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? Make the glycogen molecule more soluble. 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