Transcript Integration of Mammalian Metabolism

BC 368
Biochemistry of the
Cell II
Integration of
Mammalian
Metabolism
May 7, 2015
Highlights of Metabolism
1. ATP = universal energy currency
•expended to ensure unidirectionality of each
metabolic pathway and complete conversion to
products
coupling ATP hydrolysis to a reaction
increases K by a factor of ~108.
Highlights of Metabolism
1. ATP = universal energy currency
•expended to ensure unidirectionality of each
metabolic pathway and complete conversion to
products
•an important allosteric regulator
•generated by the oxidation of fuel molecules:
NADH and FADH2 shuttle electrons to the
ETC where the bulk of ATP is formed via
oxidative phosphorylation.
2. NADPH is the major electron
donor in reductive biosynthesis
•formed primarily via the pentose phosphate
pathway
3. Central metabolic pathways have
both anabolic and catabolic roles.
•TCA is an excellent example of an amphibolic
pathway.
Carbs, Amino Acids
Fats, Amino Acids
Amino Acids
•TCA is an excellent example of an amphibolic
pathway.
4. Distinct pathways for biosynthesis
and degradation
•ensures favorable thermodynamics for both
directions
•separate, but interrelated, control mechanisms
(often the 1st step)
•compartmentalization (e.g., cytosol vs.
mitochondrial matrix)
5. Many coenzymes
coenzyme
role
Niacin/B3 (NAD+)
redox
Riboflavin/B2 (FAD)
redox
Pantothenic acid/B5 (CoA) acyl transfer
Pyridoxal phosphate/B6 transamination
Vitamin B12
rearrangements
Thiamine/B1 (TPP)
decarboxylation
Biotin/B7
CO2 carrier
Lipoic acid
acyl carrier
Folic Acid/B9
carbon carrier
example
malate dehydrogenase
succinate dehydrogenase
pyruvate dehydrogenase
-KG --> Glu
homocysteine--> Met
pyruvate dehydrogenase
pyruvate carboxylase
pyruvate dehydrogenase
amino acid degradation
Which of the following coenzymes often
participates in carboxylation reactions?
A.
Vitamin B12
B.
TPP
C.
FAD
D.
Coenzyme A
E.
Biotin
6. Several molecules act as metabolic
junction points.
glucose-6-phosphate
glycogen
pyruvate
ribose-5-P
pyruvate
acetyl-CoA
lactate
alanine
OA
acetyl-CoA
CO2
fatty acids
ketone bodies
7. A defect in a single enzyme of
metabolism can be disastrous.
•Lack of an essential metabolite?
•Build-up of a toxic metabolite?
Small Molecule
Investigation
8. Tissues & organs are specialized.
7. Tissues & organs are specialized.
• Maintainers supply
fuel for the
consumers.
Brain
 Maintainers: liver
and adipose tissue
 Consumers: skeletal
muscles, heart,
brain
Fuel
•Interactions between tissues and organs are
mediated by hormone signals carried via
bloodstream.
Specialized Metabolism
Which of the following is false about the
metabolism of the liver?
A.
It processes most, but not all, dietary amino acids.
B.
The presence of glucose-6-phosphatase makes the
liver uniquely able to release glucose from
glycogen into the bloodstream.
C.
It synthesizes most of the urea produced in the
body.
D.
It normally fuels the body by releasing its fat stores
during fasting.
Metabolic Interrelationships
Liver- #1 metabolic player
•Responds quickly to dietary conditions because of
rapid turnover of its enzymes
•Processes most incoming nutrients
•Maintains constant concentrations of nutrients
in blood (e.g., via gluconeogenesis), smoothing
out fluctuations due to the Starve-Feed Cycle
•Processes toxins and wastes (e.g., through urea
cycle)
•Synthesizes and secretes plasma proteins
Liver- #1 metabolic player
•Primarily depends
on b-oxidation of
fatty acids for its
own energy needs.
Liver
•Amino acids go directly
to the liver through the
portal vein after
absorption.
•Uses them to make
proteins, for
gluconeogenesis, for
biosynthesis of nitrogencontaining molecules, or
for fuel.
Adipose Tissue- maintainer #2
•Stores triglycerides and releases FA’s
and glycerol as signaled by glucagon/
epinephrine
•Turnover is 50-60 g/day.
triglycerides
cAMP-activated
lipases
fatty acids + glycerol
transport in blood
muscle
heart
Albumin
liver
•Two distinct
types: white
adipose tissue and
brown adipose
tissue.
•Brown fat has
high levels of
thermogenin,
which are
metabolically
activated by cold
exposure.
Huffington Post
Skeletal Muscle (big consumer)
Case Study: Paul J. cramps up
Less than two weeks after
finishing the 2010 Boston
Marathon in 4:10, disaster
struck for Paul J. in the
Pittsburgh Marathon. He ran
the first half in 2:04 and the
second half in 2:40. Severe
leg cramps set in at around
mile 20, and he ended up on
the ground screaming in pain.
The day was cool, and he took
in lots of electrolytes.
Case Study: Paul J. cramps up
Less than two weeks after
finishing the 2010 Boston
Marathon in 4:10, disaster
struck for Paul J. in the
Pittsburgh Marathon. He ran
the first half in 2:04 and the
second half in 2:40. Severe
leg cramps set in at around
mile 20, and he ended up on
the ground screaming in pain.
The day was cool, and he took
in lots of electrolytes.
What probably went
wrong for Paul?
a) Lactic acid!
b) His fat stores ran
out.
c) His blood sugar
dropped.
d) Carnitine
deficiency!
e) Hyponatremia!
Energy Systems of Skeletal Muscle
(Phosphagen system)
Match the photo to the energy system!
a) 1= lactate; 2= phosphagen; 3= aerobic
b) 1= phosphagen; 2= aerobic; 3= lactate
c) 1= aerobic; 2= lactate; 3= phosphagen
d) 1= aerobic; 2= phosphagen; 3= lactate
1.
2.
3.
Anaerobic Conditions- bursts of
heavy activity
• ATP exhausted rapidly (1 or 2 sec); replenished by:
Phosphagen System
Anaerobic Conditions- bursts of
heavy activity
•phosphocreatine lasts ~10 seconds
•next 1 to 2 minutes
glycogen -> G-6P -> pyruvate -> lactate
Fate of Lactate
•Cooperation
between muscle and
liver (Cori cycle) to
regenerate glucose
from lactate.
•Heart also burns
lactate.
Lactate Threshold
• With low intensity work, lactate is cleared
from the bloodstream as fast as it is made.
• As work increases, there is a point when
lactate is produced too fast for the body to
clear it.
Exercise cannot be
sustained for more
than a minute or two
after lactate threshold
because of PFK-1
inhibition
work
Aerobic Conditions- rest,
runs, light activity
slow
1. glycogen -> G-6P -> pyruvate -> CO2 + H2O
•1- 2 hour supply, moderately fast
•Limited by entry of pyruvate into mitochondria
and/or O2 supply
2. fatty acids -> acetyl-CoA -> CO2 + H2O
•Many hours supply, slow
•Limited by diffusion of FA’s from blood, carnitine
Cross Country Collapse
Emily, the #2 ranked female high
school cross country runner in the
state, is competing in the Western
Maine championship. She goes into the
woods just before the mile mark but
doesn’t come out.
She had been struggling the entire
season, feeling weak and tired, and
had dropped out of three races prior to
this meet. What type of testing would
you do on Emily?
Cross Country Collapse
Emily, the #2 ranked female high
A.
school cross country runner in the
state, is competing in the Western
Maine championship. She goes into the
woods just before the mile mark but
B.
doesn’t come out.
She had been struggling the entire
C.
season, feeling weak and tired, and
had dropped out of three races prior to D.
this meet. What type of tests would you
E.
do on Emily?
Test for a
glycogen
storage disease
Test for
cardiomyopathy
Test for diabetes
Test for anemia
Test for
pregnancy
Aerobic training effects
Increased number of mitochondria
Increased hemoglobin and
hematocrit (percentage of red cells in
blood; normally 36-49%)
Increased heart efficiency
Result is increased O2 uptake and use
by tissues: VO2 max: normally ~35 mL
O2/kg/ min
VO2 max of Elite Aerobic
Athletes
Joan Benoit
79 mL/kg/min
Bjorn Daehlie
90 mL/kg/min
Lance Armstrong
84 mL/kg/min
VO2 max of Elite Animal Athletes
Pronghorn Antelope
300 mL/kg/min
10K- under 10 minutes!
Changes in metabolism over
time
During
endurance
exercise,
the
respiratory quotient (CO2 exhaled/O2
consumed) falls, indicating increased use
of fatty acids.
RQ =1.0 for carbohydrates
RQ= 0.70 for fats (more
highly reduced)
Changes in metabolism over
time
During
endurance
exercise,
the
respiratory quotient (CO2 exhaled/O2
consumed) falls, indicating increased use
of fatty acids.
Increased [acetyl CoA]
from b oxidation slows
bridging reaction
Effect is decreased
funneling of sugar into
TCA.
Changes in metabolism over
time
During
endurance
exercise,
the
respiratory quotient (CO2 exhaled/O2
consumed) falls, indicating increased use
of fatty acids.
Case Study: Paul W. is confused
Paul W. turned the corner for
the last 200 yards of the 1990
Boston Marathon. He was well
ahead of me, having passed
me in Wellesley. In the last few
minutes of the race, however,
he became confused. As he
passed by “The Pru,” he
started walking in circles. He
ended up finishing 15 minutes
behind me. What went wrong
for Paul W.?
Case Study: Paul W. is confused
Paul W. turned the corner for
the last 200 yards of the 1990
Boston Marathon. He was well
ahead of me, having passed
me in Wellesley. In the last few
minutes of the race, however,
he became confused. As he
passed by “The Pru,” he
started walking in circles. He
ended up finishing 15 minutes
behind me. What went wrong
for Paul W.?
What probably went
wrong for Paul?
a) Lactic acid!
b) His fat stores ran
out.
c) His blood sugar
dropped.
d) Carnitine
deficiency!
e) Hyponatremia!
Brain
•No significant energy reserves.
•Dependent on blood glucose at ~4.5 mM to
maintain ion gradients.
•Uses 20% of the total O2 consumed by a resting
human (only 2% of the body mass)
•After several days of low glucose, switches to
use of ketone bodies, which are degraded via
TCA. Conserves body’s proteins.
Heart
Cardiac muscle is
aerobic only with
circulating fats the
preferred fuel.
Lack of O2 leads to
tissue death (myocardial
infarction).
Hormones
Which of the following pathways is inhibited
by the action of insulin?
A.
Glycolysis
B.
Kreb’s cycle
C.
Gluconeogenesis
D.
Glycogen synthesis
E.
Fatty acid synthesis
1. Insulin (high blood sugar)
•Insulin deficiency or resistance can lead to
hyperglycemia, metabolic syndrome, and diabetes.
The insulin receptor is a receptor
tyrosine kinase (RTK).
Insulin binding triggers autophosphorylation at Tyr.
2. Epinephrine (fight or flight)
Epinephrine receptors act through G
proteins.
3. Glucagon (low
blood sugar)
Glucagon receptor also acts through
G proteins.