BIOC2600 1.8

• Amino acid metabolism II: Degradation Dr Masayo Kotaka School of Biomedical Sciences [e-mail] LKS Faculty of Medicine
• Learning Objectives After today’s lesson, you should be able to: Briefly explain the generation of amino acids by digestion of proteins and/or protein degradation Outline the process of amino acid degradation Discuss how the urea cycle is linked to the TCA cycle.
• Protein Turnover Degradation and resynthesis of proteins Amino acids can be synthesized, as we have just talked about.
• Amino acids can also be generated by digestion of proteins in the intestines and degradation of proteins within the cell.
• Degradation of proteins in cells can lead to the generation of amino acids, as some proteins are very stable, such as crystallin in eye lens, which can last more than 70 years.
• However, many proteins are short lived, especially those important in metabolic regulation.
• Cells have mechanisms for detecting and removing damaged proteins.
• Five to a-ketoglutarate: Arg, Glu, Gln, His, Pro.
• Two to fumarate: Phe, Tyr.
• Fate of carbon skeletons of amino acids after amino group removal: Amino acids result in more than one intermediate, and some amino acids result in more than one intermediate.
• Ornithine is transported back to the mitochondria for the urea cycle.
• Four to succinyl-CoA: Ile, Met, Thr, Val.
• Fate of fumarate synthesized by the urea cycle: Fumarate is hydrated to malate, oxidised to oxaloacetate, and oxaloacetate can be transminated to aspartate, converted to glucose via the gluconeogenic pathway, condensed with acetyl coA to form citrate, or converted to pyruvate.
• Ketogenic amino acids can be converted to ketone bodies.
• The urea cycle is linked to the TCA cycle via the aspartate - arginosuccinate shunt.
• Seven to Acetyl-CoA: Leu, Ile, Thr, Lys, Phe, Tyr, Trp.
• Arginine is cleaved to form ornithine and urea.
• Six to pyruvate: Ala, Cys, Gly, Ser, Thr, Trp.
• Glucogenic amino acids can be converted to glucose.
• Two to oxaloacetate: Asp, Asn.
• Gene transcription, cell-cycle progression, organ formation, circadian rhythms, inflammatory response, tumor suppression, cholesterol metabolism, antigen processing are processes regulated by protein degradation.
• In animals, amino acids undergo degradation when the amino acids are not needed for new protein synthesis during normal synthesis and degradation of cellular proteins.
• Amino acid degradation occurs in the liver, where the amino group is removed.
• Argininosuccinate is cleaved to form arginine and fumarate.
• The reaction of transferring the amino group to α - ketoglutarate is catalysed by aminotransferases.
• The amino group from glutamate can be transferred to pyruvate to form alanine.
• The urea produced is then passed to the bloodstream to be carried to the kidneys.
• Glutamate can then enter the mitochondria, the ammonium ion then disposed of by urea synthesis.
• Glutamine is then transported to liver for processing, releasing the ammonia.
• Glutamate can be converted to glutamine and transported to the liver.
• Fumarate is linked back to the TCA cycle.
• Ammonia deposited in the mitochondria of hepatocytes is converted to urea by the urea cycle.
• Alanine is transported to the liver in blood.
• Alanine transports amino groups from skeletal muscles to liver via the glucose-alanine cycle.
• In the liver cytosol, the amino group of alanine is then transferred to α-ketoglutarate to form pyruvate and glutamate.
• Carbamoyl phosphate then enters the urea cycle.
• Ammonia formed in tissues other than the liver (extrahepatic tissues) are converted to non-toxic forms before exported to blood and transported to liver or kidneys.
• Pyruvate is readily supplied from muscle glycolysis.
• Glutamate + NAD(P) + + H 2 O NH 4 + + α - ketoglutarate +NAD(P)H + H + is the reverse reaction of glutamate biosynthesis.
• The amino group of amino acids are transferred to α - ketoglutarate to form glutamate.