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Amino acid metabolism · Nitrogen balance Dietary protein amino acid pool protein synthesis catabolism, biosynthesis normal N balance: N ingested = N excreted negative N balance: N ingested < N excreted positive N balance: N ingested > N excreted N excretion (NH4+. urea) Amino acid catabolism · accounts for ~ 10% of energy requirement of adults · · · · · When: excess protein in diet protein degradation exceeds demand for new protein starvation when carbohydrates are not available protein storing seeds such as beans, peas, etc. · Glucogenic vs ketogenic amino acids · ketogenic: yield AcCoA or AcAc as end products of catabolism - leu, lys · glucogenic: are degraded to pyruvate or a member of the TCA cycle (succinylCoA, OAA, a-ketoglutarate, fumarate) In absence of sugars, glucogenic amino acids permit continued oxidation of fatty acids by maintaining TCA cycle intermediates. - ile, phe, tyr, trp · glucogenic and ketogenic: yield both ketogenic and glucogenic products. - all others N catabolism General strategy: 1. removal of N from amino acid by transamination (generally first or second step of amino acid catabolic pathways) and collection of N in glutamic acid 2. deamination of glutamic acid with release of NH4+ -glutamate dehydrogenase 3. Collection of N in glutamine or alanine for delivery to liver 4. removal of NH4+ by : i. secretion; or ii. conversion to urea or other less toxic form. Vitamine B6 family Pyridoxine Pyridoxal Pyridoxamine to e-amino of lysine Pyridoxal phosphate See Horton: page 212 section 7.7 pyridoxal phosphate Transamination reaction see text p 537 and fig 17.7. Lys-protein NH R1 H-CNH3+ COO- + a-aminoacid-1 Schiff base with enzyme R1 H-C-COONH Lys-protein Schiff base with substrate R1 H-C-COONH Lys-protein Schiff base with substrate NH2 Lys-protein R1 + H-C- O COO- a-ketoacid-1 R2 H-C-COONH Lys-protein Schiff base with substrate NH2 Lys-protein R2 + H-C- O COO- a-keto acid a-ketoacid-2 Lys-protein NH R2 H-CNH3+ COO- + a-amino acid-2 Schiff base with enzyme R2 H-C-COONH Lys-protein Schiff base with substrate Net reaction: a-amino acid-1 + a-ketoacid-2 PLP a-amino acid-2 + a-ketoacid-1 e.g. alanine + a-ketoglutarate pyruvate + glutamate Alanine-glucose cycle Muscle glucose 2 pyruvate 2 a-aa 2 a-ka 2 alanine 2 alanine glucose Liver glucose 2 pyruvate 2 Glu 2 NH4+ 2 a-kG 2 alanine glutamate dehydrogenase (see p 533 for reaction) • - release or capture of NH4+ · - located in mitochondria · - operates near equilibrium NAD NADH a-ketoglutarate + NH4+ glutamate + H2O NADP amino acid + a-ketoglutar NADPH a-keto acid + glutamate glutamate + NAD + H2O a-ketoglutar +NADH + H+ + NH4+ amino acid + NAD + H2O a-keto acid +NADH + H+ + NH4+ 3. transport of N to the liver - glutamine synthetase - glutaminase - alanine/glucose cycle 1. Glutamine synthetase ATP glutamate + NH4+ ADP + Pi glutamine 2. Glutaminase glutamine glutamate + NH4+ Note: glutamate can be used for glucose synthesis. How? MUSCLE Glu’NH2 NH4+ a-ka Pyr Glu Glucose a-aa a-KG Ala Pyr a-KG Glu Glucose Glu’NH2 NH4+ LIVER Glucose CO2 H2O Urea 2NH4+ 2NH4+ 2a-KG Ala 2Glu 2Glu’NH2 4CO2 KIDNEY H2CO3 HCO3 + H+ Urea cycle Where: Liver: mito/cyto Why: disposal of N Immediate source of N: glutamate dehydrogenase glutaminase Fate of urea: liver kidney urine How much: ~ 30g urea / day Reactions of urea cycle 1. Carbamyl phosphate synthetase I (mito) O NH4+ + HCO3- + 2 ATP H2N-C-OPO3-2 + Pi + 2 ADP carbamyl phosphate • committed step • by N’Ac glutamate 2. Ornithine transcarbamylase (mito) NH2 CH2 CH2 CH2 CH COONH3+ ornithine + NH2 C O OPO3-2 carbamyl phosphate Pi NH2 C O HN CH2 CH2 CH2 CH COONH3+ citrulline 3. Arginosuccinate synthetase (cyto) NH2 C O HN CH2 CH2 CH2 CH COO- COO- H2N COO- + CH2 CH NH3+ COO- ATP NH3+ AMP + PPi CH C NH CH2 HN CH2 COOCH2 CH2 CH COONH3+ arginosuccinate 4. Arginosuccinate lyase (cyto) H2N COO- CH C NH CH2 HN CH2 COOCH2 CH2 CH COONH3+ H2 N C NH2 HN CH2 CH2 CH2 CH COONH3+ arginine COO- + CH CH COO- fumarate 5. Arginase (cyto) H2 N C NH2 HN CH2 CH2 CH2 CH COONH3+ NH2 CH2 CH2 + CH2 CH COONH3+ ornithine NH2 C O NH2 urea NH 2 C O OPO 3-2 NH3+ aKG 2ATP HCO3 2ADP +Pi NH2 CH2 CH2 CH2 CH COONH3+ NADH + H+ NH2 C O HN CH2 CH2 CH2 CH COO- + NAD NH3+ ornithine asparate glutamate citrulline asparate glutamate MITO ornithine NH 2 C CYTO O ATP NH 2 AMP + PPi H2N H2 N C NH2 HN CH2 CH2 CH2 CH COO- COO- CH C NH CH2 HN CH2 COOCH2 CH2 CH COONH3+ NH3+ fumarate See fig 17.26 Interorgan relationships in N metabolism Epithelial cells of intestine Several steps Glu’NH2 cittruline Glu’NH2 Liver Kidney cittruline Arg Arginine Arginine Several steps Urea Urea cycle Ornithine 2 steps creatine glutamate To urine Muscle creatine P-creatine creatinine Several steps Adapted from Devlin, Biochemistry with Clinical Corrleation 4th ed.