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Amino Acid Degradation and Byproducts

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Ella Christoph

on 28 February 2016

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Transcript of Amino Acid Degradation and Byproducts

non-ketotic
hyperglycinemia
autosomal recessive
1/60,000
high Gly in CSF and plasma
some respond to benzoate
Pheochromocytoma
tumor of the adrenal medulla
increased norepinehprine or epinephrine
high expression of COMT leads to more COMT products (metanephrine and normetanephrine)
essential hypertension
usually not malignant
Serine
Pyruvate
PLP
H2O
aminoacrylate
H2O
NH4+
serine dehydratase
serine dehydratase
hydroxypyruvate
aminotransferase
PLP
alanine
pyruvate
D-glycerate
NAD
NADH
D-glycerate dehydrogenase
2-phosphoglycerate
D-glycerate kinase
ADP
ATP
3-phosphoglycerate mutase
Glycine
THF
CH3
THF
PLP
serine
hydroxymethyltransferase
PLP
CO2
glycine dehydrogenase
aminomethyltransferase
lipoamide dehydrogenase
THF
THF
CH3
NAD
NADH
Glycine Cleavage System
NH3
inhibitory neurotransmitter
glycine oxidase
O2
H2O2 +
NH4
glyoxylate
lactate dehydrogenase
insoluble kidney stones
NAD
NADH
NADH
NAD
Glycolate
Threonine
threonine dehydrogenase
α-amino β-ketobutyrate
NAD
NADH
CoA lyase
CoA
Acetyl CoA
serine dehydratase
NADH
NH3
α-ketobutyrate
α-ketoacid dehydrogenase
CoA
CO2
propionyl CoA
propionyl CoA carboxylase
ADP
ATP
CO2 + H2O
biotin
D-methylmalonyl CoA
methylmalonyl CoA mutase
(MUT)
L-methylmalonyl CoA
methylmalonyl CoA mutase
B12
propionic
aciduria

metabolic acidosis
hyperammonemia
cardiomyopathy
low protein diet + carnitine
poor outcomes
methylmalonic acidemia
metabolic acidosis
hyperammonemia
chronic kidney disease
some forms are B12 responsive
low protein diet + carnitine
poor outcomes
Alanine
alanine
aminotransferase
PLP
glutamate
α-ketoglutarate
cysteine sulfinic acid
sulfite
aminotransferase hydrolase
decarboxylase
hypotaurine
Taurine
3-phosphoadenoside 5-phosphosulfate

cysteine dioxygenase
Cysteine
supports brain development
bile acid conjugation
crosses the blood-brain barrier
may have antioxidant properties
Asparagine
asparaginase
Aspartate
asparaginase is used to treat acute lymphoblastic leukemia because rapidly growing cells rely on asparagine
aminotransferase
PLP
Oxaloacetate
arginosuccinate synthetase
Citrulline
arginosuccinase
Arginine
Fumarate
AMP
ATP
Ornithine
arginase
H2O
Urea
Arginosuccinate
Ornithine
Citrulline
Carbamoyl
Phosphate
Pi
Pi
Pi
Pi
Pi
ADP
ATP
Pi
HCO3- +
NH4
N-acetylglutamate
NAG

indicates there is enough acetyl and glutamate
Arginine stimulate NAG synthase
Glutamate
α-ketoglutarate
Glutamine
glutaminase
H2O
NH4+
intestinal cells, kidney cells, immune cells, and cancer cells are the major consumers of glutamine
glutamine analogues are used as anticancer drugs
it's a source of NH3 for amino acid synthesis, a source of carbon skeletons for energy, a transporter of toxic ammonium groups, and a nitrogen transporter for nucleotide biosynthesis
supplied to presynaptic terminals of neurons
most prominent in the kidney; activity increased by an increase in the pH
expressed in periportal hepatocytes, where it generate NH3 for urea synthesis, promotes mitochondrial respiration, and is regulated by changes in transcription
excitatory neurotransmitter
glutamine synthetase
(GS)
predominant in the liver, kidney, and astrocytes in the brain
NH4+
H2O
N-formiminoglutamate
THF
THF
N-formimino-
Histidine
NH4
2H2O
histidase
glutamate semialdehyde
NAD(P)
NAD(P)H
∆-pyrroline 5-carboxylate
proline oxidase
NAD(P)
NAD(P)H
Proline
α-ketobutyrate
cystathionine
+
cystathionine lyase
PLP
H2O
NH3
homocysteine
H2O
S-Adenosyl Homocysteine
(SAH)
H2O
Adenosine
SAM methyl transferase
SAHase
S-Adenosyl Methionine
(SAM)
methionine adenosyl transferase (MAT)
Methionine
ADP
ATP
Pi
Pi
Pi
About half the homocysteine generated by methionine is metabolized to cystathionine by CBS
S-adenosylmethionine

Cysteine
methionine synthase
THF
CH3
CH3
B12
B12
THF
THF
CH3
Homocysteinuria
S-Adenosyl Methionine Deficiency
autosomal recessive, 1/100,000
Homocysteine can covalently modify lysine residues in proteins
cognitive impairment, myopia, abnormal blood clotting, osteoporosis
increased reactive oxygen species
developmental delays are noticed ~2-3 years
treat with B6, B12, folate, decreased Methionine intake
Cysteine becomes essential
Leucine
Isoleucine
Valine
branched chain amino acid aminotransferase (BCAA aminotransferase or BCAT)
Branched-Chain α-Ketoacid Dehydrogenase Complex
(BCKD Complex)
α-ketoacid products
CoA products
Succinyl-CoA
Leucine
Isoleucine
Valine
Acetoacetate
glutamate
α-ketoglutarate
CO2
α-ketoacid dehydrogenase
E1
NAD
NADH
TPP
TPP
-CoA
FAD
FADH2
dihydrolipoamide acyl transferase
E2
dihydrolipoamide dehydrogenase
E3
Maple Syrup Urine Disease (MSUD)
BCKD complex defect
increased Leucine levels
urine smells like maple syrup; high in ketones
autosomal recessive
1/200,000; 1/380 in Mennonite population (founder effect: tyrosine to asparagine in E1)
ketoacidosis, epilepetic seizures
TPP-responsive form
treatment: MSUD formula with decreased Val, Ile, Leu (Leu is most toxic)
TPP-responsive form
Lysine
saccharopine
α-ketoglutarate
NADP
NADPH
lysine-ketoglutarate reductase
saccharopine dehydrogenase
NAD
NADH
+ H2O
α-aminoadipate semialdehyde
some reactions
α-ketoadipate
Tryptophan
tryptophan
2,3-dioxygenase
mostly in the liver
Tryptophan

THF
THF
N-formyl-
Kynurenine
anti-excitatory hormone
regulates dilation of blood vessels and the immune response
secreted in urine in B6 deficiency
Kynurenic Acid
Quinolinic Acid
NMDA Receptor
schizophrenia
increased kyurenin and kyurenic acid
depression of nicotinic and glutamate receptors
poor emotional response, psychosis, break down of thought processes
kynurenine hydroxylase
PLP
Nicotinamide
NAD
NAD
niacin (B3)
Vitamin B3 deficiency
pellagra
Hartnup Disease
defect in tryptophan transporters decreases uptake
autosomal recessive
large amounts of Trp in urine
symptoms like pellagra
xanthurenic acid and other urinary metabolites
Tyrosine
p-hydroxyphenylpyruvate
homogentisate
dioxygenase
CO2
malacetoacetate
fumarylacetoacetate
homogentisate oxidase
fumarylacetoacetate hydrolase
Tyrosinemia I
fumarylacetoacetate hydrolase deficiency
autosomal ecessive
liver and kidney problems
low protein diet
liver transplant
Tyrosine
Phenylalanine
BH4
BH2
NADPH
NADP
O2
H2O
phenylalanine hydroxylase
dihydropteridine reductase
Phenylketonuria
3 possible enzymatic defects
phenylalanine hydroxylase (most common)
dihydropidine reductase
biopterin biosynthesis
autosomal recessive; 1/12,000
intellectual disabilities, seizures, demyelination
mousy odor due to phenylacetate in urine
light skin (Tyr is precursor to melanin)
excess of phenylacetate, phenylpyruate, phenyllactate
decrease protein, supplement with Tyr
catecholamine deficiency
GTP
PLP
aminotransferase
glycine
ornithine
guanidoacetate
SAM
SAH
in kidney
SAM methyl transferase
in liver
red meat
creatine phosphokinase
ADP
ATP
Pi
creatine phosphate
Pi
H2O +
Creatinine
ATP
essential in times of growth
synthesized from Arg, Gly, and Met
about 50% of the kidney's Arg is used to make creatine
normalization facotr for products excreted in the urine
Creatine
amount found in the urine proportional to muscle mass
γ-glutamyl cysteine
ADP
ATP
Pi
glycine
Glutathione
bond between γ-carboxyl of glutamate and α-amino group of cysteine makes resistant to hydrolysis
forms glutathione disulfide (GSSG)
glutamate decarboxylase
CO2
PLP
GABA
inhibitory neurotransmitter
underproduction associated with seizures
γ-aminobutyrate
GABA-glutamate transaminase
α-ketoacid
amino acid
PLP
succinate semialdehyde
semialdehyde dehydrogenase
NADH
NAD
Succinate
energy source in the brain
Sulfate
donor for steroids, GAGs, glycolipids and glycoproteins
Coenzyme A
ethanolamine
Phosphatidylserine
Phosphatidyl-ethanolamine
CO2
phosphatidylserine decarboxylase
PURINES AND PYRIMIDINES
SAM
ε-trimethyl lysine
(released from protein in lysosomes)
Carnitine
synthesized from Lys and Met
indispensible for energy metabolism because it allows activated fatty acids to enter the mitochondria
only the kidney, liver and brain have all the enzymes for synthesis
also can get from dietary sources
3,4-dihydroxyphenylalanine (DOPA)
dopaquinone
dopachrome
Melanin
melanocytes: skin, eye hair
insoluble high-molecular weight polymers
tyrosinase
Albinoism
tyrosinase deficiency
susceptible to carcinomas due to solar radiation of DNA
eye problems
[O]
H2O
[O]
H2O
thyroglobulin
mono-iodotyrosine (MIT)
H2O2 + I+
+
di-iodotyrosine (DIT)
iodination
T4
released into the blood stream
DOPA decarboxylase
Dopamine
PLP
Norepinephrine
Norepinephrine
n-methyltransferase

Adrenaline
Noradrenaline
phosphorylation at Serine 40 (N-terminal regulatory domain)
by CaM kinases or MAP kinases
reduces the Km for BH4
limiting factor
in the cell bodies of substantia nigra and mesocorticolimbus
Parkinson's
loss of dopaminergic neurons in the substantia nigra and noradrenenergic neurons in the locus coeruleus
Lewy bodies
rhytmic tremor, rigidityakinesia
5th or 6th decade of life
3/1,000; cumulative lifetime risk of 1 in 40
no cure; current goal is to delay onset
treat with L-DOPA
major neurotransmitter of the sympathetic nerve
released from the brain and adrenal medulla
made in the locus coeruleus
stress, alertness, vigilance, memory, sleep/wake cycle
3,4-dihydroxyphenyl glycoaldehyde
metanephrine
normetanephrine
vanillylmandelic acid
(VMA)
3-methoxy-4-hydroxy phenyl glycol
(MHPG)
DHMA
DHPG
Essential Hyptertension
elevated vasoconstriction due to increased norepinephrine and neuropeptide Y
increased susceptibility to stroke and MI
DOPA β-hydroxylase
DBH Deficiency
DOPA β-hydroxylase deficiency
no plasma norepinephrine, epinephrine
high dopamine
orthostatic hypotension
treat with dihydroxyphenylserine
Clinical Depression
norepinephrine and 5HT abnormalities
sleep disruption, anxiety, anhedonia, lethargy, hopelessness
treat with noradrenergic uptake inhibitors, MAO inhibitors
Drug Abuse
elevated dopamine in reward system
changes in synaptic properties
abstinence is difficult
5-hydroxytryptophan
tryptophan hydroxylase
BH4
BH2
O2
H2O
decarboxylase
PLP
CO2
Serotonin
powerful vasoconstrictor
stimulates smooth muscle cell contraction
brain and CNS (short half-life)
neurotransmitter
regulates body temperature, sleep, vomiting, appetite
depends on the quantity of free plasma tryptophan
plasma cortisol (increased in depressed patients) decreases free tyrosine and tryptophan in plasma
higher concentrations are found in the brainstem than in the cortex
digestive tract: 95% of total body serotonin found in the enterochromaffin cells
platelets (long half-life)
take it up from the plasma; can't synthesize it
localized effect
migraines
Acetyl CoA
CoA-SH
in the pineal gland
N-acetylserotonin
SAM
SAH
Melatonin
circadian rhythym
N-ω-hydroxyarginine
Nitric Oxide
NO
vasodilator
memory and immune response
NAD(P)
NAD(P)H
BH4
BH2
nitric oxide synthetase
ornithine decarboxylase
PLP
CO2
putricine
spermidine
spermine
SAM
decarboxylated-SAM
propylamino transferase
propylamino transferase
decarboxylated-SAM
Polyamines
stabilize nucleic acids against shear and degradation
Histamine
stimulates secretion of acid in stomach
stimulates bronchoconstriction in the lungs
Cimetidine is an antihistamine receptor H2 agonist
antihistamines decrease smooth muscle cell contraction
Succinyl-CoA
Arginosuccinic aciduria
autosomal recessive
hyperammonemia
ARG deficiency
hyperarginemia
autosomal recessive
hyperammonemia
carbamoyl phosphate synthetase I (CPSI)
CPS I deficiency
most severe hyperammonemia
autosomal recessive
hyperammonemia
NAGS deficiency
N-acetylglutamate synthetase deficiency
autosomal recessive
hyperammonemia
citrin (glutamate-aspartate transporter)
ornithine-citrulline transcarbamoylase
ornithine-citrulline translocase
HHH syndrome
ornithine-citrulline translocase deficiency
autosomal recessive
hyperammonemia
Serine
PLP
cystathionine synthase
(cystathionase or
cystathionase β-synthase (CBS)
in the liver)
PLP
Acetoacetate
Acetyl CoA
Glutamate
excitatory neurotransmitter
Alanine
Acetyl CoA
CO2
Alcaptonuria
homogentisate oxidase deficiency
excess amounts of homogentisate
black urine
oxidizes in wounds
Fumarate
Acetoacetate
Vitamin C
Fe2+
BH4
BH2
NADPH
NADP
Cu2+
Fe2+
O2
tyrosine hydroxylase
BH4
homotetramer
N-terminal regulatory domain
C-terminal catalytic domain

transcriptionally
regulated
(long-term)
nicotine
calcium
AP1-type motif in the promoter region
phosphorylation
(short-term)
Packaged by Vesicular Monoamine Transporters (VMAT) into vesicles for synaptic release
(in secretory vesicles in the adrenal medulla and sympathetic ganglia)
SAM
SAH
reuptake molecule has 12 membrane-spanning regions
MAO
catechol
O-methyltansferase
3,4-dihydroxyphenyl acetaldehyde
homovanillic acid (HVA)
dihydroxyphenyl acetic acid (DOPAC)
SAM
SAH
reduction
found in plasma
oxidation (less common)
monoamine oxidase
MAO
monoamine oxidase
MAO
monoamine oxidase
MAO
monoamine oxidase
COMT
catechol
O-methyltansferase
COMT
catechol
O-methyltansferase
COMT
catechol
O-methyltansferase
COMT
oxidation
oxidation
catechol
O-methyltansferase
COMT
SAM
SAH
SAM
SAH
SAM
SAH
SAM
SAH
MAO
monoamine oxidase
found in the liver
Cu2+
in the adrenal medulla—leaves the secretory vesicles
T3
dephosphorylation

Cysteine
3-Phospho-glycerate
glycolysis intermediate
Oxalate
kidney stones
acetyl CoA
glutamine
H2O
NH4
glutamate dehydrogenase
NAD(P)
NAD(P)H
NH4
glutamate semialdehyde
NAD(P)
NAD(P)H
PLP
glutamate
δ-amino aminotransferase
H2O + CO2
X-linked
Hyperammonemia
OTC Deficiency
aspartate
The Urea Cycle
Methionine Degradation and Salvage
Branched-Chain Amino Acid Degradation
Lysine
Degradation and Byproducts

Tryptophan Degradadation and Byproducts
Phenylalanine
and Tyrosine Degradation and Byproducts

Epinephrine
C3 Amino Acids (degrade to pyruvate) and their Byproducts
C4 Family
Amino Acids that Degrade to Alpha-Ketoglutarate (C5) and their Byproducts
PAPS
Citrullinemia
autosomal recessive
hyperammonemia
phosphorylation

arginine
Full transcript