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Copyright COMMONWEALTH OF AUSTRALIA Copyright Regulation WARNING This material has been reproduced and communicated to you by or on behalf of the University of Sydney pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice Introduction to Nitrogen Metabolism Only an introduction! Amino Acids • Twenty in proteins – More involved in metabolism – Loads of different side chains – So pathways of formation and disposal varied and complex • Synthesis and degradation of proteins – Each under different control – Hard to generalise Daily Flux 10 kg pool Intake 100 g 16 g nitrogen Loss 100 g 300 g turnover 3% per day skin 0.5 g nitrogen urea 16 g nitrogen faeces 2 g nitrogen Turnover varies massively between tissues: muscle 2%, intestine 15% But muscle is greatest bulk of protein. Principles • Liver important – First place amino acids go from intestine – Conversion of amino acids • Especially to glucose – Processing of amine groups • Urea synthesis • Degradation enzymes have very high Km – Not ‘controlled’ – Only affected by [amino acid] – So excess amino acids degraded Bits to Process • Amino group – Fixed nitrogen is quite precious • Recycle if possible – But ammonia is toxic • So need to convert to non-toxic product • Carbon skeleton – Normally a 2-oxo acid • Oxidized or converted to carbohydrate or fat Transamination • Shuffling of amino groups • Involves alpha-keto (2-oxo) acids – Main acceptors • Pyruvate alanine • 2-oxo glutarate glutamate • Oxaloacetate aspartate • These are involved in other pathways – Glycolysis, Krebs Cycle Other Key Reactions • Glutamate dehydrogenase – Oxidative deamination of glutamate • Regenerates 2-oxoglutarate • Releases ammonia • Glutamine synthesis – Using glutamate and ammonia • Glutamine effectively carries two amino groups – Reaction reversible Essential Amino Acids • Can’t be synthesized by us – Sometimes conditional on age/situation • Don’t learn them all – But do know which are most definitely NOT essential Getting a Good Mixture • Protein quality – Meat generally very high • “Standard” is egg – Pulses low in methionine – Lysine relatively low in grains • Protein complementing • Protein malnutrition – If you are lacking in one amino acid, you may not be able to make an entire protein – All the other amino acids then ‘in excess’ Amino Acid Fluxes • After feeding • Portal vein (into liver) – Mixture reflects protein composition – 20% branched chain amino acids • Leucine, isoleucine, valine • Hepatic vein (out of liver) – 70% branched chain amino acids • Veins from muscle – Branched chain amino acids removed During Starvation • Hypoinsulinemia stimulates proteolysis • Muscle releases all amino acids – But large amount of alanine & glutamine • These are preferentially taken up by liver – Small amount of branched chain amino acids • Where has the alanine come from – From pyruvate transamination • Which needs glycolysis from glucose • So that’s a bit strange! Amino acids blood Protein synthesis Can the pyruvate be made from other amino acid skeletons? Cell protein proteolysis glycolysis glucose pyruvate Amino acids 2-oxoglutarate alanine 2-oxoacids glutamate oxidation CO2 Export to liver glutamine Export to liver Processing Amino Acids • During normal turnover – Many amino acids escape re-synthesis • Oxidized • During starvation – Or other times when there is high proteolysis • When diet is rich in protein – Surplus amino acids • Issue is always… – How to deal with amine groups – What to do with carbon skeletons Dealing with amine groups • Urea Cycle – Liver only • Glutamate is the main substrate – In mitochondria, oxidative deamination • Giving 2-oxoglutarate and ammonia – Ammonia quickly ‘fixed’ into carbamoyl phosphate – Glutamate also transaminated to aspartate • Carbamoyl Phopshate and aspartate – combine to give urea General Principle • Carrier is ornithine • Reacts with carbamoyl phosphate – Giving citrulline • Now add –NH2 from aspartate – Releasing fumarate, a Krebs intermediate • Split off urea – Regenerating the ornithine Urea • Non-toxic – Can be present in blood at mM levels – Cleared by kidneys • Fish can secrete ammonia – Very dilute! – Ammonia very toxic to us Processing Skeletons • Many different pathways – Each amino acid is different • Some feed into Krebs Cycle – Anaplerotic – Can be diverted to gluconeogenesis • If transamination reactions in the liver – Or at least gluconeogenic substrates • For export from muscle • Some can only be made into acetyl CoA – Ketogenic or energy production only Defects in Processing • Both in urea cycle and skeleton breakdown – See textbook for full table (18-2) • Notably phenylalanine – First step, conversion to tyrosine, sometimes defective – Build up of phenylalanine and phenylpyruvate – Developmental problems – Screening and dietary therapy • Avoid aspartame • Difficult to avoid protein Amino Acid Sythesis • Very complex! • But all pathways linked to – Glycolysis – Krebs – Pentose Phosphate Pathway • Also other nitrogenous products from amino acids – Creatine – Hormones (adrenalin) – nucleotides Only Important Things • Overview of protein fluxes • Knowing when amino acids are metabolised • What goes in and out of muscle • Transaminases • Overview of Urea Cycle