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Protein Metabolism

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Protein Metabolism Denotes the various biochemical processes responsible for the synthesis of proteins and amino acids the breakdown of proteins (and other large ... – PowerPoint PPT presentation

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Title: Protein Metabolism


1
Protein Metabolism
  • Denotes the various biochemical processes
    responsible for the synthesis of proteins and
    amino acids
  • the breakdown of proteins (and other large
    molecules, too) by catabolism

2
The Digestion and Absorption of Dietary Proteins
3
Cellular Proteins Are Degraded at Different Rates
  • Some proteins are very stable, while others are
    short lived.
  • Altering the amounts of proteins important in
    metabolic regulation can rapidly change metabolic
    patterns.
  • Cells have mechanisms for detecting and removing
    damaged proteins.
  • A significant proportion of newly synthesized
    protein molecules are defective because of errors
    in translation.
  • Other proteins may undergo oxidative damage or be
    altered in other ways with the passage of time.

4
Ubiquitin Tags Proteins for Destruction
  • How can a cell distinguish proteins that are
    meant for degradation?
  • Ubiquitin, a small (8.5-kd) protein present in
    all eukaryotic cells, is the tag that marks
    proteins for destruction.

5
  • The c-terminal glycine residue of ubiquitin (Ub)
    becomes covalently attached to the e-amino groups
    of several lysine residues on a protein destined
    to be degraded.
  • The energy for the formation of these isopeptide
    bonds (iso because e- rather than a-amino groups
    are targeted) comes from ATP hydrolysis.

6
  • Three enzymes participate in the attachment of
    ubiquitin to each protein
  • ubiquitin-activating enzyme, or E1
  • ubiquitin-conjugating enzyme, or E2
  • ubiquitin-protein ligase, or E3.

7
  • Chains of ubiquitin can be generated by the
    linkage of the e-amino group of lysine residue 48
    of one ubiquitin molecule to the terminal
    carboxylate of another.
  • Chains of four or more ubiquitin molecules are
    particularly effective in signaling degradation

8
What determines whether a protein becomes
ubiquitinated?
  • The half-life of a cytosolic protein is
    determined to a large extent by its
    amino-terminal residue the N-terminal rule.
  • In yeast if N terminus is methionine half-life gt
    20 hours, whereas if N terminus is arginine
    half-life 2 minutes.
  • A highly destabilizing N-terminal residue such as
    arginine or leucine favors rapid ubiquitination,
    whereas a stabilizing residue such as methionine
    or proline does not.
  • E3 enzymes are the readers of N-terminal
    residues.
  • Cyclin destruction boxes are amino acid sequences
    that mark cell-cycle proteins for destruction.
  • Proteins rich in proline, glutamic acid, serine,
    and threonine (PEST sequences).

9
The Proteasome Digests the Ubiquitin-Tagged
Proteins
  • A large protease complex called the proteasome or
    the 26S proteasome digests the ubiquitinated
    proteins.
  • In eukaryotes, they are located in the nucleus
    and the cytoplasm.
  • The degradation process yields peptides of about
    7-8 amino acids long, then further degraded into
    amino acids and used in synthesizing new
    proteins.
  • This ATP-driven multisubunit protease spares
    ubiquitin, which is then recycled.

10
Protein Degradation Can Be Used to Regulate
Biological Function
Example
E3
Inflammation
initiates the expression of a number of the genes
that take part in this response
11
Digested proteins
Amino Acids
Degradation in the liver
NH4
a-ketoacids
enter the metabolic mainstream as precursors to
glucose or citric acid cycle intermediates
The amino group must be removed, as there are no
nitrogenous compounds in energy-transduction
pathways
12
The fate of the a-amino group
  • The a-amino group of many aas is transferred to
    a-ketoglutarate to form glutamate.
  • Glutamate is then oxidatively deaminated to yield
    ammonium ion (NH4).

13
  • Aminotransferases (transaminases) catalyze the
    transfer of an a-amino group from an a-amino acid
    to an a-keto acid.

14
Example
  • Aspartate aminotransferase
  • Alanine aminotransferase
  • These transamination reactions are reversible and
    can thus be used to synthesize amino acids from
    a-ketoacids,

15
  • The nitrogen atom that is transferred to
    a-ketoglutarate in the transamination reaction is
    converted into free ammonium ion by oxidative
    deamination.
  • This reaction is catalyzed by glutamate
    dehydrogenase.
  • This enzyme is unusual in being able to utilize
    either NAD or NADP at least in some species.
  • The reaction proceeds by dehydrogenation of the
    C-N bond, followed by hydrolysis of the resulting
    Schiff base.

16
  • Glutamate dehydrogenase and other enzymes
    required for the production of urea are located
    in mitochondria.
  • This compartmentalization sequesters free
    ammonia, which is toxic.
  • In most terrestrial vertebrates, NH4 is
    converted into urea, which is excreted.

17
Pyridoxal Phosphate Forms Schiff-Base
Intermediates in Aminotransferases
  • All aminotransferases contain the prosthetic
    group pyridoxal phosphate (PLP), which is derived
    from pyridoxine (vitamin B6).

18
Pyridoxal phosphate derivatives can form stable
tautomeric forms
The most important functional group allows PLP to
form covalent Schiff-base intermediates with
amino acid substrates
a pyridine ring that is slightly basic
A phenolic hydroxyl group that is slightly acidic
19
  • The aldehyde group of PLP usually forms a
    Schiff-base linkage with the e-amino group of a
    specific lysine residue of the enzyme.
  • The a-amino group of the amino acid substrate
    displaces the e-amino group of the active-site
    lysine residue.

20
The Urea Cycle
  • Some of the NH4 formed in the breakdown of amino
    acids is consumed in the biosynthesis of nitrogen
    compounds.
  • In most terrestrial vertebrates, the excess NH4
    is converted into urea and then excreted.
  • The urea
  • One nitrogen atom is transferred from aspartate.
  • The other nitrogen atom is derived directly from
    free NH4 .
  • The carbon atom comes from HCO3-.

21
The Urea Cycle Reactions
  • Formation of Carbamoyl Phosphate catalyzed by
    carbamoyl phosphate synthetase.
  • The consumption of two molecules of ATP makes the
    synthesis essentially irreversible.
  • The carbamoyl group of carbamoyl phosphate has a
    high transfer potential because of its anhydride
    bond.

22
  • Carbamoyl is transferred to ornithine to form
    citrulline.
  • The reaction is catalyzed by ornithine
    transcarbamoylase.
  • Ornithine and citrulline are amino acids, but
    they are not used as building blocks of proteins.

23
  • Citrulline is transported to the cytoplasm where
    it condenses with aspartate to form
    argininosuccinate
  • The reaction is catalyzed by argininosuccinate
    synthetase.
  • The reaction is driven by the cleavage of ATP
    into AMP and PPi, and by the subsequent
    hydrolysis of PPi.

24
  • Argininosuccinase cleaves argininosuccinate into
    arginine and fumarate.
  • Thus, the carbon skeleton of aspartate is
    preserved in the form of fumarate.

25
  • Arginine is hydrolyzed to generate urea and
    ornithine in a reaction catalyzed by arginase.
  • Ornithine is then transported back into the
    mitochondrion to begin another cycle.

26
  • Mitochondrial reactions
  • The formation of NH4 by glutamate dehydrogenase.
  • Its incorporation into carbamoyl phosphate
  • Synthesis of citrulline
  • Cytosolic reactions
  • The next three reactions of the urea cycle, which
    lead to the formation of urea, take place in the
    cytosol.

27
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28
THE END
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