neurotoxin?” A. “Yes” Query:
The above mechanism can be broken down into the following subprocesses:
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enzymatic conversion of in glial cells (astrocytes) by monoamine oxidase.
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Autooxidation of MPDP to MPP+.
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Translocation of MPP+ from astrocyte to dopaminergic neurons due to selective uptake by dopamine transporter (DAT).
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MPP+ binds to and inhibits mitochondrial complex 1 resulting in cell death and damage to the substantia nigra resulting in parkinsons like symptoms.
‘MPTP’ subClassOf ‘chemical entity’ and ‘derives into’ some (MPDP and ‘in relation to’ some ‘enzymatic conversion of MPTP to MPDP’) that ‘is target in’ some ‘enzymatic conversion of MPTP to MPDP MPDP subClassOf ’chemical entity’ and ‘derives into’ some (MPP+ and ‘in relation to’ some ‘autooxidation of MPDP to MPP+’) and ‘derives from’ some (MPTP and ‘in relation to’ some ‘enzymatic conversion of MPTP to MPDP’) ‘enzymatic conversion of MPTP to MPDP’ subClassOf ‘biochemical reaction’ that ‘has target’ some MPTP that ‘has product’ some MPDP that ‘has agent’ some ‘monoamine oxidase’ ‘enzymatic conversion of MPTP to MPDP in glial cell’ subClassOf ‘enzymatic conversion of MPTP to MPDP’ that ‘is located in’ some ‘glial cell’ that ‘is part of’ some ‘mechanism of selective dopaminergic neuron death by MPTP’ ‘monoamine oxidase’ subClassOf ‘protein’ that ‘is agent in’ some ‘enzymatic conversion of MPTP to MPDP’ ‘autooxidation of MPDP to MPP+’ subClassOf ‘chemical reaction’ that ‘has target’ some ‘MPDP’ that ‘has product’ some ‘MPP+’ ‘autooxidation of MPDP to MPP+ in glial cell’ subClassOf ‘autooxidation of MPDP to MPP+’ and ‘is located in’ some ‘glial cell’ that ‘is part of’ some ‘mechanism of selective dopaminergic neuron death by MPTP’ ‘dopamine transporter’ subClassOf ‘protein’ that ‘is agent in’ some ‘Uptake of MPP+ by Dopamine transporter’ dopamine transporter mediated transport of MPP+ from synpase into dopaminergic neuron’ subClassOf ‘chemical transport’ that ‘has proper part’ some (‘process start’ and ‘has participant’ some MPP+ and ‘is located in’ some synapse and precedes some (‘chemical transport’ that ‘has agent’ some ‘dopamine transporter’ and ‘is located in’ some ‘plasma membrane’ and precedes some (‘process end’ that ‘has participant’ some MPP+ and ‘is located in’ some (cytosol that ‘is part of’ some ‘dopaminergic neuron’))))
‘MPP+ Mitochondrial Complex 1 complex formation’ subClassOf ‘molecular complex formation’ that ‘has target’ some MPP+ that ‘has target’ some ‘mitochondrial complex 1’ that ‘has product’ some ‘MPP+ mitochondrial electron transfer complex 1 complex’ and ‘results in’ some ‘mitochondrial complex 1 inhibition’ ‘mitochondrial complex 1 inhibition’ subClassOf ‘inhibition’ and ‘results in’ some ‘cellular energy depletion’ and ‘results in’ some ‘cell death’ ‘mitochondrial complex 1 inhibition in dopaminergic neuron’ subClassOf ‘mitochondrial complex 1 inhibition’ ‘mitochondrial complex 1 inhibition’ and ‘has agent’ some ‘MPP+ mitochondrial electron transfer complex 1 complex’ that ‘has target’ some (‘Mitochondrial Electron Transport Complex I’ and ‘is located in’ some ‘dopaminergic neuron’) and realizes some (‘to be inhibited’ that ‘is disposition of’ some ‘Mitochondrial Electron Transport Complex I’ and ‘in relation to’ some MPP+) and realizes some (‘to inhibit’ that ‘is disposition of’ some MPP+ and ‘in relation to’ some ‘Mitochondrial Electron Transport Complex I’) and realizes some (‘to be neurotoxic’ that ‘is disposition of’ some MPP+) and ‘results in’ some ‘dopaminergic neuron cell death’ and ‘result of’ some ‘mechanism of selective dopaminergic neuron death by MPTP’ ‘dopaminergic neuron cell death’ subClassOf ‘disease’ that ‘is result of’ some ‘mechanism of selective dopaminergic neuron death by MPTP’ that ‘is result of’ some ‘mitochondrial complex 1 inhibition in dopaminergic neuron’ that ‘is part of’ some ‘mechanism of selective dopaminergic neuron death by MPTP’ ‘mechanism of selective dopaminergic neuron death by MPTP’ subClassOf ‘mechanistic toxicology process specification’ and (‘has part’ some ‘enzymatic conversion of MPTP to MPDP in glial cell’) and (‘has part’ some ‘dopamine transporter mediated transport of MPP+ from synpase into dopaminergic neuron’) and (‘has part’ some ‘autooxidation of MPDP to MPP+ in glial cell’) and (‘has part’ some ‘MPP+ mitochondrial complex 1 complex formation in dopaminergic neuron’) and (‘results in’ some ‘mitochondrial complex 1 inhibition in dopaminergic neurons’) and (‘results in’ some ‘dopaminergic neuron cell death’) and ‘has proper part’ some (‘enzymatic conversion of MPTP to MPDP in glial cell’ and precedes some (‘autooxidation of MPDP to MPP+ in glial cell’ and precedes some (‘dopamine transporter mediated transport of MPP+ from synpase into dopaminergic neuron’ and precedes some ‘MPP+ mitochondrial complex 1 complex formation in dopaminergic neuron’ and precedes some (‘mitochondrial complex 1 inhibition in dopaminergic neurons’ and precedes some ‘dopaminergic neuron cell death’)))
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