BIOL2171 Lecture Notes - Lecture 14: Alanine Transaminase, Phenylalanine Hydroxylase, Carbamoyl Phosphate
Amino Acids as energy metabolites
• Amino acids can be converted into central metabolites by a few chemical conversions
• Major obstacles in amino acid metabolism is the removal of the amino-group
• Central enzymatic conversion of amino acids is carried out by the transaminase reaction
o This reaction is catalysed by an enzyme and a coenzyme
o The coenzyme is pyridoxalphosphate (PLP)
o Two common acceptors of amino groups in transaminase reaction
• α-ketoglutarate forming glutamate (glutamate aminotransferase): found in liver
• Pyruvate forming alanine (alanine aminotransferase): abundant in extrahepatic
tissues
o In extrahepatic tissues free ammonia is fixed in two reactions
• Glutamine dehydrogenase reaction - forig glutaate for α-ketoglutarate
• Glutamine synthase reaction
o Glutamine and alanine are released form the extrahepatic tissues and are taken up by
the liver for the final deposition of ammonia
• Free ammonia is toxic to the brain, its levels are kept low at all times
o Final removal of ammonia occurs are urea, which is generated in the urea cycle
The Urea Cycle
• Two entry points to the for ammonia in the urea cycle:
o Aspartate
o Carbamoylphosphate: used to carbamoylate ornithine forming citrulline
• Reaction occurs inside the mitochondria
• Carbamoylphosphate is formed form ammonia and bicarbonate in a reaction
requiring 2 ATP
• Citrulline fuses with aspartate for form arginosuccinate
• Fumarate is eliminated for this compound forming arginine
• Arginine is hydrolysed realising urea, and therefore regenerating ornithine
• Carbamoylphosphate synthetase located in mitochondria
▪ Due to this, transcarbamoylation of ornithine also occurs in mitochondria
o Remaining reactions in the urea cycle occur in the cytosol
• Urea cycle enzymes are particularly expressed in periportal hepatocyte: first sites of contact
with blood containing free ammonia and amino containing compounds
• Regulation of urea cycle occurs via Carbamoylphosphate synthetase
o Glutamate and acetyl-CoA come together to form N-acetylglutamate
o Enzyme activated by N-acetylglutamate
o Sufficient supply of glutamate (generated from transamination reactions in the liver) and
ATP (from acetyl-CoA oxidation in te TCA cycle) will increase the capacity of the urea
cycle
o Reaction that generates the N-acetylglutamate is allosterically controlled by arginine,
which is the immediate precursor of urea
• Elimination of urea allows for the conservation of all amino acids into energy metabolites
• Amino acids that can also be converted into acetyl-CoA are called ketogenic
• Case Study: Phenylketonuria (PKU)
o Degradation of phenylalanine occurs via tyrosine
• This reaction catalysed by phenylalanine hydroxylase
• Mutations in this enzyme occur in the most common inherited disorder of amino
acid metabolism: phenylketonuria (PKU)
o In PKU, increased amounts of phenylalanine breakdown products such as
phenylpyruvate appear in urine
o If untreated, PKU results in severe mental retardation
o Strict avoidance of phenylalanine is used to treat PKU
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