Chapter 12 Additional Pathways in Carbohydrate Metabolism

• Insulin, a 51 amino acid polypeptide that regulates carbohydrate and lipid metabolism

Glycogen Degradation

• Glucose is stored in mammals as glycogen • Glycogen is stored in cytosolic granules in muscle and liver cells •

Glycogenolysis

- degradation of glycogen • Glycogen breakdown yields glucose 1-phosphate which can be converted to glucose 6-phosphate for metabolism by glycolysis and the citric acid cycle

Glycogen particles in a liver cell section

The enzyme Glycogen Phosphorylase

• Catalyzes

phosphorolysis

- cleavage of a bond by group transfer to an oxygen atom of phosphate • Glycogen Phosphorylase removes glucose residues from the ends of glycogen • Acts only on a -1-4 linkages of a glycogen polymer • The product is glucose 1-phosphate, which is converted to glucose 6-phosphate

Cleavage of a glucose residue from the end of glycogen

glycogen phosphorylase

Degradation of Glycogen by Glycogen Phosphorylase

• Glycogen phosphorylase catalyzes the sequential removal of glucose residues from the ends of glycogen • Stops 4 glucose residues from an a 1-6 branch point • Resulting limit dextrin is further degraded by a glycogen debranching enzyme, producing a free glucose molecule and an elongated unbranched chain

Fig 12.21

Metabolism of Glucose 1-Phosphate

•

Phosphoglucomutase

catalyzes the conversion of glucose 1-phosphate to glucose 6-phosphate

Glycogen Synthesis

• Glycogen is synthesized from excess glucose for storage • Synthesis and degradation of glycogen require separate enzymatic steps • Cellular glucose is converted to glucose 6-phosphate by the enzyme hexokinase • Three separate enzymatic steps are required to incorporate one glucose 6-phosphate into glycogen • Glycogen synthase catalyzes the major regulatory step Prentice Hall c2002 Chapter 13 9

Fig 12.16

• Synthesis of glycogen from glucose 6-phosphate

Fig. 12.17 Glycogen synthase adds glucose to the end of a glycogen chain

Regulation of Glycogen Metabolism

• Muscle glycogen is fuel for muscle contraction • Liver glycogen is mostly converted to glucose for bloodstream transport to other tissues • Both mobilization and synthesis of glycogen are regulated by hormones •

Insulin

,

glucagon

and

epinephrine

are hormones that regulate glycogen metabolism

Hormones Regulate Glycogen Metabolism

•

Insulin

is produced by b -cells of the pancreas in response to high blood glucose • Insulin increases the rate of glucose transport into muscle and adipose tissue via the glucose transporter (GLUT 4) •

Glucagon

is secreted by the a to low blood glucose cells of the pancreas in response • Glucagon stimulates glycogen degradation to restore blood glucose to steady-state levels •

Epinephrine

(adrenaline) is released from the adrenal glands in response to sudden energy requirement (“fight or flight”) • Epinephrine stimulates the breakdown of glycogen to glucose 1 phosphate

Reciprocal Regulation of Glycogen Phosphorylase and Glycogen Synthase

•

Glycogen phosphorylase

and

glycogen synthase

are reciprocally regulated. When one is active the other is inactive.

• Covalent regulation by phosphorylation (-P) and dephosphorylation (-OH) and allosteric regulation.

Active form “

a

” Inactive form “

b

” Glycogen phosphorylase -P Glycogen synthase -OH -OH -P GP

a

(active form) - inhibited by glucose 6-phosphate GS

b

(inactive form) - activated by glucose 6-phosphate Prentice Hall c2002 Chapter 13 14

Gluconeogenesis

• Liver and kidney can synthesize glucose from noncarbohydrate precursors such as lactate and alanine • Under fasting conditions, gluconeogenesis supplies almost all of the body’s glucose

Fig. 12.1

• Comparison of gluconeogenesis and glycolysis

Fig 12.1

Pyruvate carboxylase

• Catalyzes a metabolically irreversible reaction • Allosterically activated by acetyl CoA • Accumulation of acetyl CoA signals abundant energy, and directs pyruvate to oxaloacetate for gluconeogenesis

Phosphoenolpyruvate carboxykinase (PEPCK)

• A decarboxylation reaction in which GTP donates a phosphoryl group

Fructose 1,6-bisphosphatase (F1,6BPase)

• Catalyzes a metabolically irreversible reaction • F1,6BPase is allosterically inhibited by AMP and fructose 2,6-

bis

phosphate (F2,6BP)

Glucose 6-phosphatase

• Catalyzes a metabolically irreversible hydrolysis reaction

Precursors for Gluconeogenesis

• Any metabolite that can be converted to pyruvate or oxaloacetate can be a glucose precursor • Major gluconeogenic precursors in mammals: (1) Lactate (2) Most amino acids (especially alanine), (3) Glycerol (from triacylglycerol hydrolysis) Prentice Hall c2002 Chapter 13 24

Lactate

• Glycolysis generates large amounts of lactate in active muscle • Liver lactate dehydrogenase converts lactate to pyruvate (a substrate for gluconeogensis) • Glucose produced by liver is delivered to peripheral tissues via the bloodstream

Fig 12.5

The Cori Cycle

• The interaction of glycolysis and gluconeogenesis

Amino Acids

• Carbon skeletons of most amino acids are catabolized to pyruvate or citric acid cycle intermediates • The

glucose-alanine cycle

: (1) Transamination of pyruvate yields alanine which travels to the liver (2) Transamination of alanine in the liver yields pyruvate for gluconeogenesis (3) Glucose is released to the bloodstream Prentice Hall c2002 Chapter 13 26

Gluconeogensis from Glycerol

Regulation of Gluconeogenesis

•

Substrate cycle

- two opposing enzymes: (1) Phosphofructokinase-1 (glycolysis) (2) Fructose 1,6-

bis

phosphatase (gluconeogenesis) • Modulating one enzyme in a substrate cycle will alter the flux through the two opposing pathways • Inhibiting Phosphofructokinase-1 stimulates gluconeogenesis • Inhibiting Fructose 1,6-

bis

phosphatase stimulates glycolysis Prentice Hall c2002 Chapter 13 28

Regulation of liver glycolysis and gluconeogenesis

The Pentose Phosphate Pathway

• Glucose can enter this pathway after conversion to glucose 6-phosphate • Pathway has two primary products: (1)

NADPH

(for reductive biosynthesis) (2)

Ribose 5-phosphate

(

R5P

) for the biosynthesis of ribonucleotides (RNA, DNA) Prentice Hall c2002 Chapter 13 30

Maintenance of Glucose Levels in Mammals

• Glucose is the major metabolic fuel in the body • Mammals maintain blood glucose levels within strict limits (~3mM to 10mM) • High levels of blood glucose are filtered out by the kidneys • The brain relies almost solely on glucose for energy needs • The liver participates in the interconversions of all types of metabolic fuels: carbohydrates, amino acids and fatty acids • Products of digestion pass immediately to the liver for metabolism or redistribution • The liver regulates distribution of dietary fuels and supplies fuel from its own reserves Prentice Hall c2002 Chapter 13 31

Fig 12.28

• Placement of the liver in circulation

Fig 12.29 Five phases of glucose homeostasis

• Graph illustrates glucose utilization after 100g glucose consumption then 40 day fast Fatty acid breakdown Protein breakdown

Entry into starvation

Fuel reserves of a human are: Glycogen in the liver and muscle Triacylglycerols in adipose tissue Tissue Proteins After an overnight fast glycogen is essentially used up.

Within 24 hours blood glucose concentration falls.

Insulin secretion slows down, glucagon is increased.

Triacylglycerols are broken down as fuel for muscle and liver.

The brain needs glucose. Proteins are degraded and their carbon skeletons used for gluconeogenesis.

The amino groups are excreted as urea.

Prentice Hall c2002 Chapter 13 34

How much energy is stored in our bodies?

How long will it last?

Prentice Hall c2002 Chapter 13 35