Transcript Principles of BIOCHEMISTRY - Illinois State University

Chapter 12
Additional Pathways in
Carbohydrate Metabolism
• Insulin, a 51 amino acid polypeptide that regulates
carbohydrate and lipid metabolism
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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
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Glycogen particles in a liver cell section
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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
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Cleavage of a glucose residue from the end
of glycogen
glycogen
phosphorylase
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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 glycogendebranching enzyme, producing a free glucose molecule
and an elongated unbranched chain
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Metabolism of Glucose 1-Phosphate
• Phosphoglucomutase catalyzes the conversion of
glucose 1-phosphate to glucose 6-phosphate
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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
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Fig 12.10
• Synthesis of
glycogen from
glucose 6-phosphate
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Fig. 12.11 Glycogen synthase adds glucose
to the end of a glycogen chain
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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
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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 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 1phosphate
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Fig 12.15 Effects of hormones on
glycogen metabolism
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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
-OH
Glycogen synthase
-OH
-P
GP a (active form) - inhibited by glucose 6-phosphate
GS b (inactive form) - activated by glucose 6-phosphate
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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
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Fig. 12.1
• Comparison of
gluconeogenesis
and glycolysis
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Fig 12.1
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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
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Phosphoenolpyruvate carboxykinase (PEPCK)
• A decarboxylation reaction in which GTP
donates a phosphoryl group
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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)
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Glucose 6-phosphatase
• Catalyzes a metabolically irreversible hydrolysis reaction
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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)
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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 12.2
The Cori Cycle
• The interaction of
glycolysis and
gluconeogenesis
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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
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Gluconeogensis from Glycerol
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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
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Regulation of liver glycolysis
and gluconeogenesis
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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)
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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
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Fig 12.19
• Placement of the liver
in circulation
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Fig 12.20 Five phases of
glucose homeostasis
• Graph illustrates glucose utilization after 100g
glucose consumption then 40 day fast
Fatty acid breakdown
Protein
breakdown
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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.
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How much energy is stored in our bodies?
How long will it last?
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