lecture 19 - metabolism and major metabolic pathways

what is digestion? (incl. the 2 types of digestion)

Digestion is the process of
breaking food down into
molecules small enough to
absorb
• Mechanical digestion,
chewing or grinding,
increases the surface area
of food
• Chemical digestion splits
food into small molecules
that can pass through
membranes; these are used
to build larger molecules

what occurs in chemical digestion

In chemical digestion, the
process of enzymatic
hydrolysis splits bonds in
molecules with the
addition of water
Digestion

description of chemical digestion in the human digestive system

describe over nourishment and obesity

Over nourishment causes obesity, which
results from excessive intake of food energy
with the excess stored as fat
• Obesity contributes to type 2 diabetes,
cancer of the colon and breasts, heart
attacks, and strokes
• Researchers have discovered several of the
mechanisms that help regulate body weight

3 hormones that regulate appetite and consumption

Hormones regulate long-term and short-
term appetite by affecting a “satiety
center” in the brain
i. Ghrelin, a hormone secreted by the
stomach wall, triggers feelings of hunger
before meals
ii. Insulin from the pancreas and PYY, a
hormone secreted by the small intestine
after meals, both suppress appetite
iii. Leptin, produced by adipose (fat)
tissue, also suppresses appetite and plays
a role in regulating body fat levels

absorption of nutrients in the small intestine

The small intestine has a huge surface area due to villi and microvilli that are exposed to
the intestinal lumen
• The enormous microvillar surface creates a brush border that greatly increases the rate
of nutrient absorption
• Transport across the epithelial cells can be passive or active, depending on the nutrient

describe the energy storage by the body in humans

The body stores energy-rich molecules that are not immediately needed
• In humans, excess energy is first stored in the liver and muscle cells in a polymer called
glycogen, which is a branched chain form of glucose
• When glycogen stores become full, excess energy is stored in fat in adipose cells in the
form of triglycerides. Triglycerides are highly reduced molecules (making multiple
oxidations possible) and anhydrous (they exclude water) making them compact
• When fewer calories are taken in than expended, the human body expends liver
glycogen first, then muscle glycogen and fat and subsequently proteins
Energy storage by the body

metabolism in the non-fasting state: carbohydrates

Carbohydrates are broken down into
glucose by various enzymes. Some glucose
is used immediately, but the majority enters
the blood stream triggering insulin release
and the uptake of glucose into cells. Excess
glucose is stored as glycogen in liver and
muscle.

metabolism in the non-fasting state: fats

• Fats are digested in the small intestine and
packaged into lipoproteins. Excess fat is
stored as droplets in fat cells. When fats are
used as an energy source, they are broken
down in cellular mitochondria through b-
oxidation.

metabolism in the non-fasting state: proteins

• Proteins are broken down into individual
amino acids and used in body cells to form
new proteins or to join the amino acid pool.
Amino acids that are in excess of the body's
needs are converted by liver enzymes into
keto acids and urea. Keto acids may be used
as sources of energy, converted into
glucose, or stored as fat. Urea is excreted
from the body in sweat and urine.

metabolism in the fasting state: carbohydrates

Carbohydrate, fats and protein are
metabolized in separate processes into a
common product called acetyl-CoA.
Acetyl-CoA is a major metabolic
pathways and is an important part of
the process which creates the energy
molecule called ATP (adenosine
triphosphate) in the mitochondria.

metabolism in the non-fasting state: what happens to blood glucose concentration after approximately 2-4 hours after a meal?

Approximately 2-4 hours after a meal,
blood glucose concentration drops to
normal baseline levels and a fasting
state begins. This drop in blood sugar
causes insulin levels to also decline.
Another hormone, glucagon, is released
and it triggers the release of glycogen
and fatty acids to fuel the body until the
next meal arrives.

metabolism in the “starvation” state - what happens after about 3 days of fasting?

After about 3 days of fasting, the stored
glycogen in the liver and muscles is
exhausted, insulin levels drop and the body
ramps up its access to stored fat. As fatty
acids flow into the blood stream, the liver
takes the excess fats and more ketone
bodies through ketosis.

metabolism in the “starvation” state - muscles and ketons

The muscles continue to burn fatty acids,
but decrease their use of ketones. The
ketone bodies then build up in the blood
stream to a level at which the brain begins
to oxidize them for fuel. As the brain uses
the ketones, it needs less glucose, so the
liver decreases the rate of gluconeogenesis.

metabolism in the “starvation” state - how do the previously discussed processes help to preserve the muscle tissue?

This helps preserve muscle tissue as the
body doesn't need to break down the
amino acids to convert them to glucose.
Due to the ability to metabolise ketones,
the human body can survive for long
periods without eating.

explain how glucose homeostasis is maintained by glycogen stores

The hormones glucagon and
insulin are both produced in
the islets of the pancreas.
Alpha cells make glucagon,
and beta cells make insulin
• The synthesis and breakdown
of glycogen is central to
maintaining metabolic balance
• insulin and glucagon regulate
the breakdown of glycogen
into glucose
• The liver is the site for glucose
homeostasis. A carbohydrate-
rich meal raises insulin levels,
which triggers the synthesis of
glycogen. Low blood sugar
causes glucagon to stimulate
the breakdown of glycogen
and release glucose

glycogen is a major form of energy storage - what is it?

glycogen is a major form of energy storage - how is a globular granule formed?

glycogen is a major form of energy storage - explain the glycogen polymer and the 2 types of alpha linkages it contains

why are glycogen energy reserves quickly mobilised?

where is glycogen stored?

explain the process of glycogen synthesis and breakdown (step-by-step) - liver

explain the process of glycogen synthesis and breakdown (step-by-step) - muscle

explain the process of glycogen synthesis and breakdown regarding the muscle and the liver

what is gluconeogenesis?

gluconeogenesis in mammals

describe the organs in relation to glycogenolysis and gluconeogenesis

glycolysis vs gluconeogeneis

describe how pyruvate is converted to phosphoenolpyruvate in gluconeogenesis

1. Gluconeogenesis begins in the mitochondria
   with the formation of oxaloacetate by the
   carboxylation of pyruvate. This reaction also
   requires one molecule of ATP and is
   catalyzed by pyruvate carboxylase. This
   enzyme is stimulated by high levels of
   acetyl-CoA (produced in β-oxidation in the
   liver) and inhibited by high levels of ADP
   and glucose.

2. To export oxaloacetate to the cytosol from
   the mitochondria, it has to be reduced to
   malate using NADH (not shown). In the
   cytosol, malate is again oxidized back to
   oxaloacetate using NAD+, where the
   remaining steps of gluconeogenesis take
   place.

3. Oxaloacetate is decarboxylated and then
   phosphorylated to form
   phosphoenolpyruvate using the enzyme
   PEPCK. A molecule of GTP is hydrolyzed to
   GDP during this reaction

describe the conversion of F1,6BP to F6P in gluconeogenesis

The next several steps in the reaction
are at equilibrium and are the same as
in glycolysis, except reversed.
• Fructose 1,6-bisphosphatase converts
fructose 1,6-bisphosphate (F1,6BP) to
fructose 6-phosphate (F6P), using one
water molecule and releasing one
phosphate
• Note that in glycolysis,
phosphofructokinase 1 converts F6P
and ATP to F1,6BP and ADP.
• In both glycolysis and gluconeogensis,
this reaction is the rate-limiting step
and is highly regulated by allostery.
F2,6BP, AMP and Citrate all act to
control this step

describe how glucose-6-phosphate is converted to glucose in gluconeogenesis

Glucose-6-phosphate is formed from fructose
6-phosphate by phosphoglucoisomerase (the
reverse of step 2 in glycolysis).
• Glucose-6-phosphate can be used in other
metabolic pathways or dephosphorylated to
free glucose by glucose-6-phosphatase.
• Whereas free glucose can easily diffuse in and
out of the cell, the phosphorylated form
(glucose-6-phosphate) is locked in the cell, a
mechanism by which intracellular glucose
levels are controlled by cells.
• The final reaction of gluconeogenesis, the
formation of glucose, occurs in the lumen of
the endoplasmic reticulum, where glucose-6-
phosphate is hydrolyzed by glucose-6-
phosphatase to produce glucose and release
an inorganic phosphate i.e. again it is not a
simple reversal of glycolysis.
• Glucose is shuttled into the cytoplasm by
glucose transporters located in the
endoplasmic reticulum's membrane

describe how fats are broken down and absorbed in the gut

In the lumen of the gut
triglycerides aggregate into fat
globules as a consequence of
the aqueous environment i.e.
they are hydrophobic
• The liver produces bile salts
(cholesterol like molecules that
are amphipathic meaning they
are both hydrophilic and
hydrophobic), that are stored in
the gall bladder
• The bile salts break down the
fat globules so that the
triglycerides can be accessed
• The pancreases secretes lipases
to breakdown fats into
monoacylglycerols and fatty
acids that can now be absorbed
by epithelial cells of the gut.

describe the uptake of fats by epithelial cells

Epithelial cells absorb fatty acids and
monoglycerides and then recombine
them back into triglycerides
• These fats are coated with
phospholipids, cholesterol, and
proteins to form water-soluble
chylomicrons
• Chylomicrons are transported into a
lacteal, a lymphatic vessel in each
villus
• Lymphatic vessels deliver
chylomicron-containing lymph to
large veins that return blood to the
heart