Amino acid oxidation and the production of urea

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Amino acid oxidation and the production of urea
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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
  intake- during surgery, advanced cancer or
  malnutrition

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• Oxidative degradation occur in 3 diff metabolic
  circumstances
• During normal synth and degradation of cellular
  protein- aa that are released from protein
  breakdown are not needed for new prot
  synthesis-degraded
• Taking a protein rich diet- aa intake exceeds the
  bodys need for prot- degraded
• During starvation or in uncontrolled DM when
  carb cannot be utilized, proteins are used as fuel

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• Under all this metabolic conditions- aa lose
  their amino groups to form a-ketoacids (the
  carbon skeleton of amino acids)
• The a-ketoacids undergo oxidation to CO2 and
  H20 and provide 3-4C for gluconeogenesis

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1. Metabolic fates of amino groups
2. Metabolic fates carbon skeletons

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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

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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 a-ketoglutarate-
  forming glutamate

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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

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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

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Urea cycle

• 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

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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
  a-ketoglutarate to form glutamate depleted
  levels of a-ketoglutarate impair fx of TCA
  cycle in neurons

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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

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Amino acid catabolism

• Involve transferring the amino nitrogen to
  a-ketoglutarate 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

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The fate of carbon skeleton
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Amino acid catabolism
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The fate of carbon skeleton

• Glucogenic aa yields pyruvate or OAA on
  degradation -----gt gluconeogenesis
• Ketogenic aa breaks down to acetyl-CoA or
  acetoacetyl-CoA- leading to the formation of
  ketone bodies

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Six aa are degraded to pyruvate

• Alanine, tryptophan, cystein, serine, glycine,
  and threonine
• All are converted to pyruvate
• Pyruvate can either be converted to acetyl-CoA
  (Ketone bodies precursor)
• Or converted to OAA (gluconeogenesis)

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Glycine degradation

• Can be degraded in 3 ways only one yield
  pyruvate
• Involve conversion of glycine to serine via
  catalysis of serine hydroxymethyl transferase.
  Serine is then converted to pyruvate

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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

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Glycine degradation

• 3) Conversion of glycine to glyoxylate by D-amino
  acid oxidase. Glyoxylate is further oxidized to
  oxalate
• Crystals of calcium oxalate account for 75 of
  all kidney stones

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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

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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

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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
  diet- provide only enough phenylalanine

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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 a-ketoacid
  dehydrogenase complex- absent in liver

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Maple syrup urine disease

• Due to the defective branched-chain a-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

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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