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Amino acid metabolism
proteins
• Only foodstuff that can form structures (tissues and enzymes)
• Made up of amino acids• Protein synthesis,
enzyme formation• Can serve as fuel during
long-term work• 0.8 g/kg recommended
for adults; probably too low for athletes
Protein structure: Amino acids
• Essential vs non-essential– Essential:
NOT made by body
– Non-essential: made by the body
Protein structure
• Carboxyl and amino termini come together to from protein structures (peptides)
Amino acid
• Digested in stomach and small intestine– Hydrocholoric acid
(stomach)– Trypsin,
chymotrypsin, carboxypeptidase (from pancreas)
– Polypeptidases and dipeptidases in intestinal cells finish digestion
Proteins in the diet
• The amino acid pool– Free amino acids in the liver, skeletal muscle, plasma, interstitial
fluid and intracellular water– All interconnected in that metabolism in one affects the others– Continuous excretion of nitrogenous end-products– Necessitates constant input of new amino acids– So, CONSTANT Protein turnover
Nitrogen balance
• Nitrogen is a component of AAs– Thus, used as a
marker of protein metabolism
• Protein intake necessary to balance nitrogen turnover (input vs excretion)– 0.8-1.0 g/kg is
sufficient for most– 1.2-1.6 g/kg is the
highest recommendation for athletes
Removal of nitrogen
• Before amino acids can be used as fuel, nitrogen group must be removed
• Two ways– Deamination– Transamination
• Glutamate is a key player in both
Removal of Nitrogen
• Deamination– Occurs in liver
1) Requires NAD+ as oxidizing agent
2) Produces ammonium ion
3) α-ketoglutarate can be used in Kreb’s cycle
• Called anaplerotic (to fill) addition to Kreb’s cycle
12
3
Removal of Nitrogen• Transamination
– Much more common
– Transfers amine group from amino acid to keto acid
• SGPT and SGOT transaminases in liver
AA
AA
Keto acid
Keto acid
Excretion of nitrogenous wastes
• Ammonia (small amt)• Most is excreted as urea• Urea cycle
1) Formation of carbamoyl phosphate from ammonia and Co2
2) Addition of aspartate3) Production of fumarate
(Kreb’s cycle intermediate)4) Produces Urea
12
4
3
Gluconeogenic amino acids
• Some amino acids used for gluconeogenesis1)Pyruvate to OOA2)OOA to PEP3)PEP begins “reverse
glycolysis” or gluconeogenesis
• So, amino acids that give rise to pyruvate and oxaloacetate– Can form
phosphoenolpyruvate– Can be converted to
glucose
1
2
Anaplerotic and cataplerotic reactions• Anaplerotic (adding to)• Cataplerotic (emptying)
– These Rx add to or deplete the Kreb’s cycle
• Glutamate-glutamine• Key intraorgan
nitrogen transport vehicle, fuel source for GI tract and immune system and gluconeogenic precursor
Branched chain amino acids
• Leucine, Isoleucine and valine (LIV)
• Catabolized mostly in skeletal muscle
• Leucine:– Forms acetyl-CoA,
acetoacetate and glutamate
• Leucine is thus called ketogenic
Transamination
AA metabolism• AA can be used in the following ways
– Structural (proteins)– Anaplerotic additions to Kreb’s cycle
• This keeps the Kreb’s cycle working
– Oxidized directly• Branched chain AA
– Other contributions to energetics• Ketogenic
– Produce ketone bodies when broken down
• Glucogenic– Contributes to gluconeogenesis
Glucose-alanine cycle• Used during fasting• Alanine can come
from glycolysis or AA metabolism– Glycolysis
• Kreb’s cycle backs up during starvation
– Pyruvate transaminated to alanine
– Alanine converted to glucose in liver
Glucose-alanine II
• Other amino acids can also form alanine (glucogenic AA, anything that gives rise to pyruvate or OOA)
• So when Pyruvate builds up, converted to Alanine (1)
• Alanine shuttled to liver– Converted to
glucose
1
Effects of endurance training on AA metab
• Greater rates of AA metabolism in trained subjects – Greater oxidation
in human subjects during exercise
AA metabolism• Note that leucine
oxidation increases during exercise– This increases is linear
with respect to exercise intensity
– Particularly true in fasted state
• Note that alanine appearance increases during exercise (1) and this can come from AA leucine (2)
• Also, glucose infusion reduces AA oxidation (3)
AA metabolism1
2
3
AA metabolism• However, exercise training does not appear to increase
AA metabolism in human subjects
– If anything, it is reduced
Ammonia scavenging during high intensity exercise
• During high intensity exercise, AMP is formed– Adenylate kinase Rx
• ADP + ADP ATP + AMP
• AMP then inhibits AK Rx if it builds up
• AMP deaminated to IMP• Muscle releases ammonia
(NH4+) during contraction
– Contains nitrogen
• Purine nucleotide cycle
Ammonia scavenging
• Formation of glutamine (1) helps to transport ammonia in blood– Ammonia is toxic– Transamination
• Glutamine goes to kidney (2)
• Urea (3) and glucose formed (4)
1
2
3
4
Neuro-endocrine control of blood glucose
Hormones
• Chemical messengers– Produced and stored in a gland– Secreted into the blood– General and specific effects
• Two basic types– Steroid
• Produced from cholesterol by adrenal cortex and gonads
– Polypeptides• Amino acids
Hormones
• Powerful effects• Precisely regulated
– Feedback control (negative feedback)
• Mechanisms of action– Affect cell permeability
(insulin)– Activate an enzyme
(epinephrine)– Protein synthesis (GH)
Blood glucose homeostasis• When fed
– Liver glycogenolysis
• When fasted– Gluconeogenesis
• SNS helps in this– Epi stimulates liver
glycogenolysis and gluconeogenesis
• Hormones– Released into blood– Epinephrine and nor-
epinephrine
• Maintenance of blood glucose levels is paramount– Fuel source– Anaplerotic additions to
Kreb’s– Allows fat metabolism– Needed by brain and
CNS• Hormones that help
maintain blood glucose– glucoregulatory
Hepatic glucose production during exercise
Glucose homeostasis• How difficult is this?• Normal adult
– Blood volume = 5L– Blood glucose = 100 mg/dl (1 g/L)– 5g or 20 kcals (4kcal/g) worth of energy– Only enough to support 1 min of maximal activity!
• This means– We must get plenty of CHO prior to and even during
activity– Liver supplements this
Glucose homeostasis• Glucose
production increased in 2 ways– Increased
absorption from gut and liver output
• Liver glycogenlosis
• Liver gluconeogenesis
Glucose homeostasis
• Note how addition of arm exercise increases catecholamine levels– glucoregulatory
hormone (raises blood glucose)
• Insulin falls– Decreases blood
glucose• Thus hormonal
changes help maintain blood glucose levels
Why increased?
Catecholamines and blood glucose• Epinephrine and nor-
epinephrine• Epi binds to β-receptor
– Activates adenylate cyclase– Muscle contraction increases
intracellular Ca2+ and Pi• Stimulates glycogenolysis
– Muscle and liver– Supports liver glucose
production – Also increases lipolytic rate
Cyclic AMP• Made from ATP (1)• Intracellular messenger• Activates many processes
in metabolism• Example
– Glycogenolysis• Epinephrine binds to
receptor (2)• Adenyl-cyclase creates
cAMP (3)• cAMP activates
phosphorylase
1
2
EPI
3
Insulin and glucagon• Insulin
– β cells of the islets of langerhans of pancreas
• Glucagon– α cells
• Along with epinephrine and nor-epinephrine, main hormones of glucose homeostasis
Insulin response to exercise
• Falls in response to exercise– Epinephrine
suppresses insulin secretion
• Thus– Glucose
production is increased
Why insulin?• Insulin
– Helps facilitate glucose transport across sarcolemma during rest
– Uses glucose transporters (GLUT)
– GLUT-4 • Insulin mobilizes
transporters from intracellular pool
• Transporters move to sarcolemma
Glucose transport: exercise• Muscular contraction
– “insulin-like” effect– GLUT-4 can
translocate due to insulin or Ca2+
• So, muscular contractions– Cause release of
Ca2+
– This causes translocation of Glut-4 receptors
– Important as epinephrine (released during exercise) inhibits insulin
insulin
Neuro-endocrine control of
hepatic glucose production • Gluconeogenesis
– Liver and kidneys• 3 different enzymes
than glycolysis– Pyruvate carboxylase– PEP carboxylase– Fructose 1,6
biphosphatase• Glucose 6-
phosphatase– Liver only
• So, muscle resynthesizes glycogen, liver and kidneys, glucose
Pyruvate kinase
Gluconeogenesis
• Those 4 enzymes are either nonexistent or in small supply in skeletal muscle
• Found in large amts in liver and kidneys• Pyruvate kinase (last step of glycolysis):
– virtually irreversible in skeletal muscle– In liver, can be inhibited by cAMP and
phosphorylation (Ca2+-dependent protein kinase)
– Reduces glycogenloysis and promotes gluconeogenesis
Gluconeogenesis• Pyruvate coverted to
oxaloacetate (A)– High acetyl-CoA, low ADP
• Oxaloacetate converted to Phosphoenolpyruvate (B)– Low ADP
• Phosphoenolpyruvate converted to Fructose 1, 6 bisphosphate (C)
• F 1,6 bisphosphate converted to F6P (D)– High citrate, low AMP
• Converted to glucose (E)
A
B
C
D
E
Hepatic glucose productionThe following hormones increase gluconeogenesis• Inhibit pyruvate kinase
– Glucagon– Epinephrine– Nor-epinephrine
• Insulin– Inhibits gluconeogenesis
Can muscle make glucose?
• Glycolytic muscle can produce glycogen from lactate– Glyconeogenesis
• Likely occurs early in recovery
• Muscle lacks G6 phosphatase– So can’t release glucose from
cell• However, it is possible that
debranching enzyme can release glucose from glycogen– May help explain very rapid inc
in blood glucose (fig 9-13)