Biochemistry Chapter 15 Principle of metabolic regulation.ppt

principle of metabolic regulation

1. LEHNINGER
PRINCIPLES OF BIOCHEMISTRY
Sixth Edition
David L. Nelson and Michael M. Cox
© 2013 W. H. Freeman and Company
CHAPTER 15
Principles of Metabolic Regulation

2. Factors affecting the activity of enzymes
4000 genes (12%) encode regulatory
proteins
Regulation also overlaps

3. Both number and catalytic activity of
enzymes is regulated
Transcriptome: the sum total of all the messenger RNA
molecules expressed from the genes of an organism
(microarray)
Proteome: the entire complement of proteins that is or can be
expressed by a cell, tissue, or organism. (SDS page)
Metablome: the total number of metabolites present within an
organism, cell, or tissue.

4. Regulation by reversible
phosphorylation

5. A typical ATP-utilizing enzyme has a Km for ATP of about 5 mM
The concentration of ATP in animal tissues is about 5 mM
Change in ATP level
will regulate
reactions of theses
enzymes

6. Control of glycogen synthesis from blood glucose

8. Hexokinase I of muscle has a low Km for glucose
Hexokinase IV of liver has a high Km for glucose
HK-I –III
Inhibited by G6P
HK-IV
High Km
Not inhibited by
G6P
Inhibited by
regulatory protein
binding with F6P,
where glucose
competes

9. The regularory protein enchors HK-IV in nucleus where its
segregated from other enzymes of glycolysis

10. Regulation of phosphofructokinase-1 (PFK-1)

11. Glucagon, a pancreatic hormone, signals low blood sugar and
lowers the level of fructose 2,6-bisphosphate in the liver.
This stimulates gluconeogenesis and the production of glucose.
Activated by
Fructose
2,6-bisphosphate
Inhibited by
Fructose
2,6-bisphosphate
Reciprocal Regulation of PFK-1 and FBPase-1

12. Fructose 2,6-bisphosphate is synthesized by the enzyme
phosphofructokinase-2 (PFK-2) and broken down by
fructose 2,6 bisphosphatase (FBPase-2)

13. Phosphofructokinase-2 (PFK-2) and
fructose 2,6 bisphosphatase (FBPase-2)
are on the same polypeptide chain and regulated by glucagon

14. Regulation of Pyruvate Kinase
Pyruvate kinase is inhibited by:
ATP
acetyl-CoA
long-chain fatty acids
High concentrations of ATP signals that glycolysis is not
needed for further production of ATP.
Acetyl-CoA and fatty acids are fuels for the citric acid
cycle. When there is plenty of fuel for the citric
acid cycle glycolysis is not needed to provide
acetyl-CoA for the citric acid cycle.

15. Regulation of Pyruvate Kinase
PK has 3 isozymes
in vertibtrates
Muscle M is not
regulated by
phosphorylation

16. Glycogen Metabolism

17. Glycogen phosphorylase degrades glycogen

19. Hydrolysis of glucose 6-phosphate occurs in the ER
of liver cells and glucose enters in blood
However, in muscles G6P enters glycolysis
(glucose 6-phosphatase is absent in muscles and adipose)

20. UDP-glucose, synthesized from glucose 1-phosphate,
is the glucose donor for glycogen synthesis

21. The suitability of sugar nucleotides for biosynthetic
reactions
1.Their formation is metabolically irreversible, contributing to
the irreversibility of the synthetic pathways in which they are
intermediates.
2.The nucleotide moiety has many groups that can undergo
monovalent interactions with enzymes; the additional free
energy of binding
3.Like phosphate, the nucleotidylgroup (UMP or AMP) is an
excellent leaving group
4.By “tagging” some hexoses with nucleotidylgroups, cells can set
them aside in a pool for one purpose (glycogen synthesis, for
example), separate from hexose phosphates destined for another
purpose (such as glycolysis).

22. Branch synthesis in glycogen
Why is glycogen branched?
1.Make the glycogen molecule more compact.
2.Increase the number of reducing ends, the ends where glycogen
synthase adds more glucose residues and where glycogen
phosphorylase removes glucose residues.

23. Glycogenin primes
the initial sugar
residues in
glycogen
The initial glucose monomer
(from UDP-glucose)
is covalently attached to a
tyrosine residue on glycogenin

25. Regulation of glycogen phosphorylase
(regulation of glycogen synthesis and breakdown)
Activated by
glucagon
Glycogen phosphorylase a; Active
and causes breakdown of glycogen

27. Glucose binds to an allosteric site on glycogen phosphorylase
a and induces a conformational change that exposes the
phosphorylated serines to phosphorylase a phosphatase.
The result is a decrease in glycogen breakdown in response to
high blood glucose levels.

28. Regulation of glycogen synthase
Insulin promotes
activation of glycogen
synthase and blocks
inactivation of
glycogen synthase
Glucagon blocks
activation of glycogen
synthase

31. 6. Enzyme Activity and Physiological Function
The Vmaxof the enzyme glycogen phosphorylase
from skeletal muscle is much greater than the Vmaxof
the same enzyme from liver tissue.
(a)What is the physiological function of glycogen
phosphorylasein skeletal muscle? In liver
tissue?
(b) Why does the Vmaxof the muscle enzyme need to
be greater than that of the liver enzyme?