Download Chapter 16

Chapter 16
Glycogen Metabolism and Gluconeogenesis
Glycogen
Glycogen is a multibranched polysaccharide of glucose that
serves as a form of energy storage in animals and fungi.
The polysaccharide structure represents the main storage
form of glucose in the body.
Glycogen
In humans, glycogen is made and stored primarily in the cells
of the liver and the muscles hydrated with three or four parts
of water.
Glycogen functions as the secondary long-term energy
storage, with the primary energy stores being fats held in
adipose tissue.
Muscle glycogen is converted into glucose by muscle cells,
and liver glycogen converts to glucose for use throughout the
body including the central nervous system.
Overview of Glucose Metabolism
Glycogen Metabolism
Gluconeogenesis
• Forms glucose from non-CBH molecules.
• In the liver.
• Protects the body, especially the brain, from the
damaging effects of hypoglycemia by ensuring
ATP synthesis can continue.
• Stimulated by insulin
Glycogen Metabolism
• Glycogenolysis –
breakdown of
glycogen in
response to low
blood glucose
• Stimulated by
glucagon
Pancreas
• Endocrine & exocrine – posterior &
slightly inferior to stomach
Exocrine function – 98% – production
of digestive enzymes by acinar cells
Endocrine function – Islets of
Langerhans;
Pancreas
3 main types of cells
α–- produce glucagon
β – produce insulin
Δ – produce somatostatin
Pancreatic Hormones
• Insulin
Target – general
Effect – ↓ blood glucose & ↑diffusion of
glucose into cells [not kidney, liver &
brain],↑glycogenesis, ↑ uptake of amino
acids & peptide formation (↓ gluconeogenesis), ↑ glucose change to fat & ↑
cellular respiration. ↓ glycogenolysis.
Pancreatic Hormones
Regulation –blood levels of glucose, amino
acids & fatty a’s.
Pancreatic Hormones
• Glucagon
Target – liver
Effect: ↑blood glucose levels by
stimulating gluconeogenesis &
glycogenolysis.
Regulation – blood glucose levels, ANS &
Insulin
Structure of Glycogen
Glycogen biosynthesis
Most important storage form of sugar in animals
Glycogen - highly branched (1 per 10) polymer of glucose with
(1,4) backbone and (1,6) branch points. More branched than
starch so more free ends.
Average molecular weight -several million in liver, muscle.
1/3 in liver (more concentrated but less overall mass (5-8%)),
2/3 in muscle (1%).
Not found in brain - brain requires free glucose (120 g/ day)
supplied in diet or from breakdown of glycogen in the liver.
Glucose levels regulated by several key hormones - insulin,
glucagon.
Glycogen biosynthesis
3 enzymes catalyze the steps involved in glycogen synthesis:
UDP-glucose pyrophosphorylase
Glycogen synthase
Glycogen branching enzyme
Glycogen biosynthesis
MgATP
Glucose
HK
MgADP
[G-1,6-P2]
G-6-P
F-6-P
phosphoglucomutase
PGI
The hydrolysis of
pyrophosphate to
inorganic phosphate is
highly exergonic and is
catalyzed by inorganic
pyrophosphatase
G-1-P
UTP
G-1-P
PPase
PPi
UDP-Glucose Pyrophosphorylase
2Pi
Metabolism of Galactose
Glycogen synthase
In this step, the glucosyl unit of UDP-glucose (UDPG) is
transferred to the C4-OH group of one of glycogen’s nonreducing
ends to form an (1,4) glycosidic bond.
Involves an oxonium ion intermediate (half-chair intermediate)
Each molecule of G1P added to glycogen regenerated needs one
molecule of UTP hydrolyzed to UDP and Pi.
UTP is replenished by nucleoside diphosphate kinase
UDP + ATP
UTP + ADP
Figure 18-7
Page 633
O
Reaction catalyzed by glycogen synthase.
Glycogen synthase
All carbohydrate biosynthesis occurs via UDP-sugars
Can only extend an already (1,4) linked glucan change.
First step is mediated by glycogenin, Glycogenin is an enzyme
involved in converting glucose to glycogen. It acts as a primer,
by polymerizing the first few glucose molecules, after which
other enzymes take over.
The protein dissociates after glycogen reaches a minimum size.
Glycogen branching
Catalyzed by amylo (1,41,6)-transglycosylase (branching
enzyme)
Rules for branching:
Includes non-reducing end
Each transferred segment must be at least 11 residues.
Each new branch point at least 4 residues away from other branch
points.
Each new point takes a more exteriorly residue and moves it
interiorly
Page 634
The branching of glycogen.
Schematic two-dimensional cross-sectional view of glycogen: A
core protein of glycogenin is surrounded by branches of glucose
units. The entire globular granule may contain around 30,000
glucose units.
Glycogen Breakdown (glycogenolysis)
Requires 3 enzymes:
1. Glycogen phosphorylase (phosphorylase) catalyzes
glycogen phosphorylysis (bond cleavage by the
substitution of a phosphate group) and yields glucose-1phosphate (G1P)
2. Glycogen debranching enzyme removes glycogen’s
branches, allowing glycogen phosphorylase to complete
it’s reactions. 92% of glycogen’s glucose residues are
converted to G1P and 8% to glucose.
3. Phosphoglucomutase converts G1P to G6P-can either
go through glycolysis (muscle cells) or converted to
glucose (liver).
Process Diagram: Phosphoglucomutase
Mechanism
Opposing Glycogen Pathways:
Synthesis & Degradation
Glycogen Storage Diseases
Glycogen storage diseases
Glycogen storage disease type I (also known as GSDI or von
Gierke disease) is an inherited disorder caused by the buildup of
glycogen in the body's cells. The accumulation of glycogen in
certain organs and tissues, especially the liver, kidneys, and
small intestines, impairs their ability to function normally.
Glycogen storage diseases
Signs and symptoms of this condition typically appear around
the age of 3 or 4 months, when babies start to sleep through the
night and do not eat as frequently as newborns. Affected infants
may have low blood sugar (hypoglycemia), which can lead to
seizures. They can also have a buildup of lactic acid in the body
(lactic acidosis), high blood levels of a waste product called
uric acid (hyperuricemia), and excess amounts of fats in the
blood (hyperlipidemia). As they get older, children with GSDI
have thin arms and legs and short stature. An enlarged liver
may give the appearance of a protruding abdomen. The kidneys
may also be enlarged. Affected individuals may also have
diarrhea and deposits of cholesterol in the skin (xanthomas).
Glycogen Synthase Reaction
Glycogen Branching Enzyme
Hormonal Control of Glycogen
Metabolism
Regulation of Phosphoprotein
Phosphatase-1 in Muscle
Noncarbohydrate Glucose Precursors
Must Be Converted to Oxaloacetate
Glycolysis & Gluconeogenesis Pathways
Pyruvate Conversion to PEP
Absorptive and Postabsorptive
States
• Metabolic controls balance blood
concentrations of nutrients between two
states:
– Absorptive
• The time during & shortly after nutrient
intake
Absorptive and Postabsorptive
States
– Postabsorptive
• The time when the GI tract is empty.
• Energy sources are supplied by the breakdown
of body reserves.
Absorptive State
• Ingested nutrients enter blood and lymphatic
system --> hepatic portal system to liver
• Lasts about 4 hours after completing a meal
Events:
Absorptive State
• Glucose
– Glucose uptake by liver  converted to
triglycerides and glycogen (10%)
– Adipose tissues store fat take up blood glucose
 to triglycerides (40%)
– Muscles take up glucose and store as glycogen
(50%)
Absorptive State
Events:
• Amino Acids  liver  Kreb's cycle or
gluconeogenesis or protein synthesis
• Lipids most packaged  VLDL lipoproteins and
are carried to adipose.
• Hormones -mostly, insulin [hypoglycemic
hormone]
Absorptive State
Figure 24.18a
Principal Pathways of the Absorptive State
Figure 24.18b
Postabsorptive State
• Need to maintain normal blood glucose level
[90-100mg/100mL]
• Very important for nervous system - can only
use glucose for energy.
Postabsorptive State
EVENTS:
• Liver glycogen is converted to glucose - lasts
about 4 hrs.
• Muscle glycogen is converted to lactic acid 
glucose in liver
• Adipose breaks triglycerides to glycerol 
glucose
Postabsorptive State
• Muscle protein  aa  converted by liver into
glucose [gluconeogenesis]
• Hormone – glucagon; Neural Control – ANS via
epinephrine
Postabsorptive State
Figure 24.20a
Principle Pathways in the Postabsorptive State
Figure 24.20b
General Adaptation Syndrome [GAS]
• Response to prolonged, extreme or unusual
stress
• Stressor – and disturbance – temperature,
toxins, poisons, heavy bleeding, emotional
upheaval
General Adaptation Syndrome [GAS]
• GAS – 3 stages
1 – Alarm Reaction = Fight or flight
Hypothalamus stimulates ANS &
adrenal medulla epinephrine/
norepinephrine;
Short lived
Consumes glycogen stores
General Adaptation Syndrome [GAS]
2 – Resistance Stage [long-term]
Provide alternative fuels when
glycogen has been depleted.
Dominated by cortisol.