Carbidopa: Difference between revisions

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== Structure ==

[[Image:512px-Carbidopa.svg.png|thumb|right|2D Structure of Carbidopa]][[Image:800px-Carbidopa ball-and-stick.png|thumb|right|Ball and Stick Model of Carbidopa]]Carbidopa is an inhibitor of DDC. It is a partially water soluble, white, crystalline compound with a molecular weight of 226.232g/mol and a melting point of 208°C. Its empirical formula is ~~C10H14N2O4•H2O~~ and its IUPAC name is (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid. Used in conjunction with Levadopa (L-DOPA), a precursor to dopamine, it increases concentrations of L-DOPA in the brain. Due to the fact Carbidopa cannot cross the blood–brain barrier, it inhibits only peripheral DDC thus preventing the conversion of L-DOPA to dopamine outside of neuronal cells. This greatly lessens the side effects caused by dopamine on the periphery, as well as increasing the concentration of L-DOPA and subsequently dopamine in the brain.<ref name="two">https://pubchem.ncbi.nlm.nih.gov/compound/carbidopa</ref>

[[Image:512px-Carbidopa.svg.png|thumb|right|2D Structure of Carbidopa]][[Image:800px-Carbidopa ball-and-stick.png|thumb|right|Ball and Stick Model of Carbidopa]]Carbidopa is an inhibitor of DDC. It is a partially water soluble, white, crystalline compound with a molecular weight of 226.232g/mol and a melting point of 208°C. Its empirical formula is C10H14N2O4•H2O and its IUPAC name is (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid. Used in conjunction with Levadopa (L-DOPA), a precursor to dopamine, it increases concentrations of L-DOPA in the brain. Due to the fact Carbidopa cannot cross the blood–brain barrier, it inhibits only peripheral DDC thus preventing the conversion of L-DOPA to dopamine outside of neuronal cells. This greatly lessens the side effects caused by dopamine on the periphery, as well as increasing the concentration of L-DOPA and subsequently dopamine in the brain.<ref name="two">https://pubchem.ncbi.nlm.nih.gov/compound/carbidopa</ref>

== Molecular Mechanism ==

The vitamin B6 (<scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>)-dependent enzyme DDC, an enzyme abundant in the nervous system as well as kidneys of humans, catalyzes the conversion of L-DOPA into dopamine.<ref name="three">PMID: 7651438</ref> The catalytically active form of DDC is a homodimer, a feature typical of this class of enzymes.<ref name= "four">PMID: 10673430</ref> DDCs active site is located between the two monomers but is mainly composed of residues from only one of the monomers. The cofactor PLP binds to Lys 303 through a Schiff base linkage and a salt bridge between the carboxylate group of Asp 271 and the protonated pyridine nitrogen of PLP, which acts as a strong electron sink capable of stabilizing the carbanionic intermediates produced by active DDC. Cofactor is further stabilized in the enzyme through a network of hydrogen bonds. Carbidopa works by forming a hydrazone linkage with the PLP cofactor through its hydrazine moiety and blocking the DDC <scene name='74/746001/Active_site_dopa_final/1'>active site</scene> residues Ile 101' and Phe 103' in the substrate binding pocket with its catechol ring.<ref name="five">doi:10.1038/nsb1101-963</ref> In addition, the 4' hydroxyl group of Carbidopas catechol ring hydrogen bonds with THR 82 and the carboxylate group binds to HIS 192, a highly-conserved residue in PLP-dependent decarboxylases.<ref name="six">PMID: 8889823</ref> Due to the fact that Carbidopa cannot cross the blood-brain barrier, its inhibiting effects only are displayed in the periphery.

The vitamin B6 (<scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>)-dependent enzyme DDC, an enzyme abundant in the nervous system as well as kidneys of humans, catalyzes the conversion of L-DOPA into dopamine.<ref name="three">PMID: 7651438</ref> The catalytically active form of DDC is a homodimer, a feature typical of this class of enzymes.<ref name= "four">PMID: 10673430</ref> DDCs active site is located between the two monomers but is mainly composed of residues from only one of the monomers. The cofactor <scene name='74/746001/Plp_binding/1'>PLP</scene> binds to Lys 303 through a Schiff base linkage and a salt bridge between the carboxylate group of Asp 271 and the protonated pyridine nitrogen of PLP, which acts as a strong electron sink capable of stabilizing the carbanionic intermediates produced by active DDC. Cofactor is further stabilized in the enzyme through a network of hydrogen bonds. Carbidopa works by forming a hydrazone linkage with the PLP cofactor through its hydrazine moiety and blocking the DDC <scene name='74/746001/Active_site_dopa_final/1'>active site</scene> residues Ile 101' and Phe 103' in the substrate binding pocket with its catechol ring.<ref name="five">doi:10.1038/nsb1101-963</ref> In addition, the 4' hydroxyl group of Carbidopas catechol ring hydrogen bonds with THR 82 and the carboxylate group binds to HIS 192, a highly-conserved residue in PLP-dependent decarboxylases.<ref name="six">PMID: 8889823</ref> Due to the fact that Carbidopa cannot cross the blood-brain barrier, its inhibiting effects only are displayed in the periphery.

==Interactions==

Carbidopa: Difference between revisions

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 == Structure ==
-[[Image:512px-Carbidopa.svg.png|thumb|right|2D Structure of Carbidopa]][[Image:800px-Carbidopa ball-and-stick.png|thumb|right|Ball and Stick Model of Carbidopa]]Carbidopa is an inhibitor of DDC. It is a partially water soluble, white, crystalline compound with a molecular weight of 226.232g/mol and a melting point of 208°C. Its empirical formula is C10H14N2O4•H2O and its IUPAC name is (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid. Used in conjunction with Levadopa (L-DOPA), a precursor to dopamine, it increases concentrations of L-DOPA in the brain. Due to the fact Carbidopa cannot cross the blood–brain barrier, it inhibits only peripheral DDC thus preventing the conversion of L-DOPA to dopamine outside of neuronal cells. This greatly lessens the side effects caused by dopamine on the periphery, as well as increasing the concentration of L-DOPA and subsequently dopamine in the brain.<ref name="two">https://pubchem.ncbi.nlm.nih.gov/compound/carbidopa</ref>
+[[Image:512px-Carbidopa.svg.png|thumb|right|2D Structure of Carbidopa]][[Image:800px-Carbidopa ball-and-stick.png|thumb|right|Ball and Stick Model of Carbidopa]]Carbidopa is an inhibitor of DDC. It is a partially water soluble, white, crystalline compound with a molecular weight of 226.232g/mol and a melting point of 208°C. Its empirical formula is C<sub>10</sub>H<sub>14</sub>N<sub>2</sub>O<sub>4</sub>•H<sub>2</sub>O and its IUPAC name is (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid. Used in conjunction with Levadopa (L-DOPA), a precursor to dopamine, it increases concentrations of L-DOPA in the brain. Due to the fact Carbidopa cannot cross the blood–brain barrier, it inhibits only peripheral DDC thus preventing the conversion of L-DOPA to dopamine outside of neuronal cells. This greatly lessens the side effects caused by dopamine on the periphery, as well as increasing the concentration of L-DOPA and subsequently dopamine in the brain.<ref name="two">https://pubchem.ncbi.nlm.nih.gov/compound/carbidopa</ref>
 == Molecular Mechanism ==
-The vitamin B6 (<scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>)-dependent enzyme DDC, an enzyme abundant in the nervous system as well as kidneys of humans, catalyzes the conversion of L-DOPA into dopamine.<ref name="three">PMID: 7651438</ref> The catalytically active form of DDC is a homodimer, a feature typical of this class of enzymes.<ref name= "four">PMID: 10673430</ref> DDCs active site is located between the two monomers but is mainly composed of residues from only one of the monomers. The cofactor PLP binds to Lys 303 through a Schiff base linkage and a salt bridge between the carboxylate group of Asp 271 and the protonated pyridine nitrogen of PLP, which acts as a strong electron sink capable of stabilizing the carbanionic intermediates produced by active DDC. Cofactor is further stabilized in the enzyme through a network of hydrogen bonds. Carbidopa works by forming a hydrazone linkage with the PLP cofactor through its hydrazine moiety and blocking the DDC <scene name='74/746001/Active_site_dopa_final/1'>active site</scene> residues Ile 101' and Phe 103' in the substrate binding pocket with its catechol ring.<ref name="five">doi:10.1038/nsb1101-963</ref> In addition, the 4' hydroxyl group of Carbidopas catechol ring hydrogen bonds with THR 82 and the carboxylate group binds to HIS 192, a highly-conserved residue in PLP-dependent decarboxylases.<ref name="six">PMID: 8889823</ref> Due to the fact that Carbidopa cannot cross the blood-brain barrier, its inhibiting effects only are displayed in the periphery.
+The vitamin B6 (<scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>)-dependent enzyme DDC, an enzyme abundant in the nervous system as well as kidneys of humans, catalyzes the conversion of L-DOPA into dopamine.<ref name="three">PMID: 7651438</ref> The catalytically active form of DDC is a homodimer, a feature typical of this class of enzymes.<ref name= "four">PMID: 10673430</ref> DDCs active site is located between the two monomers but is mainly composed of residues from only one of the monomers. The cofactor <scene name='74/746001/Plp_binding/1'>PLP</scene> binds to Lys 303 through a Schiff base linkage and a salt bridge between the carboxylate group of Asp 271 and the protonated pyridine nitrogen of PLP, which acts as a strong electron sink capable of stabilizing the carbanionic intermediates produced by active DDC. Cofactor is further stabilized in the enzyme through a network of hydrogen bonds. Carbidopa works by forming a hydrazone linkage with the PLP cofactor through its hydrazine moiety and blocking the DDC <scene name='74/746001/Active_site_dopa_final/1'>active site</scene> residues Ile 101' and Phe 103' in the substrate binding pocket with its catechol ring.<ref name="five">doi:10.1038/nsb1101-963</ref> In addition, the 4' hydroxyl group of Carbidopas catechol ring hydrogen bonds with THR 82 and the carboxylate group binds to HIS 192, a highly-conserved residue in PLP-dependent decarboxylases.<ref name="six">PMID: 8889823</ref> Due to the fact that Carbidopa cannot cross the blood-brain barrier, its inhibiting effects only are displayed in the periphery.
 ==Interactions==