View
223
Download
4
Category
Preview:
Citation preview
Metabolismo de aminoácidos
Metabolismo do Esqueleto Carbonado
Licenciatura em Ciências da Saúde (Ano 2014-2015)
Isabel Tavares de Almeida Faculdade de Farmácia da ULisboa
Metabolismo de L-Phe e L-Tyr - Biosíntese de Catecolaminas -
DOPA, dopamine, norepinephrine,
and epinephrine are all neurotransmitters
Tirosina Hidroxilase /BH4
10
L-DOPA in Parkinsonism
Blood Brain
Blood Brain Barrier
L-DOPA L-DOPA Dopamine
Dopamine
HO
HOCH2-C-CO2H
CH3
NHNH2Carbidopa
Blocks
Parkinsonism associated with
dopamine in brain through loss of
neurons in basal ganglia. Carbidopa + L-DOPA
Licenciatura Ciências Saúde; Dezembro 2012
Metabolismo de L-Phe e L-Tyr - Biosíntese de Melanina -
Tirosina Hidroxilase /BH4 Tirosinase
Metabolismo de L-Phe e L-Tyr - Biosíntese de Melanina -
Tirosina Hidroxilase /BH4
Melanin (black polymer) formed in
skin (melanocytes), eyes, and hair
In skin, protects against sunlight
Albinism: genetic deficiency of
Tyrosinase
Tirosinase
Triptofano Hidroxilase /BH4
• Serotonin formed in:
• Brain (neurotransmitter; regulation of sleep, mood, appetite)
• Platelets (platelet aggregation, vasoconstriction)
• Smooth muscle (contraction)
• Gastrointestinal tract
• Drugs affecting serotonin actions used to treat:
• Depression
• Migraine
• Schizophrenia
• Obsessive-compulsive disorders
• Chemotherapy-induced emesis
• Some hallucinogens (e.g., LSD) act as serotonin agonists
Metabolismo de L-Trp - Biosíntese de Serotonina -
Triptofano Hidroxilase /BH4
NH
CH2CHO
HO
NH
CH2CO2H
HO
5-Hydroxyindoleacetic acid (5-HIAA)
Monoamine oxidase
(MAO)
Aldehyde
dehydrogenase
Metabolismo de L-Trp - Biosíntese do Ácido 5-OH-indolacético -
Triptofano Hidroxilase /BH4
NH
CH2CHO
HO
NH
CH2CO2H
HO
5-Hydroxyindoleacetic acid (5-HIAA)
Monoamine oxidase
(MAO)
Aldehyde
dehydrogenase
Carcinoid tumors:
• Malignant GI tumor type
• Excretion of large amounts of 5-HIAA
Metabolismo L-Trp - Biosíntese do Ácido 5-OH-indolacético -
18
Tryptophan Metabolism: Serotonin
Formation
NH
CH2CHCO2-
NH3
+
NH
CH2CHCO2-
NH3
HO
+
NH
CH2CH2NH2
HO
Tryptophan
(Trp)
Indole ring
Trp
hydroxylase
O2
5-Hydroxy-
tryptophan
Decarboxylase
CO2 5-Hydroxy-
tryptamine (5-HT);
Serotonin
Triptofano Hidroxilase /BH4
NH
CH2CHO
HO
NH
CH2CO2H
HO
5-Hydroxyindoleacetic acid (5-HIAA)
Monoamine oxidase
(MAO)
Aldehyde
dehydrogenase
Metabolismo L-Trp - Biosíntese do Ácido 5-OH-indolacético -
CHCH2NHR'
HO
HO
R
CHCHO
HO
HO
R
MAO
(mitocôndria)
R R’
OH H Norepi
OH CH3 Epi
H H Dopamine
R=OH Vanillylmandelic acid (VMA)
R=H Homovanillic acid (HVA)
CHCO2H
HO
HO
R
Aldehyde
dehydrogenase
Triptofano Hidroxilase /BH4
NH
CH2CHO
HO
NH
CH2CO2H
HO
5-Hydroxyindoleacetic acid (5-HIAA)
Monoamine oxidase
(MAO)
Aldehyde
dehydrogenase
Metabolismo L-Trp - Biosíntese do Ácido 5-OH-indolacético -
CHCH2NHR'
HO
HO
R
CHCHO
HO
HO
R
CHCO2H
HO
HO
R
MAO
(mitocôndria)
R R’
OH H Norepi
OH CH3 Epi
H H Dopamine
R=OH Vanillylmandelic acid (VMA)
R=H Homovanillic acid (HVA)
MAO inhibitors (e.g., tranylcypromine) are useful
in the treatment of depression
Brain levels of dopamine and norepi.; also
serotonin
Aldehyde
dehydrogenase
21
Monoamine Oxidase (MAO)
MAO
(in mitochondria)
R R’
OH H Norepi
OH CH3 Epi
H H Dopamine
CHCH2NHR'
HO
HO
R
CHCHO
HO
HO
R
CHCO2H
HO
HO
RUrinary metabolite
MAO inhibitors (e.g., tranylcypromine) are useful
in the treatment of depression
Brain levels of dopamine and norepi.; also
serotonin
Aldehyde
dehydrogenase
R=OH Vanillylmandelic acid (VMA) R=H Homovanillic acid (HVA)
Triptofano Hidroxilase /BH4
Melatonin:
("hormone of darkness“)
Formed principally in pineal gland
It helps regulate other hormones and maintains the body's
circadian rhythm.
Synthesis controlled by light, among other factors
Induces skin lightening
Suppresses ovarian function
Possible use in sleep disorders
Metabolismo L-Trp - Biosíntese de Melatonina -
Triptofano Hidroxilase /BH4 Indolamina 2,3-dioxygenase
Niacina (ou ácido nicotinico):
precursor do NAD
Metabolismo L-Trp - Biosíntese do Ácido Nicotínico -
Catabolismo L-Phe e L-Tyr - Via catabólica principal -
Fenilcetonúria
Tirosinémia Tipo II
Tirosinémia Tipo III
Alcaptonúria
Tirosinémia Tipo I
Catabolismo L-Phe e L-Tyr - Doenças Hereditárias Associadas-
Fenilcetonúria
Tirosinémia Tipo II
Tirosinémia Tipo III
Alcaptonúria
Tirosinémia Tipo I
hPAH deficiency PKU / HPA
• Most frequent disorder aa metabolism (1:10000) - 226 patients in the Portuguese population (till 2005);
• Severe psychomotor delay if untreated;
• High phenotypic heterogeneity – Classical PKU (> 1200 µM), Mild PKU (900-1200 µM), non-PKU HPA (360-900 µM);
• Dietetic restriction –implemented soon after birth (< 720 µM)
Phenylketonuria (PKU; OMIM # 261600) Metabolismo L-Phe
Metabolismo Aminoácidos Aromáticos (L-Phe; L-Tyr; L-Trp)
NH2
HOOC
NH2
HOOC
OHPAH
NH2
HOOC
OH TH NH2
HOOC
OH
OH
NH2
NH
HOOC
NH2
NH
HOOC
OH
TPH
CO2,H2O
Dopamine
Noradrenaline
Adrenaline
Melatonin
Serotonin
O2
O
NH
NNH2
NH
NH
H
H
OH
OH
L-Phe L-Tyr
L-Tyr L-DOPA
L-Trp 5-OH-L-Trp
BH4
O
N
NNH2
NH
NH
H
H
OH
OH
OH
4a-OH-BH4
H2O
O
N
NNH2
NH
H
H
OH
OH
N
q-BH2
NADH
NAD+
PCDDHPR
Guanosine triphosphate
7,8-Dihydroneopterin triphosphate
6-Pyruvoyol-tetrahydropterin
GTP-CH
6-PTPS
SR
12
34
4a5 6
78
O
NH
NNH2
NH
H
H
OH
OH
N
BH2
NADH
NAD+
DHFR
Catabolismo Aminoácidos Aromáticos - Alcaptonúria -
Alcaptonúria
• Descrita pela primeira vez no Séc. 16
• Caracterizada em 1859 por Garrod
• Base dos estudos que o levaram ao
desenvolvimento do conceito das Doenças
Metabólicas como Doenças Hereditárias
Alcaptonúria
• Deficiency of homogentisate dioxygenase
• Urine turns dark on standing (Oxidation of
homogentisic acid
• Asymptomatic in childhood
• Tendency toward arthritis in adulthood and connective
tissue pigmentation (ochronosis) due to oxidation of
homogentisate to benzoquinone acetate, which
polimerizes and binds to connective tissue
Alcaptonúria (OMIM # 203500) Metabolismo L-Tyr
Tyrosinémia Tipo I
Babies usually show effects of the condition
within the first few months of life:
diarrhea and bloody stools; vomiting; poor
weight gain; extreme sleepiness; irritability
Liver problems leading to enlarged liver,
yellowing of the skin; tendency to bleed and
bruise easily; swelling of the legs and abdomen
Without prompt and careful treatment, babies
with severe liver and kidney problems usually
die.
Tirosinémia tipo I (OMIM # 276700) Metabolismo L-Tyr
Aminoácidos Ramificados e DoençaS Hereditárias Associadas - MSUD -
BCKDH (Branched Chain alpha-Ketoacid DeHydrogenase)
A protein complex found in the mitochondria of all cells, presenting 3 catalytic
subunits (encoded by different genes):
. A branched-chain alpha-keto acid decarboxylase (E1),
. A dihydrolipoyl transacylase (E2),
. A dihydrolipoamide dehydrogenase (E3), also found in pyruvate and alpha-
ketoglutarate dehydrogenase complexes
The activity of the complex is regulated by specific kinase/phosphatase.
MSUD (Maple Syrup Urine Disease)
(Maple Syrup: xarope de ácer)
Maple Syrup Urine Disease (MSUD) derives its name from the
characteristic sweet smell, like that of maple syrup, of the urine of affected
individuals.
It is an autosomal recessive genetic disease, with an incidence of about 1
in 185,000 live births.
The symptoms vary, some cases being more severe than others. The
"classical" form of the disease appears within a few days after birth, when
the smell of the infant's urine becomes noticeable.
If untreated, MSUD can cause mental retardation; the severe form of the
disease can involve convulsions, leading to coma and even death.
Aminoácidos Ramificados e DoençaS Hereditárias Associadas - MSUD -
Hcy
ATP
Met
SAM
SAH
DNA
RNA
Protein
Lipids
etc
Methylated
Acceptor
DIET
3Pi
Cystathionine
CBS
Cysteine
B6
Betaine
DMG
Choline
BHMT MS
B12
SAHH
MTs
MAT
CH3THF
THF
CH2THF
MTHFR
TRANSSULFURATION PATHWAY
REMETHYLATION PATHWAY
HOMOCISTEINE METABOLISM
Serina Ado
Serine
Glycine
Ado
Folate Cycle
Methionine Cycle
Ado
DHF
Timidina 5´Fosfato
Timidilato Sintase
DNA
Uridina 5`P
50
Homocysteine
Homocysteinuria
• Rare; deficiency of cystathionine b-synthase
• Dislocated optical lenses
• Mental retardation
• Osteoporosis
• Cardiovascular disease death
Blood levels of homocysteine associated with
cardiovascular disease
• May be related to dietary folate deficiency
• Folate enhances conversion of
homocysteine to methionine
Recommended