Download Carbidopa (Lodosyn)*, the little helper in a big fight.

Carbidopa (Lodosyn)*, the little helper in a big fight.
Christina Zhukovsky
Proteins and Drugs 5c, Sp 2011
Uppsala University
*Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1996
All rights reserved
Parkinson’s disease; the tremors of
longevity
Carbidopa
A degenerative and progressive CNS disorder that
affects the midbrain region, substantia negra, causing
degeneration of dopamine-producing cells.
Symptoms:
Characterized by tremors, rigidity, postural
instability and brandykinesia (slowness of movement
once action begins)
Treatments:
Carbidopa-Levodopa, Dopamine Agonists,
MAO B and COMT inhibitors, Anticholinergics, NMDA
blocking drugs, stem cell.
Facts
Mm: 226.23 g/mol
OH
Formula: C10H14N2O4
PDB: 1JS3
Drug bank: DB00190
KEGG: D00558
O
Molecular structures and interactions
OH
OH
The large domain of DDC contains the PLP binding site
that is composed of “a central, seven-stranded
mixed beta-sheet enclosed by eight alpha-helices in a
alpha/beta fold.”5 A small domain (residues 433-435),
facing the large domain is compacted tightly against it.
The small domain has a four-stranded antiparallel betasheet with three helices. The N-terminal domain
(residues 75-77) of DDC contains two parallel helices
which are linked by an extended strand. This domain
covers the top of the second subunit. The first helix of
one subunit is aligned antiparallel to the corresponding
helix of the other subunit. Additionally the N-terminal and
small domain form a small two-stranded B-sheet.
NH
H2N
Carbidopa does not directly treat Parkinsons
disease, but rather prolongs the half-life of
levodopa, allowing for its absorption through the
blood brain level, lowering of dosage needed for a
particular effect by 75%*6, and reduction of
levodopa side-effects (nausea, drowsiness etc)
Treatments
Targeting DDC, a long road.
Treatment
Description
Side-effects
CarbidopaLevodopa
Most used and
effective
treatment drug.
Combined with
Carbidopa,
Levodopa is
prevented from
premature
conversion to
dopamine outside
of the brain.
dyskinesia
Dopamine
Agonists
Mimics dopamine.
Not as effective as
CarbidopaLevodopa but lasts
longer.
hallucinations,
drowsiness, water
retention, increased
compulsive
behavior.
MAO B
inhibitors
Inhibition of
monoamine oxidase
B, an enzyme that
metabolizes
dopamine
cannot be used in
conjunction with
antidepressants,
antiobiotics like
Cipro, St. John’s
wart herb or some
narcotics.
COMT
inhibitors
Anticholinergics
Glutamate
NMDA blocking
drugs
Stem cell
Surgery
O
CO2 OH
OH
OH
NH2
DOPA Carboxylase
NH2
OH
OH
L-Dopa (Ldihydroxyphenylalanine)
Dopamine
Fig 1
Fig 1: Illustration of levodopa decarboxyaltion by DDC into
dopamine
Prolongs the effects
of carbidopalevodopa by
blocking catechol
Omethyltransferase
enzyme that breaks
down levodopa.
Some inhibitors like
Tasmar are linked to
liver damage and
liver failure but
Entacapone does
not have such
effects. Instead it
was found that
Levodopa side
effects may worsen.
Discoloration of
urine.
memory
Used to control
Parkinsons’
impairments,
tremors.
confusion,
constipation,
dryness of mouth
and eyes, and issues
with urination.
Provides short-term appearance of
relief of early
purple blotches of
the skin,
Parkonsons’.
hallucinations.
Injection into the
brain of hRPE
(human Retinal
Pigment Epithelial)
Insertion of
electrode into brain
for deep brain
stimulation.
When Levodopa is orally administered, it is rapidly
decarboxylated by DDC (DOPA Carboxylase) in
extracerebral tissue.
Fig 4
Levodopa is necessary in its unconverted form
because it can pass through the blood-brain
barrier where it is stored in the dopaminergic
nerve terminal granulae. It is released into the
synapse after axonal electric stimulation and then
converted to dopamine
Naturally in the body, L-Tyrosine is converted to
Dopamine with an additional step of converting the
L-Tyrosine to L-Dopa followed by L-Dopa
decarboxylation to Dopamine.
O
O
O2 tetrahydrobiopterin
H2O, Dihydrobiopterin OH
Tyrosine hydroxylase
NH2
OH
OH
L-Dopa (Ldihydroxyphenylalanine)
L-Tyrosine
Fig 2: Natural conversion of L-Tyrosine into L-Dopa to be later
converted to Dopamine, Norepinephrine, or Epinephrine
Fig 2
Without Carbidopa very little Levodopa remains to
be transported across the blood-brain barrier and
the free dopamine outside the brain causes many
side-effects in patients.
DDC uses PLP (pyridoxal phosphate) as a
cofactor, which is a target for Carbidopa.
Fig 5: DDC with PLP cofactor and Carbidopa
interacting
(shown as ball
*
and stick models ) with
active site highlighted in
purple.
Fig 5
O
HO
Final Metabolism of Carbidopa
ONH
K303
NH2
N
The half life of Carbidopa is approximately 1.5hrs.
Eventually it is metabolized by α-methyl-3methoxy4hydroxyphenylpropionic acid and α-methyl-3,4
dihydroxyphenylpropionic acid . Carbidopa is then
excreted unchanged or as glucorinide conjugate in urine.
OH
Carbidopa
OH
2-
OPO3
PLP
1
N
H
CH3
Fig 3
Fig 3: First step in the Carbidopa PLP reaction with PLP attached to
DDC via Lys 303 residue.
infection,
hemmorages,
stroke, only for
those that
responded well to
CarbidopaLevodopa
treatment.
The DDC’s active site is mostly composed of residues
from one of the monomers but it’s located near the
monomer-monomer interaction site. PLP (Pyridoxal 5'phosphate-dependent enzyme) is bound to DDC through
a Lys 303 residue. The carbanionic intermediates formed
during reactions are stabilized by the salt bridge between
the carboxylate of Asp 271 and the protonated pyridine
nitrogen of the cofactor that creates an electron sink.
Two active site residues Ile 101 and Phe 103 are part of
the substrate binding pocket and are later in contact with
the ring of carbidopa.
OH
OH
NH2
Fig 4: Ribbon
representation of DDC
with PLP co-factors as
ball and stick models and
active sites highlighted in
orange.
PLP is attached to the DDC through K303 residue.
Carbidopa, a competitive inhibitor, mimics an
external aldimine and makes a hydrazine with the
PLP cofactor
The key feature of PLP chemistry is PLP’s function
as carbanion stabilizer.
References
1.TIANTAN PUHUA STEM CELL CENTER (http://www.stemcellspuhua.com)
2.www.parkinson.org/Parkinson-s-Disease/Treatment
3.http://www.mayoclinic.com
4.Daidone F. et al. Computer-Aided Drug Design of Inhibitors of 1-DOPA-Decarboxylase: A Target for Treatment of Parkinsons.
5.Burkhard, P., et al: Structural Insight Into Parkinson's Disease Treatment Gained from Drug-Inhibited Dopa Decarboxylase
Nat.Struct.Biol. 8 pp. 963 (2001)
6.www.drugs.com/pro/stalevo.html
7.http://www.biotech-genom.uniroma1.it/cgi-bin/campusnet/home.pl
8.Christenson, et al. On the Identity of DOPA Decarboxylase and 5-hydroxytryptophan Decarboxylase Proceedings of the National
Academy of Sciences of the United States of America, Vol. 69, No. 2. (Feb., 1972), pp. 343-347.
9.Deep, et al.Stimulation of dopa decarboxylase activity in striatum of healthy human brain secondary to NMDA receptor antagonism
with a low dose of amantadine Synapse Volume: 34, Issue: 4, 15 December 1999. pp. 313 - 318.
10.http://www.rcsb.org/pdb/explore/explore.do?structureId=1JS3
11.Davie, et al. "A review of Parkinson's disease". (2008) Br. Med. Bull. 86 (1): 109–27
12.Toney, M.D. "Reaction specificity in pyridoxal enzymes." Archives of biochemistry and biophysics (2005) 433: 279-287
13.Borglum et al. "Two novel variants in the DOPA decarboxylase gene: association with bipolar affective disorder". (2009)
Molecular Psychiatry 4 (6): 545–541
*(Molecules drawn using Chemdraw Ultra 7.0)
*Ribbon Structures from PDB