Metabolismo de aminoácidos Metabolismo do Esqueleto …º... · • Brain (neurotransmitter; regulation of sleep, mood, appetite)

Metabolismo de aminoácidos

Metabolismo do Esqueleto Carbonado

Licenciatura em Ciências da Saúde (Ano 2014-2015)

Isabel Tavares de Almeida Faculdade de Farmácia da ULisboa

Aminoácidos Aromáticos

(L-Phe)

L-Fenilalanina

L-Tirosina L-Triptofano (L-Tyr)

(L-Trp)

Aminoácidos Ramificados

L-Valina

L-Leucina L-Isoleucina (L-Leu)

(L-Ile)

(L-Val)

Aminoácidos Aromáticos

(L-Phe)

L-Fenilalanina

L-Tirosina L-Triptofano (L-Tyr)

(L-Trp)

Catabolismo de L-Phe e L-Tyr

Metabolismo de L-Phe e L-Tyr - Biosíntese de Catecolaminas -

Tirosina Hidroxilase /BH4

Metabolismo de L-Phe e L-Tyr - Biosíntese de Catecolaminas -

DOPA, dopamine, norepinephrine,

and epinephrine are all neurotransmitters


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 -


Melanin (black polymer) formed in

skin (melanocytes), eyes, and hair

In skin, protects against sunlight

Albinism: genetic deficiency of

Tyrosinase

Tirosinase

Catabolismo de L-Trp

Metabolismo de L-Trp - Biosíntese de Serotonina -

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 -


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 -


NH

CH2CHO

HO

NH

CH2CO2H

HO


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


NH

CH2CHO

HO

NH

CH2CO2H

HO


Monoamine oxidase

(MAO)

Aldehyde

dehydrogenase


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


NH

CH2CHO

HO

NH

CH2CO2H

HO


Monoamine oxidase

(MAO)

Aldehyde

dehydrogenase


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)


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

Phenylketonuria (PKU; OMIM # 261600) Metabolismo L-Phe



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)



Programa Nacional de Rastreio Neo-natal

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 - Tyr -

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

Alcaptonúria

Tirosinémia Tipo I

X

Metabolismo L-Tyr

Aminoácidos Ramificados

L-Valina

L-Leucina L-Isoleucina (L-Leu)

(L-Ile)

(L-Val)

Catabolismos dos Aminoácidos Ramificados

MSUD

Catabolismos dos Aminoácidos Ramificados

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

Metionina

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

Metabolismo de aminoácidos Metabolismo do Esqueleto …º... · • Brain (neurotransmitter; regulation of sleep, mood, appetite)

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