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Regulao metablica : mecanismos moleculares

AULA 14

Regulao metablica : mecanismos moleculares

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REGULAO DE VIAS METABLICAS

A B C D E

E 1 etapa reguladora

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REGULAO DE VIAS METABLICAS

A B C D E

NAD+ NADH

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REGULAO DE VIAS METABLICAS

A B C D E

E 1 etapa reguladora

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REGULAO DE VIAS METABLICAS

A B C D E

-Pi

-PiPi-

3. Alterao covalente > fosforilao > activao ou inibio

actividade de protena cinase ou de fosfatase

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REGULAO DE VIAS METABLICAS

5. Alterao da quantidade de enzima

regulao da expresso do gene que codifica para a protena

6. Carga energtica

7. Activao ou inactivao mediada por

interaco protena / protena

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REGULAO DE VIAS METABLICAS

Exemplos:

1. Citrato sintetase

2. Gliceraldedo-3-fosfato desidrogenase

3. Glicognio sintetase

4. Fosfofructo-cinase5. 3- HMG-reductase

6. Acetil-coA carboxilase

7. Apo C / lipoprotena lipase

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Acetil-CoA carboxilase

Acetil-CoA

oxaloacetato

citrato Malonil-CoA

CO2

Existe em diversas formas que

exibem actividades diferentes

1. - fosforilada

1. Conformao diferente

ATP

ADP

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Fontes de cidos gordos

glucose

piruvato

gliceraldedo-3-Pi

acetil-CoA

malonil-CoA

palmitoil-CoA

acetil-CoA

piruvato

Sintetasede cidos

gordos

Acetil-CoAcarboxilase

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Sntese de malonil-CoA

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P citrato

citrato

P

parcialmenteactiva

activa inactiva

PATP ADP

H2O

Proteina cinase AMPdependente

Protena fosfatase 2A

Regulao da acetil-CoA carboxilase

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AMP-cinase

Cataliza a fosforilao da Acetil-CoA carboxilase INACTIVAO

activada por AMP baixa carga energtica

paragem da sntese de c.gordos

Ocorre

-oxidao de c.gordos

Aumento da conc. de ATP inibio da AMP-cinase

recomeo da sntese de c.gordos

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activa inactiva

PATP ADP

H2O

Hipoglicemia

glucagon inibio da fosfatase

-

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REGULAO DE VIAS METABLICAS

A B C D E

E 1 etapa reguladora

As vias de sntese e de degradao so diferentes

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SINAIS

RECEPTORES

ALTERAES METABLICAS

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GLUCAGON / EPINEFRINA

Estrutura de uma protena G trimrica

R

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Diseases Associated with G Protein Coupled Receptor Mutations

Opsin Color blindness

Rhodopsin Retinitis pigmentosa

Rhodopsin Congenital night blindness

V2 vasopressin Nephrogenic diabetes insipidus ACTH Familial ACTH resistance

LH Familial male precocious puberty

TSH Familial nonautoimmune hypertyroidism

Ca2+ Familial hyperparathyroidism

Thromboxane A2 Congenital bleeding

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Protena tirosina cinase

Substrato + ATP substrato-Pi + ADP

Protena tirosina fosfatase

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Tyrosine kinases - catalyze transfer of a g-phosphate from ATP to the

hydroxyl group on tyrosine residues of protein substrates.

-CH2-C-COO-

H

NH3+

HO-CH2-C-COO-

H

NH3+

NH3+

HO-

CH3-C-C-COO-

HHO

H

Tyrosine

Serine

Threonine

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Tyrosine Protein Phosphorylation

Eukaryotic cells coordinate functions through environmental signals -

soluble factors, extracellular matrix, neighboring cells.

Membrane receptors receive these cues and transduce signals into

the cell for appropriate response.

Tyrosine kinase signalling is the major mechanism for receptor signal

transduction.

Tyrosine protein phosphorylation is rare (1%) relative toserine/thrreonine phosphorylation.

TK pathways mediate cell growth, differentiation, host defense, and

metabolic regulation.

Protein tyrosine phosphorylation is the net effect of protein tyrosine

kinases (TKs) and protein tyrosine phosphatases (PTPs).

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Protein Tyrosine Kinases (TKs)

Receptor tyrosine kinases (RTK)

insulin receptor

EGF receptor

PDGF receptor

TrkA

Non-receptor tyrosine kinases (NRTK) c-Src

Janus kinases (Jak)

Csk (C-terminal src kinase) Focal adhesion kinase (FAK)

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Protein Tyrosine Phosphatases (PTPs)

Receptor-like or Transmembrane PTPs

CD45 PTPa

LAR

Non-receptor or Cytoplasmic PTPs PTP1B

SHP1

SHP2

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Receptor Tyrosine Kinases

From Hubbard (2000) Annu. Rev. Biochem. 69,373.

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Receptor Dimerization and Kinase Activation

From Hunter (2001) Nature 411,355.