Renal Module

1. Dr Zahid Azeem Raja
Assistant Professor
AJK Medical College,
Muzaffarabad
Class-2019--- Renal Module

2. 1- Amino Acid Pool
2- Protein turn over
3- Why different proteins possess different lifespan
4- Protein degradation pathways
5- Proteosome action on protein molecules
6- Lysosomal degradation of proteins

3. Amino Acid Pool (AAP)
Free amino acids are present throughout the body, for
example in
cells
 blood
 the extracellular fluids.
All these free amino acids collectively considered as
single entity and named as Amino Acid Pool.

4. Contributor of AAP
This pool is supplied by three sources:
1) amino acids provided by the degradation of body
proteins
2) amino acids derived from dietary protein
3) synthesis of nonessential amino acids from simple
intermediates of metabolism

5. Routes for depletion of AAP
the amino pool is depleted by three routes:
1) synthesis of body protein
2) amino acids consumed as precursors of essential
nitrogen-containing small molecules
3)conversion of amino acids to glucose, glycogen,
fatty acids, ketone bodies, or CO2 + H2O

7.  Although the amino acid pool is small (comprised
of about 90–100 g of amino acids) in comparison
with the amount of protein in the body (about 12
kg in a 70-kg man),
 It is conceptually at the center of whole-body
nitrogen metabolism.

8. Protein Turnover
In healthy adults, the total amount of protein in the
body remains constant, because the rate of protein
synthesis is just sufficient to replace the protein that
is degraded. This process called protein turnover.
This leads to the hydrolysis and resynthesis of 300–400
g of body protein each day.
The rate of protein turnover varies widely for individual
proteins.

9. Life of Proteins
 Short-lived proteins (for example, many regulatory
proteins and misfolded proteins) are rapidly
degraded, having half-lives measured in minutes or
hours.
 Long-lived proteins, with half-lives of days to weeks,
constitute the majority of proteins in the cell.
Structural proteins, such as collagen, are
metabolically stable, and have half-lives measured in
months or years.

10. Protein Degradation
There are two major enzyme systems responsible for
degrading damaged or unneeded proteins:
A)The ATP-dependent ubiquitin-proteasome system of
the cytosol. (80-90%)
B)ATP-independent degradative enzyme system of the
lysosome (10-20%)

11. Proteasomes degrade mainly endogenous proteins, that
is, proteins that were synthesized within the cell.
Lysosomal enzymes (acid hydrolases) degrade primarily
extracellular proteins, such as plasma proteins that
are taken into the cell by endocytosis, and cell-surface
membrane proteins that are used in receptor-
mediated endocytosis.

12. Ubiquitin-Proteasome Proteolytic Pathway
Proteins selected for degradation by the ubiquitin-
proteasome system are first covalently attached to
ubiquitin, a small, globular, non-enzymatic protein.
Ubiquitination of the target substrate occurs through
linkage of the α-carboxyl group of the C-terminal
glycine of ubiquitin to the ε-amino group of a lysine
on the protein substrate by a three-step, enzyme-
catalyzed, ATP-dependent process.

13. Continue
 The consecutive addition of ubiquitin moieties
generates a polyubiquitin chain.
 Proteins tagged with ubiquitin are then recognized by
a large, barrel-shaped, macromolecular, proteolytic
complex called a proteasome, which functions like a
garbage disposal.

15. Continue
The proteasome unfolds, deubiquitinates, and cuts the
target protein into fragments that are then further
degraded to amino acids, which enter the amino acid
pool.
Selective degradation of proteins by the ubiquitin-
proteosome complex requires energy in the form of
ATP.

16. AMP

19. Chemical signals for protein degradation
Some structural aspect of the protein influence half
lives of any protein.
 Some proteins that have been chemically altered by
oxidation or tagged with ubiquitin are
preferentially degraded.

20. The half-life of a protein is influenced by the nature of
the N-terminal residue.
 For example, proteins that have serine as the N-
terminal amino acid are long-lived, with a half-life of
more than 20 hours.
 In contrast, proteins with aspartate as the N-
terminal amino acid have a half-life of only 3 minutes.

21. Proteins rich in sequences containing proline,
glutamate, serine, and threonine (called PEST
sequences after the one-letter designations or
these amino acids) are rapidly degraded and,
therefore, exhibit short intracellular half-lives.

23. LysosomalLysosomal
EnzymesEnzymes
50 different degradative
enzymes
Acid hydrolasesAcid hydrolases
Active at pH 5
(inside lysosome)
Inactive if released
into cytosol (pH 7.2)
Acidic pHAcidic pH of lysosomes
maintained by a proton
pump
in the lysosomal membrane
Requires ATP

24. Different pathways lead to the lysosome
1) Phagocytosis
–Cell “eating” of material
> 250nm
2) Pinocytosis
–Cell “drinking”
< 150nm
3) Receptor Mediated
Endocytosis
-clathrin-coated pits
4) Autophagy
–“self eat” of old worn out organelles,
– important in cell degradation during apoptosis

25. Protein degradation in the lysosomesProtein degradation in the lysosomes
 Lysosomes degrade extracellular proteins that the cell incorporates
by endocytosis.
 Lysosomes can also degrade intracellular proteins that are enclosed
in other membrane-limited organellas.
 In well-nourished cells, lysosomal protein degradation is non-
selective (non-regulated).
 In starved cells, lysosomes degrade preferentially proteins
containing a KFERQKFERQ “signal” peptide.
 The regression of the uterus after childbirth is mediated largely by
lysosomal protein degradation

26. THE END