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# 1 Amino Acid Metabolism

# 1 Amino Acid Metabolism. 1. General Features Nitrogen Balance & Metabolic Pools 2. Degradation Transamination & Glutamate Dehydrogenases 3. Urea Cycle 4. Sulfur-containing amino acids 5. Creatine & Creatinine. Objectives.

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# 1 Amino Acid Metabolism

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  1. # 1 Amino Acid Metabolism 1. General Features Nitrogen Balance & Metabolic Pools 2. Degradation Transamination & Glutamate Dehydrogenases 3. Urea Cycle 4. Sulfur-containing amino acids 5. Creatine & Creatinine

  2. Objectives • Outline the general features of the amino acid (AA) pool & how these relate to positive & negative N balance. • Essential vs non-essential AAs • Interorgan transport and utilization of glutamine and alanine

  3. N balance = Nin - Nout • Major dietary source of N is Protein (>95%), since the diet has very few free amino acids • AA are used for Protein Synthesis & N containing compounds 3 AA in excess are degraded (used for energy) N is disposed of in urea (80%), ammonia, uric acid or creatinine in urine with small amounts in fecal matter (undigested)

  4. Positive Nitrogen Balance

  5. Negative Nitrogen Balance 1. Stress 2. Decreased Intake 3. Lack of an essential AA

  6. Specificity of Some Proteolytic Enzymes Very few AA are present in the free form in the diet. Most are absorbed following digestion as AA + peptides (important in transport deficiencies). Various enzymes cleave different bonds.

  7. Sterospecific Transport Systems for Amino Acids Uptake (transport) systems exist especially in intestine & kidney. Lack of specific transporter results in a disease state. This can be partially overcome through uptake of peptides.

  8. Metabolic Pool of Amino Acids • Metabolic pool AA has no storage form in mammals (as with other life forms) as free AA or as specialized storage form (such as glycogen for glucose, TG for FA) but a certain percentage of muscle & structural proteins are “expendable”. • AA are used for proteins, N compounds, energy (also via glucose) but increased protein breakdown will eventually compromise normal protein function. • Therefore need a small mobile pool of free AA in cells and blood • Pool size is regulated (no more than 50% changes) • Pool size is small relative to flux • 16g in = 16g out : Nequilibrium [AA = 30g] [300g cell protein]

  9. Metabolic Pool of Amino Acids

  10. The three major draws on the amino acid pool are: • AA → Proteins (not covered here) • AA →Catabolism (NH4+ discarded, glutamine used) • AA → N containing compounds as - whole/part AA integrated or - only the amino (N) group is used • AA catabolized, then NH4+ incorporated into glutamine This synthesis is not compromised even when dietary P is decreased because they are essential for cellular function.

  11. Major Functions of Amino Acids Derived from Dietary Protein Oxidation Glycogenic amino acids: --Blood glucose--Energy Ketogenic amino acids: -Acetyl CoA-Stored fat-Energy Biosynthesis of nitrogen-containing metabolites

  12. Maintenance of Pool Size • Surplus AA to biosynthetic requirements are degraded • AA oxidation is the major mechanism of degradation Rate • Oxidation  Pool Size and relates to enzyme induction. • Balanced composition of AA pool is important to meet all cell requirements for all AA

  13. Summary of Protein Metabolism a) αketo acids are funneled into the Krebs cycle (glucogenic/ketogenic) b) NH4+ is cleared via urea,NH4+, with uric acid however major product is urea (80%) c) Creatine/creatinine  important for energy consideration

  14. Essential & Non-essential AA 1. EAA : Humans (mammals) cannot synthesize their carbon skeletons de novo. Some EAA are considered essential because we cannot synthesize enough, especially for growth (children). 2. NEAA: Synthesized from intermediates of glucose/TCA cycle except TYR (cannot make aromatic ring). 3. The grouping of E vs NE was determined experimentally by feeding diets lacking in a single AA and measuring Nin/Nout. . If balance negative then = EAA

  15. Essential & Non-essential AA 1. The difference between EAA & vitamins that is AA are needed in substrate amounts to make proteins and nitrogen compounds. Vitamins are needed in catalytic amounts (co-factors for enzymes) and therefore can be reused. 2. All AA must be provided simultaneously (not hours after). 3. Normally: no “disease” can be attributed to deficiency in a single AA except Pellagra which is due to a lack of niacin nicotinate a component of NAD TRP  nicotinate  NAD Corn P is deficient in TRP therefore corn diet  pellagra. Preparation is important: Because TRP → necessary to make niacin Corn + Alkali absorptionof nicotinate present in corn → niacin

  16. Essential & Non-essential AA  Conditionally essential (i) ARG:can be made, but not enough (ii) HIS: controversial (essential for growth in children) (iii) PHE essential, TYR can be made from PHE but when enzyme is missing (phenyl- ketonuria) then PHE > TYR; Therefore TYR is essential (iv) MET CYS; Similarly, if MET > CYS then CYS essential  Even with excess, important in excretion NH4+ therefore continue to be made

  17. Glycogenic and KetogenicAmino Acids 1.Glucogenic: converted to glucose via pyruvate 2.Ketogenic: converted to ketone bodies 3.Some are both 4.During fasting when FA are the major fuel FA cannot be converted to glucose therefore AA →glucose & ketone bodies (especially for brain) -AA → pyruvate → liver → glucose -keto AA + FA → ketone bodies (acetoacetate & 3 hydroxybutyrate)

  18. Specialized Amino Acid Roles 1. Certain NEAA continue being synthesized even when adequate levels are supplied in diet because of a specialized role 2. ARG → urea synthesis ASP → urea synthesis GLU → conduit for disposal of N 3. ALA & GLN → key role in exchange between tissues (liver & skeletal muscle) 4. Liver: major site gluconeogenesis (AA → Glucose) major site urea synthesis (kidneys to a lesser extent) 5. Skeletal Muscle: 60% total body protein, 50% total body AA pool and is the major source to provide AA carbons → hepatic gluconeogenesis

  19. AA are released from muscle during the post- absorptive state (O/N fast). Of the AA released by muscle ALA= 30% & GLN= 25% (total> 50%) But output (ALA+GLN) > abundance in muscle proteins which contain 7-10% ALA & 6% GLN Where does this ALA & GLN come from?

  20. Sources of Alanine (from Muscle) (i)Muscle: Protein → ALA + AA AA → NH4+ + α keto acids α keto acids → ALA (“simplest” AA). Therefore total ALA released > ALA derived from proteins (ii) Liver: ALA →NH4+ + α keto acids NH4+→ urea (iii) As well Glucose → Pyruvate (no N) → ALA (with N) Therefore ALA serves as a vehicle for transport of NH4+ from muscle to liver (NH4+ is generated through breakdown of AA  →energy). (iv) Because free NH4+ is very toxic even at low levels therefore Pyruvate + NH4+ →ALA (non-toxic) (v) In liver: NH4+ → urea for excretion

  21. Sources of Glutamine (from Muscle) (i) Extra GLN released is also made from other AA & serves as a non-toxic transport of NH4+ from muscle → kidneys & gut (previous fig) (ii) Kidneys: GLN → ALA (to the Liver ) & GLN → glucose (blood) +NH4+ (Urine) (iii) Gut: GLN →ALA (to the liver)

  22. Response to Food Deprivation (i) For the first 7 days, maintain blood glucose (brain use 65% of glucose  400 - 600 Cal) (ii) > 7 days: Protein proteolysis decreases (protect essential proteins) therefore use over a prolonged period compromises organism. (iii) → Switch to Ketone bodies

  23. Case # 1 Amino Acid Metabolism: General Features Case Discussion A worker reported to a physician with many of the symptoms of pellagra: swollen tongue, dermatitis, and nervous disturbances. The man's diet consisted principally of sweet corn with a small amount of other sources of protein. The identical twin of the man had no similar complaints, and although the twin's diet was high in sweet corn, it was mixed with significant amounts of beans.

  24. 2. Is tryptophan an EAA? 1. Sweet corn protein is deficient in 1. Tryptophan 2. Glutamic acid 3. Lysine 4. Arginine YES 3. Pellagra is caused by a deficiency in A. Pyridoxal phosphate B. Ascorbic Acid C. Niacin D. Vitamin B12 E. Riboflavin

  25. 3. Match the numbers with the following letters as appropriate: A. Sweet corn protein 1. High Biologic Value B. Bean proteins 2 Deficient in tryptophan C. Both 3. Calorie value D. Neither 4. Essential fatty acids 4. A vitamin is defined as a compound that is 1. An essential component of the body 2. Mainly synthesized in plants 3. Not synthesized in adequate amounts in the body 4. Only synthesized in animals 5. The identical twin, who had no complaints 1. Had sufficient tryptophan to biosynthesize niacin 2. Derived enough niacin from beans 3. Did not cook his food in water 4. Added vitamin C to his diet

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