MBBS amino acid metabolism 2023 - Tagged.pdf

Amino acid metabolism MBBS 1 NAM Dr Despo Papachristodoulou  Learning outcomes Explain the concept of protein turnover, dynamic equilibrium and amino acid pools; Explain Explain the concept of nitrogen balance and the causes of po...

Amino acid metabolism MBBS 1 NAM Dr Despo Papachristodoulou  Learning outcomes Explain the concept of protein turnover, dynamic equilibrium and amino acid pools; Explain Explain the concept of nitrogen balance and the causes of positive and negative nitrogen Explain balance Outline the pathways of protein degradation Outline Explain how amino acids are classified as essential or nonessential and the significance of Explain this classification Explain the terms transamination, deamination and trans deamination Explain Describe the action and significance of aminotransferase enzymes Describe Explain the importance of glutamate, glutamine, aspartate and alanine in amino acid Explain metabolism.  Is dietary protein essential? Some amino acids are essential Amino acids are required as building blocks for proteins Also for synthesis of neurotransmitters, creatine, carnitine, haem, purines and pyrimidines They act as a source of blood glucose in fasting and starvation Nitrogen balance  Protein turnover Body proteins continuously degraded to amino acids and re-synthesised. average turnover in an adult 300g-400g per day. Turnover variable Most proteins have half-lives of several days. structural proteins e.g. collagen may have half lives of years. Hormones & digestive enzymes degraded very rapidly, with half-lives of minutes.  Amino acid pool free amino acids very low concentrations inside cells or in the blood stream mixing and exchange with other free amino acids distributed throughout the body.  Protein requirements no ‘storage’ form of protein in the body protein is needed in the diet to replace the lost amino acids, and allow for tissue repair recommendation: 50 – 70 g protein per day high protein intake in a well-fed individual is wasteful: surplus amino acids are rapidly catabolised and the nitrogen excreted as urea in the urine.  Essential amino acids Valine 20 amino acids commonly found as ‘building blocks’ of Methionine proteins (Histidine) Lysine Plants and micro organisms Phenylalanine can synthesise all 20 amino Leucine acids from NH3 and CO2 Isoleucine Humans can synthesise only Threonine 10 amino acids from other Tryptophan intermediates (Arginine) They rely on dietary sources  Nitrogen Balance In normal healthy adults, total amount of nitrogen taken in the diet as protein should be equal to the amount of nitrogen excreted from the body in the form of urea, uric acid, creatinine, & NH4+ N intake = N excretion The subject is then described as being in nitrogen balance.  Positive nitrogen balance N intake > N excretion protein synthesis exceeds the rate of breakdown. during normal growth in children in convalescence after serious illness after immobilisation after an accident, in pregnancy  Negative nitrogen balance N intake < N excretion in starvation, during serious illness, In late stages of some cancers, in injury and trauma. If not corrected and becomes prolonged, there will be irreversible loss of essential body tissue will ultimately lead to death.  Pathways of Protein Degradation Most cellular proteins - recognised as ‘old’ or damaged removed by the ubiquitin breakdown system Foreign ‘exogenous’ proteins ‘old’ or damaged sub cellular organelles taken into vesicles by endocytosis, or autophagocytosis, vesicle fuses with lysosomes, proteolytic enzymes degrade proteins into amino acids Starvation and hormones e.g. cortisol increase rates of protein breakdown in muscle Amino acid degradation AMINO ACIDS ↓ NH2 oxo acid (keto acid) CH3 I C=O I COOH Transamination and deamination The N part of the amino acid is removed by transfer to an acceptor molecule amino acid + 2-oxoglutarate ↨ oxo acid + glutamate RELEASE OF NH2 GROUP AS AMMONIA NH3 or NH4+  Fate of the oxo-acids after losing their amino groups, most of the 20 amino acids become oxo acids can be metabolised by the TCA pathway to CO2 and H2O and provide a source of ATP. in starvation, the carbon skeletons of 13 of the amino acids can also be converted back to glucose, by the liver, and these are classified as ‘glucogenic’.  KETOGENIC AMINO ACIDS Leucine and lysine can only be degraded to acetyl CoA and are therefore classified as ‘ketogenic’. cannot be converted into glucose Phenylalanine and tyrosine catabolised with part of their chemical structure being converted into glucose count as both glucogenic and ketogenic (also tryptophan & isoleucine ) AMINO ACID METABOLISM  role of the liver in N metabolism removal of amino acids, glucose & fats from the portal blood supply absorbed amino acids used for synthesis of cellular proteins synthesis of plasma proteins (albumin, clotting factors, lipid transport proteins etc) synthesis of haem, purines & pyrimidines for DNA & RNA degradation of excess amino acids by trans- deamination conversion of NH3 to urea for excretion (urea / ornithine cycle) CENTRAL ROLE OF THE LIVER Transport of ‘amino groups’ and ‘ammonia’ to the liver skeletal muscle continuously degrades proteins to amino acids the liver is the only organ which can convert the amino groups of these amino acids to urea for excretion from the body The amino groups (NH2) are transported as glutamine in the blood stream GLUTAMINE METABOLISM  Important amino acids in the inter-organ transport of nitrogen Alanine Glutamate Glutamine aspartate  Importance of glutamine safe carrier of ammonia in the blood Ammonia is toxic to the brain Glutamine can carry 2 ammonia equivalents to the liver for urea formation Glutamine can deliver ammonium ions to the kidney for pH regulation (buffering H+) THE UREA CYCLE UREA CYCLE (ORNITHINE CYCLE) END PRODUCTS OF NITROGEN METABOLISM UREA protein breakdown CREATININE creatine phosphate breakdown URIC ACID DNA & RNA breakdown AMMONIA (NH4+) control of body pH  Ammonia is neurotoxic Exact mechanism not known Cerebral oedema, coma and death Seems to involve cell death  Impaired conversion of NH3 to urea (HYPERAMMONAEMIA) LIVER FAILURE (viral hepatitis, ischaemia, liver cirrhosis, toxins eg aflatoxin in mouldy peanuts) GENETIC DEFECTS reduction in catalytic activity of any enzyme of the urea cycle eg ornithine transcarbamoylase deficiency X linked inheritance, 1 in 30, 000 live births  Treatment for hyperammonaemia Can you find out?