amino acid metablism 1. ex biochem c8-aa metabolism 2 overview of aa metabolism principal source of...
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Amino Acid Metablism
1
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Ex Biochem c8-AA metabolism 2
Overview of AA metabolism Principal source of AA from food protein
Broken down to free AA, absorbed into blood >50% dietary AA taken up by liver Essential AA: can not synthesized by body, arg, his,
Isoleu, leu, lys, met, phenylala, threonine, tryptophan, val
AA pool: AA in blood and extracellular fluids No ability to store AA, extra AA used as fuels Very small compared to total protein in body AA and protein turnover very quickly
Liver responsible for much of AA metabolism Kidney in smaller extent
Skeletal muscle the largest repository of free and protein-bound AA in body
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Ex Biochem c8-AA metabolism 3
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Ex Biochem c8-AA metabolism 4
Overview of AA metabolism
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Ex Biochem c8-AA metabolism 5
AA transporters AA have charged groups, they need protein
transporters to transfer between extracellular and intracellular compartments
2 broad categories of AA transporters Na-dependent: move into cell down Na concentration
gradient, can be moved against AA concentration gradient
Na-independent AA transporters may have broad specificity,
recognizing several AA Some have narrow specificity, recognizing only 1-2
closely related AA Competition for the same transporters
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Ex Biochem c8-AA metabolism 6
Degradation of AA Balance among AA can be achieved by conversion
reactions One AA changed into another by transfer of amino group
18 AA are glucogenic: provide all or part of their carbon atom for gluconeogenesis Ketogenic: leucine, lysine
AA undergo constant oxidative degradation: Normal synthesis and degradation, not immediately used
for protein synthesis Ingest more AA than body can use to make proteins Starvation Overtaining, imbalance in protein turnover
(testosterone/cortisol ratio)
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Ex Biochem c8-AA metabolism 7
Transamination reactions Transfer of amino groups in all AA except thr, lys
Aminotransferase enzyme, transaminase Most transfer to a-ketoglutarate, making glutamate
Freely reversible, net direction depend on relative concentration of 4 reactants
Alanine aminotransferase (glutamate pyruvate transaminase, GPT) Alanine + a-KG < pyruvate + glutamate
Aspartate aminotransferase (glutamate oxaloacetate transaminase, GOT) Asp + a-KG < oxaloacetate + glutamate
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Ex Biochem c8-AA metabolism 8
Transamination reactions
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Ex Biochem c8-AA metabolism 9
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Ex Biochem c8-AA metabolism 10
Deamination reactions Nitrogen from amino groups in liver in the form of
glutamate can be released as ammonia Glutamate + H2O + NAD+ a-KG + NADH + H+ +
NH4+ Glutamate dehydrogenase
Production of NH4 and its release from muscle proportional to exercise intensity Glutamate DHase reactions Deamination of AMP by AMP deaminase
NH4+ play a role in peripheral and central fatigue Increased acidity in muscle Cross blood brain barrier, increased NH4+ uptake by
brain
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Ex Biochem c8-AA metabolism 11
Glutamine Special AA even though not essential
Important fuel for gut and immune system (macrophages, lymphocytes)
Free glutamine concentration high in variety of cells and in blood ~60% AA pool Mostly synthesized from glutamate by glutamine
synthetase Deamination of glutamine
Glutaminase: glutamine + H2O glutamate + NH4+
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Ex Biochem c8-AA metabolism 12
Glutamine synthesis
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Ex Biochem c8-AA metabolism 13
Branched-chain amino acids, BCAA Most common essential AA in proteins Metabolized mainly in skeletal muscle
Increased BCAA oxidation during exercise, used as fuel or provide carbon backbone for CAC intermediates
BCAA aminotransferease, branched chain ketoacid dehydrogenase (BCKAD), acyl-CoA DHase
BCKAD inhibited by BCKAD kinase, response to exercise
Glucose-alanine cycle: transfer amino group from muscle to liver for urea synthesis
Leucine can enhance protein synthesis by stimulating initiation of translation mTOR
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Ex Biochem c8-AA metabolism 14
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Ex Biochem c8-AA metabolism 15Metabolism of BCAA
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Ex Biochem c8-AA metabolism 16
Glucose-alanine cycle
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Urea cycle NH4+ very toxic, especially to brain
Temporary safe forms: glutamate, glutamine Converted to urea, secreted in urine
Muscle release alanine, glutamine N from BCAA glutamate ala or gln
Nitrogen in liver Ala glu by alanine aminotransferease Gln glu by glutaminase NH4+ taken up from blood The above 3 provide NH4+ for urea synthesis The other NH3 in urea from aspartate
Regulation point: carbamoyl phosphate synthetase Metabolically expensive: 4 ATP for 1 urea
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Ex Biochem c8-AA metabolism 21
The Urea Cycle -Overview
Carbamoyl phosphate
CO2
2ATP
2ADP + 2H2O
+ NH4+
H3N-CHCH2COO-COO-
Aspartate
+
H2N-C-NH2
Ureacycle
Urea
C C
H
COO-H
-OOCFumarate
H2N-C-OPO32-
O
O
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Ex Biochem c8-AA metabolism 22
The Urea Cycle
H2N-C-OPO32-
O
(CH2)3
NH3+
CH-NH3+
COO-
Ornithine
Aspartate
(CH2)3
NH
CH-NH3+
COO-
C
NH2
O
Citrulline (CH2)3
NH
CH-NH3+
COO-
C
NH2
Argininosuccinate
N-CHCH2COO-
COO-
H3N-CHCH2COO-COO-
+
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Ex Biochem c8-AA metabolism 23
The Urea Cycle
(CH2)3
NH3+
CH-NH3+
COO-
Ornithine
(CH2)3
NH
CH-NH3+
COO-
C
NH2
NH2+
Arginine
H2N-C-NH2
O
Urea
C CH
COO-H
-OOCFumarate
(CH2)3
NH
CH-NH3+
COO-
C
NH2
Argininosuccinate
N-CHCH2COO-
COO-
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Ex Biochem c8-AA metabolism 24
Fate of AA carbon skeletons
18 AA can be source for gluconeogenesis Leucine and lysine only form acetoacetyl
CoA and acetyl CoA: ketogenic Many AA have carbon skeletons as CAC
intermediates or substances directly related to CAC
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Ex Biochem c8-AA metabolism 25
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Ex Biochem c8-AA metabolism 26
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Ex Biochem c8-AA metabolism 27AA metabolism duringmoderate-intensity exercise
Study of AA metabolism during exercise is complex Measurement of AA differences between arterial and venous blood Muscle biopsy Only see the equilibrium between AA synthesis and breakdown,
unless use stable isotope During ex in postabsorptive state, skeletal muscle is in net
protein catabolic state Most AA produced by net protein catabolism released into blood,
except glutamate and alanine Net uptake of glutamate at rest and even more during
exercise, glutamate used as precursor for glutamine Release of ala and gln far out of proportion to their content in
skeletal muscle, synthesized in skeletal muscle at accelerated rate during exercise
Ala release decline with exercise duration, less glucose pyruvate
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Ex Biochem c8-AA metabolism 28AA metabolism duringmoderate-intensity exercise Exercise in low-glycogen, protein breakdown
greater, corresponding increase in release of most AA from muscle Induce protein breakdown to release BCAA, use BCAA
as fuel Decrease in total adenine nucleotide content during
prolonged exercise Prevent AMP accumulation, AMP IMP by adenylate
deaminase Can reduce TAN by up to 50%, need to regenerate
adenine purine nucleotide cycle, use aspartate, cost GTP
Predominantly after exercise, activities of the enzymes involved too long to produce appreciable AMP during ex
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Ex Biochem c8-AA metabolism 29
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Ex Biochem c8-AA metabolism 30
Purine nucleotide cycle
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Ex Biochem c8-AA metabolism 31
Purine nucleotide cycle
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Ex Biochem c8-AA metabolism 32
Purine nucleotide cycle
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Ex Biochem c8-AA metabolism 33AA metabolism duringhigh-intensity exercise
Only modest increase in glutamine and alanine release from muscle, when exercise intensity is high Glutamine synthesis require ATP and glutamate Glutamate is source of a-KG, CAC intermediate
Increased adenylate deaminase reaction during high-intensity exercise Recruitment of type II muscle fiber, in which
adenylate deaminase activity is high Increase release of NH4+, IMP is trapped within
muscle
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Ex Biochem c8-AA metabolism 34
Central fatigue theory voluntary maximal work of the muscle < the work
when motor nerve was electrically stimulated Fatigue in central nervous system Increased production of serotonin in brain Increased ammonia entry to brain
Tryptophan as precursor for serotonin synthesis Most tryptophan bind to albumin ↑ FFA during exercise compete for albumin, ↑free Trp
BCAA compete with trp for blood brain barrier BCAA supplementation helpful? Endurance exercise? most animal studies support the theory, but most human
studies failed to show benefit effect ↑ammonia, combination use with arginine?
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Ex Biochem c8-AA metabolism 35
Central fatigue theory
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Ex Biochem c8-AA metabolism 36Central fatigue – supplementation of CHO and BCAA
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Ex Biochem c8-AA metabolism 38
Additional roles for AA
Precursors for many biologically active compounds
Neurotransmitters Tyrosine: dopamine, norepinephrine,
epinephrine Histidine: histamine Tryptophan: serotonin, role in central fatigue
Maintain cellular redox state: glutathione
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Ex Biochem c8-AA metabolism 39
Glutathione
Glutathione, GSH(reduced form)
Glutathione, GS-SG(oxidized form)
2e- oxidation
2e- reduction
A disulfide bond
O O
HN
NH3+
-O
SH
NH O
OO-
O O
HN
NH3+
-O
S
NH O
OO-
O O
NHNH3
+
-O
SHN
O
OO-
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Ex Biochem c8-AA metabolism 40
Some Small Peptides
-Alanyl-L-histidine (Carnosine)
L-Aspartyl-L-phenylalanine methyl ester(Aspartame)
H3N-CH-C-NH-CH-C-OCH3
O
CH2CH2
C6H5COO-
O+H3N-CH2-CH2-C-NH-CH-COO-
O
CH2
N
NH
+
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Tamaki et al, 1992
Aguiar et al, 2013