7-signal - Biochemistry of Metabolism Signal Transduction...

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Signal Transduction Copyright © 1999-2008 by Joyce J. Diwan. All rights reserved. Biochemistry of Metabolism
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Many enzymes are regulated by covalent attachment of phosphate , in ester linkage, to the side-chain hydroxyl group of a particular amino acid residue (serine, threonine, or tyrosine). H 3 N + C COO - CH OH CH 3 H threonine (Thr) H 3 N + C COO - CH 2 OH H serine (Ser)
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A protein kinase transfers the terminal phosphate of ATP to a hydroxyl group on a protein. A protein phosphatase catalyzes removal of the P i by hydrolysis. Protein OH + ATP Protein O P O O - O - + ADP P i H 2 O Protein Kinase Protein Phosphatase
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Phosphorylation may directly alter activity of an enzyme, e.g., by promoting a conformational change. Alternatively, altered activity may result from binding another protein that specifically recognizes a phosphorylated domain. E.g., 14-3-3 proteins bind to domains that include phosphorylated Ser or Thr in the sequence RXXX[pS/pT]XP, where X can be different amino acids. Binding to 14-3-3 is a mechanism by which some proteins (e.g., transcription factors) may be retained in the cytosol, & prevented from entering the nucleus.
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Protein kinases and phosphatases are themselves regulated by complex signal cascades. For example: Some protein kinases are activated by Ca ++ - calmodulin . Protein Kinase A is activated by cyclic-AMP (cAMP). Protein OH + ATP Protein O P O O - O - + ADP P i H 2 O Protein Kinase Protein Phosphatase
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Adenylate Cyclase (Adenylyl Cyclase) catalyzes: ATP cAMP + PP i Binding of certain hormones (e.g., epinephrine) to the outer surface of a cell activates Adenylate Cyclase to form cAMP within the cell. Cyclic AMP is thus considered to be a second messenger . N N N N NH 2 O OH O H H H H 2 C H O P O O- 1' 3' 5' 4' 2' cAMP
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Phosphodiesterase enzymes catalyze: cAMP + H 2 O AMP The phosphodiesterase that cleaves cAMP is activated by phosphorylation catalyzed by Protein Kinase A. Thus cAMP stimulates its own degradation , leading to rapid turnoff of a cAMP signal. N N N N NH 2 O OH O H H H H 2 C H O P O O- 1' 3' 5' 4' 2' cAMP
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Protein Kinase A (cAMP-Dependent Protein Kinase) transfers P i from ATP to OH of a Ser or Thr in a particular 5-amino acid sequence. Protein Kinase A in the resting state is a complex of: 2 catalytic subunits ( C ) 2 regulatory subunits ( R ). R 2 C 2
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R 2 C 2 Each regulatory subunit ( R ) of Protein Kinase A contains a pseudosubstrate sequence, like the substrate domain of a target protein but with Ala substituting for the Ser/Thr. The pseudosubstrate domain of ( R ), which lacks a hydroxyl that can be phosphorylated, binds to the active site of ( C ), blocking its activity.
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R 2 C 2 + 4 cAMP R 2 cAMP 4 + 2 C When each ( R ) binds 2 cAMP, a conformational change causes ( R ) to release ( C ). The catalytic subunits can then catalyze
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7-signal - Biochemistry of Metabolism Signal Transduction...

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