Download Glycogen Metabolism, Electron Transport/Oxidative Phosphorylation

Glycogen Metabolism, Electron
Transport/Oxidative
Phosphorylation
Pawlose Ketema
Introduction to Glycogen
• Glycogen is the storage form of glucose.
• It is a long polymer of glucose molecules
that branches about every ten glucose
residues.
• Glycogen consists of two types of bond
linkage; α-1,4 glycosidic linkage as well as
α-1,6 glycosidic linkage (branching points).
• There are two types of cells in the body
that are responsible for storing glycogen.
• Each cell have a different role in regulating
the amount of glucose that is there at a
given time.
Glycogen: Polymer of Glucose
• In a wide range of organisms, excess glucose
is converted to polymeric forms for storage
as glycogen in vertebrates and as starch in
plants.
• The only difference between the two is
what bonds link the glucose monomers.
• Glycogen is found primarily in the liver and
skeletal muscle.
• Exists in a branched spiral, very compact
Glycogen in the liver
• Cells such as hepatocytes can use
glycogen to regulate the blood glucose
levels of the body. This is especially
important because our brain almost
exclusively depend on glucose for energy.
• So if for instance our blood glucose level
is low, the liver will breakdown glycogen
releasing glucose thus bringing the blood
glucose level to its normal concentration.
This is especially true during state of
fasting.
Glycogen granules in a hepatocyte.
Glycogen in skeletal muscles
• Our body depends on glycogen
breakdown during periods of
vigorous activity. The glucose
obtained from glycogen can be
used to produce energy under
anaerobic activity( no O2).
• It is important to recognize that
glycogen stored in skeletal
muscle provides rapid energy
needed for sudden and
strenuous activity.
Glycogen Breakdown
• Glycogen breakdown is catalyzed by the
enzyme glycogen phosphorylase.
• In skeletal muscle and liver, the glucose units
of the outer branches of glycogen enter the
glycolytic pathway through the action of
three enzymes:
• Glycogen phosphorylase- release G-1-P
• Glycogen debranching enzymerestructuring glycogen
• Phosphoglucomutase – conversion of G-1-P
to G-6-P
Glycogen
(Glucose)n-1
(Glucose)n
Glucose-!-Phosphate
Glucose-6-Phsophate
Fate of Glucose-6-Phophate
1. In skeletal muscle it can enter glycolysis and serve as an energy
source to support muscle contraction.
2. In liver it can release glucose into the blood when the blood glucose
level drops, as it does between meals.
3. G-6-P can also enter pentose phosphate pathway to produce
NADPH.
Metabolism: Glucose and Insulin
• What we know:
• Glucose is a quick, easy form of
energy
• Our brain only uses glucose as a
source of energy , so it’s important
to have!
• Glucose is broken down via
glycolysis into ATP, NADH and
Pyruvate, which then go on to
make more energy…
• However, glucose is transported in
the blood. How does it get into the
cell to undergo glycolysis?
Insulin: Energy Gatekeeper
•
•
•
•
Insulin is like a key: it opens up cells so glucose
can enter from the blood
• sugar content in the blood is called blood
sugar
It is a peptide hormone, produced in the beta
cells of the pancreas
According to various feedback mechanisms,
insulin is released when sugar levels are high in
the blood, usually after a meal
• this time is called “post-prandial”, or posteating
Insulin is a protein homo-hexamer arranged
around a zinc iron -- quaternary Structure?
Meet Hanna
•
•
•
•
Hanna just ate a piece of cake
What is happening in her body?
• Sugars broken down by gastric enzymes and transported
into the blood
• Pancreas beta-cells sense sugar influx and release insulin
• Insulin spreads throughout the body and binds to cells,
allowing glucose inside
Result: huge influx of sugar is quickly taken out of the blood
and into cells where it is converted to energy or stored for
future use
Body’s response to “challenge” is so quick that hyperglycemia
never happens
Meet Dan the Diabetic
• Dan just ate a cookie
• What is happening in his body?
• Sugars broken down by gastric
enzymes and transported into
the blood, then…
What then???
• It depends on what kind
of diabetic Dan is
Meet Dan the Diabetic
• Type 1: Auto-Immune. Body is
destroying beta cells, insulin is no
longer produced
• No insulin, no sugar transport
• Type 2: Dan has eaten so much sugar
over a lifetime that his cells won’t
acknowledge insulin anymore
 cells have “down regulated”
(decreased) the amount of insulin
receptors on the cell surface
 Insulin doesn’t bind, no sugar
transport
The result is the same: sugar stays in the
blood, unable to gain access to cells and
be transformed into energy or stored for
later
(Sneak preview for your 11/11 lecture)
Hyperglycemia
• Too much glucose in blood
 Often suggests malfunction in insulin pathway
• Often seen in diabetes mellitus
• Chronic hyperglycemia carries several long term effects:
 Increased risk of cardiovascular disease and stroke
 Frequent hunger, thirst, and need for urination
 Tissue damage (e.g., retinopathy, nephropathy, neuropathy)
 Ketoacidosis
Consequences of Hyperglycemia
• Sugar in the blood is damaging for vital organs such as kidneys, eyes
and circulation problems in extremities
• If an area cannot get blood, it cannot get oxygen and cannot get
immuno-protective cells like WBC…
• Limb infections for diabetics are sometimes life-threatening
• Because there is no circulation, bacteria that are usually killed by
oxygen (anaerobic) can thrive -- these are the most dangerous
kind!
• Cells cannot access main energy source
• Urine is saturated with sugar
• Conclusion: Hyperglycemia is not good or fun or desired!
Hypoglycemia
• Too little glucose in blood
• A number of potential causes:
 Improper insulin dosage in diabetes patients
 Oversecretion of bodily insulin
 Long-term fasting
 Liver dysfunction due to alcohol
The Brain.
Most researchers agree: it is important.
• Body responds via glucagon and epinephrine
• This is a medical emergency
 CNS requires continuous supply of glucose
 Even brief denial of glucose to brain can cause long-term damage
Healthy Hanna and the Fasting State
• It’s been awhile since that piece of cake! How
does Hanna’s body get energy?
• When blood sugar is low, a peptide hormone
called glucagon is released from the alpha cells
of the pancreas
• promotes mobilization and breakdown of
stored glycogen
• quick and easy
• glucose molecules are released and body
can survive until next influx of fuel
Feeding, Fasting, and Blood Sugar
• Feeding: Consuming a meal
 Breakdown of carbs = sharp increase in blood glucose
 Body responds with insulin
 Glucagon inhibited (unless meal is predominantly protein)
• Fasting: Skipping a meal, or otherwise refraining from eating
 Glucose steadily falling
 Insulin falls, glucagon/epinephrine rise
 Body calls upon storage to meet energy demands
Feed/Fast Cycle Summarized
The key is that insulin and glucagon
work in tandem to maintain blood
glucose levels in response to food
intake, or lack thereof.
Alternate Pathways: Resources
• What happens if there’s no sugar in your blood?
• Glucagon is released and glycogen broken down
• What happens when there’s no more glycogen to use?
• Next, the body begins to mobilize (from adipose) and break down free
fatty acids for energy
• This can happen during exercise or short-term fasting
• What happens when you run out of fat?
• Next, your body begins to break down proteins for energy
• This occurs only after several days of no food.
• The accessible sources of proteins in your body are muscles and
lean body tissue. You start to “eat” your muscles
• 1) sugar (easy to move and store), 2) fats (HUGELY energetic, 2.25x sugar)
and hopefully never 3) proteins (last resource, energetically equal to sugar)
Oxidative Phosphorylation
Oxidative Phosphorylation
• AKA, The Electron
Transport Chain
• Does everybody
remember The Mighty
Mitochondria, The
Powerhouse of the Cell?
Mitochondria
• Mitochondria produce energy for the cell
• this energy is ATP
• Obviously, the mitochondria aren’t the ONLY source of ATP
• Glycolysis, Citric Acid Cycle, etc
• Most efficient mechanism of ATP production is Oxidative
Phosphorylation, which is conducted through an electron transport
chain
Oxidative Phosphorylation
• The only aerobic (oxygen-requiring) energy process in the body
of the three main parts of cellular respiration
• Oxidative = oxidation, oxygen
• Phosphorylation = attaching a P directly to ADP, making ATP
• Making ATP via oxidation
• Substrates: NADH and FADH2 produced from glycolysis and the
TCA cycle
• NADH = 3 ATP, FADH2 = 2 ATP
Oxidative Phosphorylation
•
•
•
Glycolysis and the citric acid cycle
yield NADH and FADH2.
Both these electron carriers are
energy-rich molecules because their
electrons have a high transfer [redox]
potentials.
Oxidative phosphorylation is the
process of converting this high redox
potential into energy-rich ATP
molecules.
26
•
•
•
Mitochondrial structure
plays a critical role in
forming and utilizing the
proton gradient to
synthesize ATP.
Protons are “pumped”
from the matrix across the
inner membrane into the
intermembrane space.
ATP is synthesized in the
matrix, as protons flow
back through the
membrane.
27
Chemiosmotic Potential
• The result of introducing NADH into the electron transfer chain
• NADH ➔ NAD+ and H+ and 2e• NAD+ goes back into the cytoplasm to work as a redox cofactor
• The electrons are handed off through a series of carriers, releasing
small energies
• The H+ are transported through the membrane to collect on the
opposite side
• This creates an overwhelming number of H+ on ONE side of the
membrane, leading to 1) a molecule imbalance (H versus no H)
and 2) a charge imbalance (+ vs - )
• The body, due to homeostasis/osmosis/equilibrium, REALLY wants
to correct that imbalance (there is stress)
• This creates a gradient that the body harnesses to create ATP
Chemiosmotic Potential
•
•
H+ are gathered on one side of the mitochondrial membrane,
donated from metabolic cofactors NADH and FADH2
They are slowly “leaked” across the membrane through a molecular
machine that fuses P to ADP, creating ATP
• Think about it like stuffing water into a balloon. The balloon stretches and
pressure builds: if you let the water out slowly, one spurt at a time, it will be
high-pressure and could be used to move an object
ATP Synthase
Video: https://www.youtube.com/watch?v=3y1dO4nNaKY
OxPhos Products and Waste
• Substrates: NADH and FADH2
• Citric Acid Cycle occurs in the mitochondrial matrix, so all the
necessary ingredients are within reach
• O2 (oxygen) is split and capped with spare hydrogens, creating 2x
H2O as “waste”
• The process is aerobic, or requires oxygen
• Desired product: ATP from ADP + P
OxPhos Inhibitors
•
•
OxPhos is the most prolific generator of ATP in the body
• What would happen if it were disrupted or “tricked”?
Electron Chain Inhibitors or “de-couplers” are used as poisons
• Cyanide: takes the place of oxygen on cytochrome C oxidase,
preventing the reduction of O2 to H2O
• leads to “suffocation” where the victim is breathing but cannot
use the oxygen to create ATP, and so dies
• Carbon monoxide and hydrogen sulfide also work this way
OxPhos Inhibitors
• CCCP and 2,4-dinitrophenol are ionophores, or molecules
that carry H+ across membranes, from high concentration to
low concentration
• this disrupts the ion gradient, weakening (but not eliminating)
the chemiosmotic force that moves ATP synthase
• Called an “uncoupler”
• Not fatal but dangerous, lessens the “bang for buck” of
fuel
• Used as a weight-loss supplement in the 1930’s
• Why and how did this make sense?
• Food ➡ NADH ➡ ATP
Let’s Do The Math...
• 1 glucose molecule
• Glycolysis: 2 NADH, 2 ATP, 2 Pyruvate
• 2 ATP, 2 NADH = 6 ATP
• 8 ATP total
• 2 pyruvate go through TCA cycle
• Pyruvate ➡ Acetyl-Coa creates 2
NADH
• 2 NADH = 6 ATP
• 2 GTP, 6 NADH, 2 FADH
• 2 GTP, 6 NADH = 18 ATP, 2 FADH = 4
• 30 ATP total
• 8 ATP (Glycolysis) + 30 ATP (TCA) = 38
ATP
Glucose: 4 kCal/g
Other Sources of Energy
•
•
•
Glucose = 4 kCal/g
Proteins = 4 kCal/g
• Same caloric count as glucose, but much more “nutritious”
• Contains N-compounds and necessary building blocks for life,
essential amino acids
Lipids (Fats) = 9 kCal/g
• All free fatty acids broken down to Acetyl-CoA, which goes directly to
the TCA cycle
• LOTS OF ENERGY