prentice hall c2002chapter 131 chapter 13 additional pathways in carbohydrate metabolism insulin, a...

Prentice Hall c2002 Chapter 13 1

Chapter 13 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 -1-4 linkages of a glycogen polymer

• The product is glucose 1-phosphate, which is converted to glucose 6-phosphate


Fig 13.1 Cleavage of a glucose residue from the end of glycogen


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 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

Prentice Hall c2002 Chapter 13 7Fig 13.3


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


Fig 13.4

• Synthesis of glycogen from

glucose 6-phosphate


Fig. 13.5 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 -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 cells of the pancreas in response to low blood glucose

• 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


Fig 13.6 Effects of hormones on glycogen metabolism


Reciprocal Regulation of GlycogenPhosphorylase 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 -OH

Glycogen synthase -OH -PGP a (active form) - inhibited by glucose 6-phosphate

GS b (inactive form) - activated by glucose 6-phosphate


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

2 Pyruvate + 2 NADH + 4 ATP + 2 GTP + 6 H2O + 2 H+

Glucose + 2 NAD+ + 4 ADP + 2 GDP + 6 Pi


Fig. 13.10

• Comparison of gluconeogenesis and glycolysis


Fig 13.10


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-bisphosphate (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)


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 13.12

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


Gluconeogensis from Glycerol


Regulation of Gluconeogenesis

• Substrate cycle - two opposing enzymes: (1) Phosphofructokinase-1 (glycolysis)(2) Fructose 1,6-bisphosphatase (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-bisphosphatase stimulates glycolysis


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)


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


Fig 13.23

• Placement of the liver in circulation


Fig 13.24 Five phases of glucose homeostasis

• Graph illustrates glucose utilization after 100g glucose consumption then 40 day fast

Fatty acid breakdown

Proteinbreakdown


Entry into starvation

Fuel reserves of a human are:Glycogen in the liver and muscleTriacylglycerols in adipose tissueTissue 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.


How much energy is stored in our bodies?How long will it last?

prentice hall c2002chapter 131 chapter 13 additional pathways in carbohydrate metabolism insulin, a...

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