Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download 12-Amino_acids
Document related concepts
Transcript
Amino acid metabolism © Michael Palmer 2016 1 Metabolic uses of amino acids • building blocks for protein synthesis • precursors of nucleotides and heme • source of energy • neurotransmitters • precursors of neurotransmitters and hormones © Michael Palmer 2016 2 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 © Michael Palmer 2016 3 Amino acid breakdown pathways join mainstream carbon utilization at different points of entry © Michael Palmer 2016 4 Transamination of amino acids © Michael Palmer 2016 5 The reaction mechanism of transamination © Michael Palmer 2016 6 The ping pong bi bi mechanism of transamination © Michael Palmer 2016 7 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 © Michael Palmer 2016 8 The urea cycle, part 1: carbamoylphosphate synthetase © Michael Palmer 2016 9 The urea cycle, part 2: subsequent reactions © Michael Palmer 2016 10 The urea cycle in context © Michael Palmer 2016 11 The urea cycle spans mitochondria and cytosol © Michael Palmer 2016 12 The glucose-alanine cycle © Michael Palmer 2016 13 Nitrogen transport by glutamine © Michael Palmer 2016 14 The central role of glutamate in nitrogen disposal © Michael Palmer 2016 15 Control of ammonia levels in the liver lobule © Michael Palmer 2016 16 Regulation of the urea cycle © Michael Palmer 2016 17 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 © Michael Palmer 2016 18 Asparagine degradation © Michael Palmer 2016 19 Serine dehydratase © Michael Palmer 2016 20 Serine-pyruvate transaminase © Michael Palmer 2016 21 Degradation of leucine © Michael Palmer 2016 22 Degradation of phenylalanine and tyrosine © Michael Palmer 2016 23 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 © Michael Palmer 2016 24 The Guthrie test for diagnosing phenylketonuria © Michael Palmer 2016 25 Ochratoxin A inhibits phenylalanyl-tRNA synthetase © Michael Palmer 2016 26 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 © Michael Palmer 2016 27
