# 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

• 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

ammonia.N balance = Nin .Nout 1 Major dietary source of N is Protein (>95%). since the diet has very few free amino acids 2 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%). uric acid or creatinine in urine with small amounts in fecal matter (undigested) .

Positive Nitrogen Balance .

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

5 7.5 to 2. Most are absorbed following digestion as AA + peptides (important in transport deficiencies). Various enzymes cleave different bonds.5 1. lysyl bonds Aromatic amino acyl bonds (Phe. Tyr) Wide range of specificity C-terminal amino acid N-terminal amino acid Carboxypeptidas e Intestine Aminopeptidase Intestinal mucosa Very few AA are present in the free form in the diet.5 to 8.5 to 8. Trp.5 7.5 Major site of action Arginyl.Specificity of Some Proteolytic Enzymes Enzyme Trypsin Chymotrypsin Pepsin Occurrence Intestine Intestine Stomach pH optimum 7. .5 to 8.

throenine Human disease Isoleucine. cystine Hartnup disease Cystinuria Glycinuria Uptake (transport) systems exist especially in intestine & kidney. Small neutral amino acids 2. phenylalanine Arginine. leucine. serine. . Proline. omithine. glycine 5. This can be partially overcome through uptake of peptides. lysine. tryptophan.Sterospecific Transport Systems for Amino Acids Amino acid specificity 1. Basic amino acids 4. Large neutral and aromatic amino acids 3. tyrosine. Lack of specific transporter results in a disease state. Acidic amino acids Glutamic and aspartic acids Amino acids transported Alanine. valine.

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] . TG for FA) but a certain percentage of muscle & structural proteins are “expendable”. • AA are used for proteins.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. N compounds.

Metabolic Pool of Amino Acids .

The three major draws on the amino acid pool are: 1 AA → Proteins (not covered here) 2 AA → Catabolism (NH4+ discarded. . then NH4+ incorporated into glutamine This synthesis is not compromised even when dietary P is decreased because they are essential for cellular function.whole/part AA integrated or .only the amino (N) group is used • AA catabolized. glutamine used) 3 AA → N containing compounds as .

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 Heme Choline Glycosamine Blood cell PL Sugar Nucleotides Protein synthesis Biogenic amines Carnitine Creatine phosphate DNA Protein Neurotransmitters Heart « Energy » .

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 .

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

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

Vitamins are needed in catalytic amounts (co-factors for enzymes) and therefore can be reused. All AA must be provided simultaneously (not hours after). 2. 3.Essential & Non-essential AA 1. Preparation is important: Because TRP → necessary to make niacin Corn + Alkali  absorption of nicotinate present in corn → niacin . 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. The difference between EAA & vitamins that is AA are needed in substrate amounts to make proteins and nitrogen compounds.

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

Aspartate Cysteine.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) Alanine. Glycine Histidine.Ketogenic: converted to ketone bodies 3. Valine Leucine Lysine . Glutamate Glutamine. Serine Threonine. Arginine Asparagine.Glucogenic: converted to glucose via pyruvate 2.Glycogenic and Ketogenic Amino Acids Glycogenic Glycogenic and Ketogenic Isoleucome Phenytolanine Tryptophen Tyrosine Ketogenic 1. Methionine Proline.Some are both 4.

ARG → urea synthesis ASP → urea synthesis GLU → conduit for disposal of N 3. Certain NEAA continue being synthesized even when adequate levels are supplied in diet because of a specialized role 2. 50% total body AA pool and is the major source to provide AA carbons → hepatic gluconeogenesis .Specialized Amino Acid Roles 1. 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.

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? .

(iv) Because free NH4+ is very toxic even at low levels therefore Pyruvate + NH4+ → ALA (non-toxic) (v) In liver: NH4+ → urea for excretion (i)Muscle: .Sources of Alanine (from 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).

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) .

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

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

Vitamin B12 E. Lysine 4.1. Is tryptophan an EAA? YES 3. Tryptophan 2. Pellagra is caused by a deficiency in A. Glutamic acid 3. Pyridoxal phosphate B. Ascorbic Acid C. Arginine 2. Sweet corn protein is deficient in 1. Niacin D. Riboflavin .

Only synthesized in animals 5. Essential fatty acids 4. The identical twin. Neither 4. High Biologic Value B. Bean proteins 2 Deficient in tryptophan C. An essential component of the body 2. Added vitamin C to his diet . who had no complaints 1.3. Not synthesized in adequate amounts in the body 4. Match the numbers with the following letters as appropriate: A. Mainly synthesized in plants 3. A vitamin is defined as a compound that is 1. Did not cook his food in water 4. Sweet corn protein 1. Both 3. Had sufficient tryptophan to biosynthesize niacin 2. Derived enough niacin from beans 3. Calorie value D.