Download 12-Amino-acids - WatCut

Metabolic uses of amino acids
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building blocks for protein synthesis
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precursors of nucleotides and heme
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source of energy
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neurotransmitters
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precursors of neurotransmitters and hormones
Outline of amino acid degradation
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The liver is the major site of degradation for most amino
acids, but muscle and kidney dominate the degradation of
specific ones
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Nitrogen is removed from the carbon skeleton and transferred
to α-ketoglutarate, which yields glutamate
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The carbon skeletons are converted to intermediates of the
mainstream carbon oxidation pathways via specific adapter
pathways
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Surplus nitrogen is removed from glutamate, incorporated
into urea, and excreted
Amino acid breakdown pathways join mainstream
carbon utilization at different points of entry
© Michael Palmer 2014
Transamination of amino acids
© Michael Palmer 2014
The reaction mechanism of transamination
© Michael Palmer 2014
The ping pong bi bi mechanism of transamination
© Michael Palmer 2014
Nitrogen disposal and excretion
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Nitrogen accruing outside the liver is transported to the liver
as glutamine or alanine
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In the liver, nitrogen is released as free ammonia
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Ammonia is incorporated into urea
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Urea is released from the liver into the bloodstream and
excreted through the kidneys
The urea cycle, part 1: carbamoylphosphate
synthetase
© Michael Palmer 2014
The urea cycle, part 2: subsequent reactions
© Michael Palmer 2014
The urea cycle in context
© Michael Palmer 2014
The urea cycle spans mitochondria and cytosol
© Michael Palmer 2014
The glucose-alanine cycle
© Michael Palmer 2014
Nitrogen transport by glutamine
© Michael Palmer 2014
The central role of glutamate in nitrogen disposal
© Michael Palmer 2014
Control of ammonia levels in the liver lobule
© Michael Palmer 2014
Regulation of the urea cycle
© Michael Palmer 2014
Hereditary enzyme defects in the urea cycle
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may affect any of the enzymes in the cycle
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urea cannot be synthesized, nitrogen disposal is disrupted
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ammonia accumulates, as do other metabolites depending on
the deficient enzyme
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treatment
○
protein-limited diet
○
arginine substitution
○
alternate pathway therapy
Asparagine degradation
© Michael Palmer 2014
Serine dehydratase
© Michael Palmer 2014
Serine-pyruvate transaminase
© Michael Palmer 2014
Degradation of leucine
© Michael Palmer 2014
Degradation of phenylalanine and tyrosine
© Michael Palmer 2014
Phenylketonuria (PKU)
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homozygous defect of phenylalanine hydroxylase
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affects one in 10,000 newborns among Caucasians; frequency
differs with race
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excess of phenylalanine causes symptoms only after birth;
intrauterine development normal
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cognitive and neurological deficits, probably due to cerebral
serotonin deficit
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treatment with phenylalanine-restricted diet
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some cases are due to reduced affinity of enzyme for cofactor
THB, can be treated with high dosages of THB
The Guthrie test for diagnosing phenylketonuria
© Michael Palmer 2014
Ochratoxin A inhibits phenylalanyl-tRNA
synthetase
© Michael Palmer 2014
Tyrosinemia
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homozygous defect of fumarylacetoacetate hydrolase
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fumarylacetoacetate and preceding metabolites back up
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fumaryl- and maleylacetoacetate react with glutathione and
other nucleophiles, causing liver toxicity
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the drug NTCB inhibits p-hydroxyphenylpyruvate
dioxygenase, intercepting the degradative pathway upstream
of the toxic metabolites
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dietary restriction of tyrosine required to prevent neurological
deficit