Transcript Lehninger Principles of Biochemistry

David L. Nelson and Michael M. Cox
LEHNINGER
PRINCIPLES OF BIOCHEMISTRY
Sixth Edition
CHAPTER 15
Principles of Metabolic Regulation
© 2013 W. H. Freeman and Company
Factors affecting the activity of enzymes
Regulation by reversible
phosphorylation
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
Control of glycogen synthesis from blood glucose
Hexokinase I of muscle has a low Km for glucose
Hexokinase IV of liver has a high Km for glucose
Regulation of phosphofructokinase-1 (PFK-1)
Reciprocal Regulation of PFK-1 and FBPase-1
Activated by
Fructose
2,6-bisphosphate
Inhibited by
Fructose
2,6-bisphosphate
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.
Fructose 2,6-bisphosphate is synthesized by the enzyme
phosphofructokinase-2 (PFK-2) and broken down by
fructose 2,6 bisphosphatase (FBPase-2)
Phosphofructokinase-2 (PFK-2) and
fructose 2,6 bisphosphatase (FBPase-2)
are on the same polypeptide chain and regulated by glucagon
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.
Regulation of Pyruvate Kinase
Glycogen Metabolism
Glycogen phosphorylase degrades glycogen
Hydrolysis of glucose 6-phosphate occurs in the ER
UDP-glucose, synthesized from glucose 1-phosphate,
is the glucose donor for glycogen synthesis
Branch synthesis in glycogen
Why is glycogen branched?
1. Make the glycogen molecule more soluble.
2. Increase the number of reducing ends, the ends where glycogen
synthase adds more glucose residues and where glycogen
phosphorylase removes glucose residues.
Glycogenin primes
the initial sugar
residues in
glycogen
The initial glucose monomer
(from UDP-glucose)
is covalently attached to a
tyrosine residue on glycogenin
Regulation of glycogen phosphorylase
Activated by
glucagon
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.
Regulation of glycogen synthase
Insulin promotes
activation of glycogen
synthase and blocks
inactivation of
glycogen synthase
Glucagon blocks
activation of glycogen
synthase