Carbidopa

(Lodosyn) is a drug given, in conjunction with Levadopa, to those with Parkinson's Disease in order to inhibit the extracranial metabolism of Levadopa to dopamine, allowing a greater portion of the drug to cross the blood-brain barrier and produce the desired anti-parkinsonian effects in the nerve cell. It works by inhibiting the enzymatic activity of aromatic-L-amino-acid decarboxylase (DOPA Decarboxylase or DDC)^[1].

Structure

2D Structure of Carbidopa

Ball and Stick Model of Carbidopa

Molecular Mechanism

The conversion of L-DOPA into dopamine is catalyzed by the vitamin B6 ()-dependent enzyme DDC, an enzyme abundant in the nervous system as well as kidneys of humans^[3] The catalytically active form of DDC is a homodimer, a feature typical of this class of enzymes^[4]. 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. the 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 residues Ile 101' and Phe 103' in the substrate binding pocket with its catechol ring^[5]. Due to the fact that Carbidopa cannot cross the blood-brain barrier, its inhibiting effects only are displayed in the periphery.

Disease in Humans

Parkinson's disease (PD) is a chronic, progressive neurological disease whose symptoms include bradykinesia, tremors, postural instability and rigidity. Although the exact cause of the disease is currently unknown, it is believe to be caused by the apoptosis of dopanergic cells in the substantia nigra of the brain and subsequent loss of dopamine.^[6]