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Metabolic uses of amino acids
● building blocks for protein synthesis
● precursors of nucleotides and heme
● source of energy
● neurotransmitters
● precursors of neurotransmitters and hormones
Outline of amino acid degradation
● The liver is the major site of degradation for most amino acids, but muscle and kidney dominate the degradation of specific ones
● Nitrogen is removed from the carbon skeleton and transferred to α-ketoglutarate, which yields glutamate
● The carbon skeletons are converted to intermediates of the mainstream carbon oxidation pathways via specific adapter pathways
● 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
● Nitrogen accruing outside the liver is transported to the liver as glutamine or alanine
● In the liver, nitrogen is released as free ammonia
● Ammonia is incorporated into urea
● 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
● may affect any of the enzymes in the cycle
● urea cannot be synthesized, nitrogen disposal is disrupted
● ammonia accumulates, as do other metabolites depending on the deficient enzyme
● 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)
● homozygous defect of phenylalanine hydroxylase
● affects one in 10,000 newborns among Caucasians; frequency differs with race
● excess of phenylalanine causes symptoms only after birth; intrauterine development normal
● cognitive and neurological deficits, probably due to cerebral serotonin deficit
● treatment with phenylalanine-restricted diet
● 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
● homozygous defect of fumarylacetoacetate hydrolase
● fumarylacetoacetate and preceding metabolites back up
● fumaryl- and maleylacetoacetate react with glutathione and other nucleophiles, causing liver toxicity
● the drug NTCB inhibits p-hydroxyphenylpyruvate dioxygenase, intercepting the degradative pathway upstream of the toxic metabolites
● dietary restriction of tyrosine required to prevent neurological deficit
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