Protein Metabolism Lecture Notes PDF

Protein metabolism Dr. Nabil Hasona Dr. Nabil Hasona  Steps CO2 NH3 Cytoplasm Mitochondria...

Protein metabolism Dr. Nabil Hasona Dr. Nabil Hasona  Steps CO2 NH3 Cytoplasm Mitochondria CO2 + NH3 2ATP Carbamoyl-phosphate synthetase 1 2 ADP+1 Pi O O ll ll H2N – C – O – P – OH Carbamoyl-phosphate l CH2–CH2–CH2–CH–COOH OH Pi l l CH2–CH2–CH2–CH–COOH Ornithine NH NH2 transcarbamoylase l l l Ornithine Citrulline NH2 NH2 O=C–NH2 HOOC–CH2–CH–COOH O Ornithine Citrulline l ll NH2 Aspartic acid H2N–C–NH2 Urea Arginase Arginino-succinate ATP synthetase CH2–CH2–CH2–CH–COOH AMP+PPi l l H2O H2O CH2–CH2–CH2–CH–COOH NH NH2 l l l Arginine Arginino succinate NH NH2 NH2–C=NH l Arginino succinase NH–C=NH l HOOC–C–H Fumarate Dr. Nabil Hasona HOOC–CH2–CH–COOH ll H–C–COOH  Carbamoyl- phosphate synthetase I is different from carbamoyl phosphate synthetase II CPS I CPS II Site Mitochondria Cytoplasm Pathway Urea synthesis Pyrimidine synthesis +ve N-acetyl Nil effector glutamate Inhibitor Nil CTP Source Ammonia Glutamine of N Dr. Nabil Hasona  O Sources of the atoms of urea: ll H2N–C–NH2 1- C & O: from CO2 2- 1st N atom: from NH3 3- 2nd N atom: from aspartate Glutamate is usually the immediate precursor of both NH3 &aspartate H2O Glutamate Oxaloacetate NAD NADH+H Oxidative α- ketoglutarate α- ketoglutarate deamination Transamination NH3 Dr. Nabil Hasona Aspartate Overall reaction: NH3 + CO2 + Aspartate Urea + fumarate There in no net gain or loss of ornithine, citrulline , argininosuccinate or arginine. Ornithine is regenerated with each turn of the urea cycle. The release of the high energy phosphate of carbamoyl phosphate as inorganic phosphate drives the reaction in the forward direction. Dr. Nabil Hasona  Fate of fumarate & its link to TCA cycle CO2 NH3 Oxaloacetate Carbamoyl-phosphate Malate NADH+H NAD 3ATP Ornithine Fumarate TCA CYCLE Citrulline Ornithine Citrulline Aspartate Urea Arginine Arginino succinate Fumarate Transamination Cytoplasmic H2O fumarase Malate or Fasting dehydrogenase state Malate Malate Oxaloacetate PEP Glucose shuttle Fed state NAD NADH+H NADP Malic NADPH+H enzyme 3ATP Oxaloacetate ATP citrate lyase Pyruvic acid Pyruvic acid Citrate Citrate Acetyl COA f.a. Dr. Nabil Hasona synthesis Bioenergetics: Urea cycle consumes four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP). 1 ATP ADP + Pi ~P 1 ATP ADP + Pi Adenosine ~ P 1 ATP AMP + Pi + Pi ~P ►However. One NADH+H molecule is produced by oxidative deamination of glutamate to NH3 and α-ketoglutarate. Glutamate provides the NH3 used in the initial synthesis of carbamoyl phosphate. ► Also fumarate in the cycle may be converted to malate in the cytosol. Malate then oxidized to oxaloacetate gives 1 NADH+H equivalent to 3 ATP obtained from 3ADP, So the net energy expenditure is only one high energy phosphate. The two NADH+H produced can provide energy for the formation of 5 ATP, a net production of one high energy phosphate bond for the urea cycle. However, if gluconeogenesis is underway in the cytosol, the latter reducing equivalent is used to drive the reversal of the glyceraldehyde 3-p dehydrogenase step instead of generating ATP. So the net energy expenditure is only one high energy phosphate. Dr. Nabil Hasona  Regulation: Carbamoyl phosphate synthetase 1 is the key & it has an absolute requirement for N-Acetylglutamic acid which act as an allosteric activa tor. The synthesis of N- Acetylglutamate from glutamic acid & acetyl CO A is ++ by high protein diet & a.as especially arginine → ↑rate of urea cycle. Acetate GLUTAMATE Acetyl CO A a.as esp arginine Synthetase ++ N- ACETYL GLUTAMATE CO A ALLOSTERICALLY ++ Dr. Nabil Hasona carbamoyl phosphate synthetase 1