Transcript METABOLISM OF AMINO ACIDS

Amino acid oxidation and the
production of urea
Catabolism of proteins and aa nitrogen
• How the nitrogen of aa is converted to urea and the
rare disorders that accompany defects in urea
biosynthesis
• Normal condition- nitrogen intake match nitrogen
excreted
• Positive nitrogen balance- an excess of ingested over
excreted nitrogen- during growth and pregnancy
• Negative nitrogen balance – output exceeds intakeduring surgery, advanced cancer or malnutrition
Oxidative degradation occur in 3 diff metabolic
circumstances:
1) During normal synth and degradation of
cellular protein- aa that are released from
protein breakdown are not needed for new
prot synthesis-degraded
2) Taking a protein rich diet- aa intake exceeds the
body’s need for prot- degraded
3) During starvation or in uncontrolled DM –
when carb cannot be utilized, proteins are used
as fuel
• Under all this metabolic conditions- aa lose their amino groups to
form α-ketoacids (the carbon skeleton of amino acids)
• The α-ketoacids undergo oxidation to CO2 and H20 and provide
3-4C for gluconeogenesis
1) Metabolic fates of amino groups
2) Metabolic fates carbon skeletons
Metabolic fates of amino groups
• Degradation of ingested proteins to aa occurs in
gastrointestinal tract
• Entry of protein dietary will stimulate the
hormone gastrin – will stimulate the production
of HCl- kill most bacteria, denaturing agent for
protein, unfolding globular proteins, and make
internal peptide bonds more accessible to
enzymatic hydrolysis
• Pepsin is activated to cleave the polypeptide to
smaller peptide
Dietary protein is enzymatically
degraded to amino acids
• Once protein are degraded
to amino acids, aa are
transported to liver- to
remove the amino groups
– by aminotransferases or
transaminases
• The amino groups are
transferred αketoglutarate- forming
glutamate
Glutamate releases its amino group as
ammonia in the liver
• Amino groups must be removed from
glutamate for excretion
• In hepatocytes, glutamate is transported from
cytosol to mitoch – undergoes oxidative
deamination- cat by glutamate dehydrogenase
produced NH4+
• NH4+ is transported by glutamine to liver to
be secreted thru urea cycle
Excretion of excess nitrogen
• Excess nitrogen – excreted in one of three forms: ammonia
(as ammonium ion), urea and uric acid
• Fish – excrete ammonia – protected by the toxic activity
through excretion and rapid dilution by environment
• Terrestrial animals- excrete urea- water soluble compounds
• Birds- excrete uric acid – insoluble in water- to avoid excess
weight
• High blood urea level as a consequence (not a cause) of
impaired renal fx
• Central pathway in nitrogen
metabolism- urea cycle
• Start with the reaction of
ammonium ion and C02 to
produce carbamoyl phosphate
• Step 1- Carbamoyl phosphate +
ornithine →citrulline (carbamoyl
phosphatase 1
• Citrulline + Nitrogen
(2nd)→arginino succinate
• Arginino succinate → fumarate
and arginine
• Arginine → urea and regenerate
ornithin
• Fumarate enter the TCA cycle
Urea cycle
Ammonia intoxication
• Ammonia produced by enteric bacteria and produced
by tissues are rapidly cleared from circulation by the
liver and converted to urea
• Ammonia is toxic to central nerveous system
• Ammonia levels may rise to toxic levels in impaired
hepatic function – cirrhosis
• Ammonia is toxic to brain – reacts with α-ketoglutarate
to form glutamate – depleted levels of α-ketoglutarate
– impair fx of TCA cycle in neurons
Ammonia intoxication
• Mammals with genetic defects in any enzyme
involved in urea formation cannot tolerate
protein rich diet- as free ammonia cant be
converted to urea- lead to hyperammonemia
• Protein free diet is not an option. Mammals
are incapable of synthesizing all 20 amino
acids, thus must come from diet
Amino acid catabolism
• Involve transferring the
amino nitrogen to αketoglutarate to produce
glutamate- leaving behind
the carbon skeleton
• After removal of their
amino groups, the carbon
skeleton of aa undergo
oxidation to compounds
that can enter the TCA cycle
• In liver
The fate of carbon skeleton
Amino acid catabolism
The fate of carbon skeleton
• Glucogenic aa yields pyruvate or OAA on
degradation -----> gluconeogenesis
• Ketogenic aa breaks down to acetyl-CoA or
acetoacetyl-CoA- leading to the formation of
ketone bodies
Six aa are degraded to pyruvate
• Alanine, tryptophan, cystein, serine, glycine,
and threonine
• All are converted to pyruvate
• Pyruvate can either be converted to acetylCoA (Ketone bodies precursor)
• Or converted to OAA (gluconeogenesis)
Glycine degradation
• Can be degraded in 3 ways – only one yield
pyruvate
1) Involve conversion of glycine to serine via
catalysis of serine hydroxymethyl transferase.
Serine is then converted to pyruvate
Glycine degradation
2) Glycine undergoes oxidative cleavage to CO2,
NH4+ and a methylene group – catalysed by
glycine cleavage enzyme (or glycine synthase)
• This pathway is critical in mammals
• Defects in glycine cleavage enzyme- lead to
elevated serum of glycine – inhibit
neurotransmitter- mental retardation
Glycine degradation
3) Conversion of glycine to glyoxylate by Damino acid oxidase. Glyoxylate is further
oxidized to oxalate
• Crystals of calcium oxalate account for 75% of
all kidney stones
Ketogenic amino acid
• Phenylalanine, tyrosine, isoleucine, leucine,
tryptophan, threonine, and lysine
• Breakdown of trp – precursor to synthesis
 NAD and NADP in animals
 Serotonin – a neurotransmitter in
vertebrate
Phenylalanine catabolism
• Phenylalanine- precursor for dopamin (a
neurotransmitter) and hormones
(norepinephrine and epinephrine)
• Breakdown of phenylalanine- catalysed by
phenylalanine carboxylase
• Deficiency of this enzyme lead to
phenylketoneuria (PKU) disease – due to
elevated levels of phenylalanine
PKU
• Defiency of phenylalanine carboxylase cause
phenylalanine undergoes transamination with pyruvate –
yield phenylpyruvate –
• Accumulate in blood and tissues- excreted thru urine
• Other than being excreted as urine directly, some of
phenylpyruvate are reduced to phenylacetate – give odor
to urine – nurses have traditionally used to detect PKU in
infants
• Accumulation of phenylalanine in early life impairs
normal development of the brain- mental retardation
• Due to excess of phenylalanine competing with other aa
for transport across the blood brain-barrier- deficit
required metabolites
• Mental retardation can be prevented by rigid dietprovide only enough phenylalanine
The fate of branched amino acid
• Isoleucine, leucine, and valine
• Degraded only in extrahepatic tissues –
oxidized as fuels in muscles, adipose, kidney
• Due to the presence of branched-chain αketoacid dehydrogenase complex- absent in
liver
Maple syrup urine disease
• Due to the defective branched-chain α-ketoacid
dehydrogenase complex• Lead to accumulation of leucine in blood- and
excreted to urine – smell like maple syrup
• Untreated lead to abnormal development of the
brain, mental retardation, and death in early
infacy
• Treatment include limiting the intake of valine,
isoleucine, and leucine
Metabolic disorders related to urea
cycle
• Defects in urea synthesis results in ammonia
intoxication
• More severe if the metabolic blocks occur at
reactions 1 or 2 – some intermediate
compound have been synthesized
• Due to defects in any several enzyme involved
in the cycle