DOPA decarboxylase: Difference between revisions

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[[image:dopa.png|thumb|left|300px|'''Dopamine Synthesis''']]'''DOPA decarboxylase''' (DDC, aromatic L-amino acid decarboxylase, tryptophan decarboxylase, 5-hydroxytryptophan decarboxylase, AAAD) ([[EC Number|EC]] 4.1.1.28) is an approximately 104 kDa protein that belongs to the '''aspartate aminotransferase family''' (fold type 1) of '''[http://en.wikipedia.org/wiki/Pyridoxal_phosphate ''PLP'']-dependent''' (vitamin B6-dependent) enzymes. The catalytically active form of the enzyme exists as a homodimer, typical of this class of enzymes.<ref name="schneider">PMID:10673430 </ref> The homodimeric form of the enzyme purified from [http://en.wikipedia.org/wiki/Sus_scrofa ''sus scrofa''] is shown in complex with the inhibitor '''[http://en.wikipedia.org/wiki/Carbidopa ''carbidopa'']''' to the right.

DOPA decarboxylase is responsible for the synthesis of '''[http://en.wikipedia.org/wiki/Dopamine ''dopamine'']''' and [http://en.wikipedia.org/wiki/Serotoninn ''serotonin''] from '''[http://en.wikipedia.org/wiki/L-dopa ''L-DOPA'']''' and [http://en.wikipedia.org/wiki/L-5-Hydroxytryptophan ''L-5-hydroxytryptophan''], respectively. ~~Due~~ to ~~its role in~~ dopamine ~~biosynthesis~~, DOPA ~~decarboxylase has been implicated in~~ '''[http://en.wikipedia.org/wiki/Parkinson%27s_disease ''Parkinson's disease'']''', ~~a disease thought to be~~ the ~~result~~ of the ~~degeneration~~ of ~~dopamine-producing cells~~ in the ~~brain~~. ~~In fact, decarboxylation~~ of ~~L-DOPA by DOPA decarboxylase~~ is ~~the controlling step for~~ the formation of ~~dopamine in patients with Parkinson~~'~~s <ref name="hadjiiconstantinou">PMID~~:~~1904055 <~~/~~ref>~~ Currently, treatment for the disease is aimed at DOPA decarboxylase inhibition. Since dopamine cannot cross the blood-brain barrier, it cannot be used to directly treat Parkinson's disease. Thus, exogenously administered L-DOPA is the primary treatment for patients suffering from this neurodegenerative disease. Unfortunately, DOPA decarboxylase rapidly converts L-DOPA to dopamine in the blood stream, with only a small percentage reaching the brain. By inhibiting the enzyme, greater amounts of exogenously administered L-DOPA can reach the brain, where it can then be converted to dopamine. <ref name="burkhard">PMID:11685243 </ref> . See also [[DOPA Decarboxylase]] and [[User:Brian Hernandez/DOPA Decarboxylase]].

DDC catalyzes the conversion of aromatic amino acids into their corresponding amines. DOPA decarboxylase is responsible for the synthesis of '''[http://en.wikipedia.org/wiki/Dopamine ''dopamine'']''' and [http://en.wikipedia.org/wiki/Serotoninn ''serotonin''] from '''[http://en.wikipedia.org/wiki/L-dopa ''L-DOPA'']''' and [http://en.wikipedia.org/wiki/L-5-Hydroxytryptophan ''L-5-hydroxytryptophan''], respectively. It is highly stereospecific, yet relatively nonspecific in terms of substrate, making it a somewhat uninteresting enzyme to study. Although it is not typically a rate-determining step of dopamine synthesis, the decarboxylation of L-DOPA to dopamine by DDC is the controlling step for individuals with '''[http://en.wikipedia.org/wiki/Parkinson%27s_disease ''Parkinson's disease'']'''<ref name="hadjiiconstantinou">PMID:1904055 </ref> , the second most common neurodegenerative disorder, occuring in 1% of the population over the age of 65. The loss of dopaminergic neurons is the main cause of cognitive impairment and tremors observed in patients with the disease. The hallmark of the disease is the formation of [http://en.wikipedia.org/wiki/alpha-synuclein ''alpha-synuclein''] containing [http://en.wikipedia.org/wiki/Lewy bodies ''Lewy bodies''].

Currently, treatment for the disease is aimed at DOPA decarboxylase inhibition. Since dopamine cannot cross the blood-brain barrier, it cannot be used to directly treat Parkinson's disease. Thus, exogenously administered L-DOPA is the primary treatment for patients suffering from this neurodegenerative disease. Unfortunately, DOPA decarboxylase rapidly converts L-DOPA to dopamine in the blood stream, with only a small percentage reaching the brain. By inhibiting the enzyme, greater amounts of exogenously administered L-DOPA can reach the brain, where it can then be converted to dopamine. <ref name="burkhard">PMID:11685243 </ref> . See also [[DOPA Decarboxylase]] and [[User:Brian Hernandez/DOPA Decarboxylase]]. Unfortunately, with continued L-Dopa treatment, up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications (referred to as the "on-off phenomenon". <ref name="lees">PMID:1904055 </ref>. Clearly, a better understanding of the catalytic mechanism and enzymatic activity of DDC in both healthy and PD individuals is critical to drug design and treatment of the disease.

==PLP-Dependent Enzymes==

DOPA decarboxylase: Difference between revisions

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 [[image:dopa.png|thumb|left|300px|'''Dopamine Synthesis''']]'''DOPA decarboxylase''' (DDC, aromatic L-amino acid decarboxylase, tryptophan decarboxylase, 5-hydroxytryptophan decarboxylase, AAAD) ([[EC Number|EC]] 4.1.1.28) is an approximately 104 kDa protein that belongs to the '''aspartate aminotransferase family''' (fold type 1) of '''[http://en.wikipedia.org/wiki/Pyridoxal_phosphate ''PLP'']-dependent''' (vitamin B6-dependent) enzymes. The catalytically active form of the enzyme exists as a homodimer, typical of this class of enzymes.<ref name="schneider">PMID:10673430 </ref> The homodimeric form of the enzyme purified from [http://en.wikipedia.org/wiki/Sus_scrofa ''sus scrofa''] is shown in complex with the inhibitor '''[http://en.wikipedia.org/wiki/Carbidopa ''carbidopa'']''' to the right.
-DOPA decarboxylase is responsible for the synthesis of '''[http://en.wikipedia.org/wiki/Dopamine ''dopamine'']''' and [http://en.wikipedia.org/wiki/Serotoninn ''serotonin''] from '''[http://en.wikipedia.org/wiki/L-dopa ''L-DOPA'']''' and [http://en.wikipedia.org/wiki/L-5-Hydroxytryptophan ''L-5-hydroxytryptophan''], respectively. Due to its role in dopamine biosynthesis, DOPA decarboxylase has been implicated in '''[http://en.wikipedia.org/wiki/Parkinson%27s_disease ''Parkinson's disease'']''', a disease thought to be the result of the degeneration of dopamine-producing cells in the brain. In fact, decarboxylation of L-DOPA by DOPA decarboxylase is the controlling step for the formation of dopamine in patients with Parkinson's <ref name="hadjiiconstantinou">PMID:1904055 </ref>  Currently, treatment for the disease is aimed at DOPA decarboxylase inhibition. Since dopamine cannot cross the blood-brain barrier, it cannot be used to directly treat Parkinson's disease. Thus, exogenously administered L-DOPA is the primary treatment for patients suffering from this neurodegenerative disease. Unfortunately, DOPA decarboxylase rapidly converts L-DOPA to dopamine in the blood stream, with only a small percentage reaching the brain. By inhibiting the enzyme,  greater amounts of exogenously administered L-DOPA can reach the brain, where it can then be converted to dopamine. <ref name="burkhard">PMID:11685243 </ref>  .  See also [[DOPA Decarboxylase]] and [[User:Brian Hernandez/DOPA Decarboxylase]].
+DDC catalyzes the conversion of aromatic amino acids into their corresponding amines. DOPA decarboxylase is responsible for the synthesis of '''[http://en.wikipedia.org/wiki/Dopamine ''dopamine'']''' and [http://en.wikipedia.org/wiki/Serotoninn ''serotonin''] from '''[http://en.wikipedia.org/wiki/L-dopa ''L-DOPA'']''' and [http://en.wikipedia.org/wiki/L-5-Hydroxytryptophan ''L-5-hydroxytryptophan''], respectively. It is highly stereospecific, yet relatively nonspecific in terms of substrate, making it a somewhat uninteresting enzyme to study. Although it is not typically a rate-determining step of dopamine synthesis, the decarboxylation of L-DOPA to dopamine by DDC is the controlling step for individuals with '''[http://en.wikipedia.org/wiki/Parkinson%27s_disease ''Parkinson's disease'']'''<ref name="hadjiiconstantinou">PMID:1904055 </ref> , the second most common neurodegenerative disorder, occuring in 1% of the population over the age of 65. The loss of dopaminergic neurons is the main cause of cognitive impairment and tremors observed in patients with the disease. The hallmark of the disease is the formation of [http://en.wikipedia.org/wiki/alpha-synuclein ''alpha-synuclein''] containing [http://en.wikipedia.org/wiki/Lewy bodies ''Lewy bodies''].
+Currently, treatment for the disease is aimed at DOPA decarboxylase inhibition. Since dopamine cannot cross the blood-brain barrier, it cannot be used to directly treat Parkinson's disease. Thus, exogenously administered L-DOPA is the primary treatment for patients suffering from this neurodegenerative disease. Unfortunately, DOPA decarboxylase rapidly converts L-DOPA to dopamine in the blood stream, with only a small percentage reaching the brain. By inhibiting the enzyme,  greater amounts of exogenously administered L-DOPA can reach the brain, where it can then be converted to dopamine. <ref name="burkhard">PMID:11685243 </ref>  .  See also [[DOPA Decarboxylase]] and [[User:Brian Hernandez/DOPA Decarboxylase]]. Unfortunately, with continued L-Dopa treatment,  up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications (referred to as the "on-off phenomenon". <ref name="lees">PMID:1904055 </ref>. Clearly, a better understanding of the catalytic mechanism and enzymatic activity of DDC in both healthy and PD individuals is critical to drug design and treatment of the disease.
 ==PLP-Dependent Enzymes==