Amino Acid Metabolism

Amino Acids are Central to a number of different metabolisms

Dietary ProteinsAmino Acids Body Proteins or Amino Acids can give off NH3 to make urea/Keto Acids (ketone
& carboxylic acid provide carbons) to make CO2 + H2O, Fat, Glucose/Neurotransmitters Polyamines/Purines,
Pyrimidines, Heme, Niacin
Nitrogen used to make urea
Carbon used for synthesis of carbs/fat or used directly for energy
Several important small molecules are synthesized from amino acids

Protein Digestion
The diet contains few Free Amino Acidsmost are proteins & polypeptides which are not absorbed intact (except in
newborns)they must be broken down into smaller fragments via Proteases (break amide bonds)these are synthesized
& stored in an inactive zymogen state. Activated by cleavage of a portion of the proteinliberating an active enzyme
Endoproteases: cleave internal amide bonds
Exoproteases: cut bonds @ the N- or C-terminal residue of the polypeptide (aminopeptidases & carboxypeptidases)

3 Phases of Digestion
1) Gastric Phase Digestion: in the stomach
Proton-potassium pump H/K+ATPase (in Gastric Parietal Cell)
Is ATP dependent
Responsible for acidifying the stomach
The target of modern acid reflux drugs
Inhibitors: Omeprazole (Losec)/Esomeprazole (Nexium)/Lansoprazole (Zoton)/Pantoprazole
(Protium)/Rabeprazole (Pariet)
Pepsinogen (produced in gastric chief cells)
Autoactivates to become Pepsin & Pepsin autocatalytically forms more Pepsin (an acid stable acid
protease)
Cleaves denatured proteins into large peptides & amino acids (acid from parietal cells denatures protein to
be more susceptible to pepsin cleavage)
Pyrolic Sphincter controls release of peptides & amino acids into Duodenum

2) Pancreatic Phase Digestion: things which happen in small intestine as result of enzymes from pancreas
CCK-PZ from Amino Acid stimulated Duodonal endocrine cells
Is released to blood stream
Stimulates release pancreatic zymogens from acinar cells
Stimulates release of enteropeptidase from mucosal cells
Secretin from Duodenal Endocrine Cells
Is released to blood stream
Stimulates acinar cells to neutralize gastric acid w/ bicarb
Enteropeptidase cleaves Trypsinogen to Trypsin (intestinal mucosal cells make & secrete enteropeptidase)
Trypsin converts all pancreatic Zymogens to Proteases
Serine endo-proteases & zinc exo-peptidases each recognize & cleave @ specific amino acid
residues w/in the large peptides released into the duodenum
Pancreatic Acinar Cells Make & Store: Trypsinogen / Chymotrypsinogen / Proelastase / Procarboxypeptidase A&B
Trypsin is a Serine proteasethe catalytic step uses a serine side chain OH in the active site of enzyme to cleave the
peptide bond. It is also an Endo-proteaseit cleaves internal peptide bonds immediately following Lys or Arg (Lys-X
or Arg-X) (+ charged amino acids)
Chymotrypsin: a Serine protease & endo-peptidaseit cleaves following Trp/Tyr/Phe/Met/Leu (neutral/hydrophobic)
Elastase: a Serine protease & endo-peptidase cleaves following Ala/Gly/Ser (small neutral side chains)
Carboxypeptidase: A & B are Zinc proteases catalytic step @ zinc ion in active site of enzyme to cleave the peptide
bond. They are exo-proteasescleaving @ C-terminal residues
Carboxypeptidase A: can remove all C-terminal AA except Arg/Lys/ProArg & Lys have (+) side chains &
Proline is the only AA w/ 2ndary Amino group
Carboxypeptidase B: specifically removes C-terminal Arg & Lys

Summary of Gastric & Pancreatic Digestive Proteases
Protease Source Protease Family Proenzyme Activation Specificity
Pepsin (endo-) Stomach Aspartate Pepsinogen Autoactivtion/H+;Pepsin Aromatic
(Tyr/Phe/Trp)
Acidic (Glu)
Trypsin (endo-) Pancreas Serine Trysinogen Enteropeptidase
trypsin
Basic (Arg/Lys)
Chymotrypsin
(endo-)
Pancreas Serine Chymotrypsin Trypsin Bulky aromatic
(Trp/Phe/Tyr/Met)
Elastase (endo-) Pancreas Serine Prolastase Trypsin Small neutral R groups
(Gly/Ser/Ala)
Carboxypeptidase
A (exo-)
Pancreas Zinc Procarboxypeptidase
A
Trypsin Aromatic
(Tyr/Phe/Trp)
Hydrophobic
(Val/Leu/Ile)
Carboxypeptidase
B (exo-)
Pancreas Zinc Procarboxypeptidase
B
Trypsin Basic (Arg/Lys)
These active proteases break down the dietary proteins & polypeptides to ~40% free amino acids & ~60% small
peptides (2-8 residues)

3) Intestinal Phase: small intestine
Small peptides (2-8 amino acids residues) & AA continue to intestine
Intestinal epithelial cells make & secret aminopeptidases & dipeptidases these convert polypeptides to
1) free amino acids; 2) dipeptides; 3) Tripeptides
Amino Acids, di- & tri-peptides are transported into epithelial cells.
Co-transported w/ Na+ ions
Driven by Na+ ion Concentration gradient
Driven by electrical gradient
Inside epithelial cells Di- & Tri-peptidases finish the job making free individual amino acids (transported out of
epithelial into blood)

Phases of Digestion & Absorption of Protein & its Degradative Products
Phase of Digestion Location Agents Outcome
Gatric Digestion Stomach Stomach acid
pepsin
Denaturation
Large peptide fragments + some free amino
acids
Pancreatic Proteases Lumen of
small intestine
Trypsin, chymotrypsin,
elastase, &
carboxypeptidase
Free amino acids & oligopeptides (2-8AA)
Brush Border Surface Brush border
surface of
intestine
Endopeptidases &
Aminopeptidases
Free amino acids & di-/tripeptides
Absorption Intestinal
epithelial cell
brush border
membrane
Transport systems Uptake into epithelial cell
Cleavage of di-
/tripeptides
Transport to capillaries
Epithelial cell-
cytoplasm
Contraluminal
Dipeptidases
Tripeptidases
Facilitated diffusion
Free amino acids from di-/tripeptides

Amino acids transported into capillaries

Protein Nutrition
3 ways to test effectiveness of diff proteins
Method 1: measure ability of protein to prevent weight-loss in adult animalsfed a diet consisting of carbs, fat,
minerals (cows milk 100% of initial body wt vs. corn meal 30%)
Method 2: measure effect of protein on rate of growth of young animals (casein-milk best/most adequate growth-
wheat/gliadin no growth unless Lys added/zein-corn weight lossTrp added maintain wt or Lys added gain wt.
Remove Trp & Lys can result in death.
Most common deficiencies of plant proteins are Cys, Met, Trp, & Lysthese are present in low amount is plants
Rose & St. Julian fed rats: dextrin, sucrose, agar, salt, vitamins, lard, cod liver oil, 19/20 AAs & weighed daily
Essential AA: Arg/His/Iso/Lys/Leu/Met/Phe/Thr/Trp/Val (all are Required for Growth/can NOT be
synthesized by the body)
Histidine: is still controversial it does not appear to be required in adult human, but pathway for
synthesis has never been found (plenty stored in muscle)
Non-essential AA: Ala/Asn/Asp/Cys/Glu/Gly/Hydroxyproline/Pro/Ser/Tyr (all can be synthesized from
other AAs)
Method 3: Nitrogen Balance (Status) can be used to determine if an amino acid or type of protein is sufficient
for growth. By omitting it from diet to test whether essential or notmeasure amount N going in (protein
consumed & N going out (urea in urine). Normally Nin Nout = 0 (balanced!)
if essential AA are not replaced in dietary intake then protein synthesis (which usually requires all AA)
will not proceed/incorporation of AA from food into de novo synthesis of body protein is
blockedthe pool of AA (w/ 1 or more essential AA missing) will increase because they cannot be
incorporated into protein.
Breakdown (muscle tissue) continues & the buildup of AA leads to excessive breakdown of all AAs,
so the amount of nitrogen excreted is greater than the amount of protein digested (Negative Nitrogen
Balance).
Negative Nitrogen Balance: N in urine exceeds that ingested there is a net protein breakdown & diet
is inadequate w/ regard to 1 or more essential AA (Remove Met = (-)N & add it back balance re-
established) or (Remove Arg = N balance maintained. It is non-essential & readily synthesized in
liverit operates in a cycle & much of it is destroyed so in growing rat & human it is essential because
cycle does not provide enough Arg for growth needs

Protein in Foods
Complete Protein: protein source w/ all the essential AA in human nutrition in adequate amounts for human use
(animal protein except gelatin & soy protein)
Complementry Proteins: combos of 2 or more protein sources that provide all the essential AA when added
together (legumes, grains, combination)
Mutual supplementation: combining complete protein w/ incomplete protein is complementary (except milk
& legumes)
Food combining (complementary proteins @ each meal for vegetarian) is not necessarywhat counts is total
intake of complementary proteins spread over the course of the day
Incomplete: protein lacking or low in 1 or more of the essential AA (can not serve as sole source of protein in
diet/limiting AA is the indispensable AA present in the lowest quantity in food/most plants are incomplete except
Soy)
High-Quality Protein: an easily digestible complete protein
Limiting Amino Acid: essential AA that is present in dietary protein in the shortest supply relative to
amount needed for protein synthesis in body
Vegetarian: from a nutritional point of view only vegans are in jeopardy of protein-energy malnutritionmost
are well-educated about protein nutrition so they are aware of what to eat
Evaluation of Protein Quality
2 important Aspects:
1) Amino acid profile (compared to ideal pattern): AA, or chemical, score concept
2) Digestibility of Protein
Protein Digestibility Corrected Amino Acid Score (PDCAAS)

PDCAAS (%) = Mg of limiting AA in 1g of test protein x True fecal Digestibility (%)
Mg of same AA in 1g of reference or ideal protein

Types of Vegetarians
1) Lacto-ovo Vegetarians: include milk or milk products & eggs but omit meat/shellfish/poultry from diet
2) Lacto-vegetarian: include milk or milk products but exclude meat/fish/poultry/eggs from diet
3) Semi-vegetarian/partial vegetarian: include some but not all groups of animal derived foods in their diet usually
exclude meat & may occasionally include poultry/fish/shellfish
4) Vegans (aka strict vegetarians or total vegetarians): exclude all animal-derived foods (including
meat/poultry/fish/shellfish/eggs/cheese/milk
Other methods of Evaluating Protein Quality
Protein Efficiency Ratio (PER)
-Assesses wt gain of growing animals on particular protein source (rats/chicks)
-Diet containing ~10% protein is fed for 10days or so
-PER = wt gain (g) / protein consumed (g)
Biological Value
-Determine how much nitrogen of a particular protein source is retained compared to the amount of protein absorbed
Positive Nitrogen Balance: occurs when body accumulating significant amounts of proteinOnly measurable in
Growing Children & Pregnant Women
Rule on Thhmb: an adult on a normal diet requires in the range of 0.8 grams of protein per kg body wt(-)N
balance can occur when the body is under particular stress & total Nitrogen excretion is elevated in cases of burn,
injury, or sepsis

Considerations w/ Regard to Nitrogen Balance Determination
-Must make sure urine collection is a true 24-hr sample
-Energy & carb intake is an influencecarb is protein sparing (ex: a given amount of protein may allow nitrogen
balance when kcals are adequate, but may not if kcals are low)
-Quality of Proteinrequires smaller amounts of high quality protein to maintain N balance compared to lower quality
proteins
-Often overestimate nitrogen retention due to poor ability to estimate true nitrogen losses
-Says nothing about nitrogen in specific areas of the body or about amino acid balance

Biological Value
Similar to Nitrogen Status Concept
2 diets (1 w/ protein, the other protein-free) that are fed to either humans or animals for 7-10days
Urinary & fecal Collections are made
Maximum biological value = 100

Protein Intake Recommendations
RDA (Recommended Daily Value) = 0.8g/kg body wt for adults
No adjustment for strength trainingmany experts recommend up to 2.0g/kg, thoug
No adjustment for elderlysome research suggests higher protein requirements (perhaps 1-1.2g/kg)
Pregnancy & lactation: RDA + 25g/day
AMDR (Acceptable Macronutrient Distribution Range)
For protein, the top of the recommended range as a percentage of energy is 30%

Protein-Energy Malnutrition (PEM)deficiency of protein & food energy/worlds most widespread malnutrition
problemincluding Marasmus (severe deprivation, or impaired absorption of protein, energy, vits & minerals) and
Kwashiorkor (mal=bad, poor)
Dysentary: GI tract infection caused by amoeba or bacteriumgives severe diarrhea (dys=bad, entery=intestine)

Markers of Protein Status
Protein Normal Range life
Serum Albumin 3.0-5.0 g/dL 20days
Serum Transferrin 215-380 mg/dL 8-9days
Serum Transthyretin (pre-albumin) 15-36 mg/dL (OSU>17) 2-3days
Retinal binding protein 2.6-7.6 mg/dL 10-12 hours
3-methylhistidineproduced by muscle breakdown (not specific to skeletal, though)
Urinary creatine/Creatine height index

Clinical Connection:
Hyperammonemias: causeexcessive Glutamine
Acquired = liver disease leads to portal-systemic shunting
Inherited = Urea cycle enzyme defects of carbamoyl phosphate synthetase I or Ornithine Transcarbamolase Lead
to Severe Hyperammonemia
Disease Effects:
1) Entry of H2O to produce intracranial mass (Edema)
2) Dysfunctional Astrocytes
3) Hepatic Encephalopathy can result (in absence of Glutamate)
Gut bacteria are also a source of AmmoniaLactulose reduces production of Ammonia by gut flora
Urea is less toxic & is an effective disposal mechanism: 1) excreted in urine; 2) urea cycle disorders can necessitate low
protein diets
Common problems w/ system: 1) Elevated Ammonia (Urea Cycle is not functioning properlyliver problem); 2)
Elevated Blood Urea Nitrogen (Bun): Liver making urea, but kidney is failing to excrete it (so kidney problem)

How Do we know Proteins Turnover?
Give/feed N-Leu to rats
After 3 days take out liver, isolate & hydrolyze protein w/ HCL, analyze Amino Acids
Find N-Leu/N-Glu/N-Asp/N-Arg/N-Gly: nitrogen makes its way into other AA (Note: AA that are most highly
labeled Glutamic Acid, Aspartic Acid & Asparagine)
Study found that proteins are turned overconstantly being degraded & synthesizedin normal adult these
processes are balanced.
Diff proteins have diff turn-over rates

How Does N move from 1 AA to Another
If muscle extract is added to a mixture of N-Glutamte + PyruvateN-labeled Alanine is produced
& if muscle extract added to mixture of N-Alanine + -ketoglutaric acidN-labeled Glutamate produced.
The rxn is reversible & equilibrium constant is ~1
Transaminase catalyzed the rxnaka Aminotransferases (in older texts): there are specific transaminases for
most AAGlutamate/-Ketoglutarate is usually involved in a partner rxn

Transamination
Pyridoxal Phosphate (PLP): is ALWAYS a cofactor in transaminases (& other rxns involving AA)/it is derived from
Vitamin B6
Using phosphate it is bound to enzyme by non-covalent interactions
In absence of substrate, the aldehyde group forms a Schiff Base w/ the epsilon-amino group of a specific Lys
residue in the enzymethis is the idling form of the enzyme
When substrate is bound in the pocketthe Lys is released & the amino group of the AA reacts w/ the
Pyridoxal Phosphate to form a new Schiff Base
Keep in mind the following Points:
All 20 standard AA (except Lys,Pro,Thr) utilize transaminase @ some point in their metabolism (Not
Necessarily the 1
st
Step!!!)
-KG/glutamate exchange always accompanies the Amino-acid/keto-acid conversion
Clinical Connection:
Pyridoxine Deficiency: pediatric disease due to lack of Pyridoxine (or Vit B6)symptoms=seizures, irritability, cheilitis
(lip inflammation), conjunctivitis & neurologic symptoms. Suspected cause of seizures due to abnormalities in normal
ratio of Glutamic acid to GABA
Familial Pyridoxine-Dependent Epilepsy: causes seizures @ birth or shortly afterwards

What does Aldehyde of Pyridoxal Phosphate do?
It spontaneously undergoes rxn w/ amines to form Imines or Shiff Bases (rxn is a Reversible Equilibrium)

Deamination: Removal of Amino Group & No transfer of Amino Group to another compound
Transamination: Transfer Amino Group from 1 AA to Carbon Skeleton of Another (PLP dependent)
Some examples of Aminotransferases
a) Alanine Aminotransferase (ALT, SGPT)
b) Aspartate Aminotransferase (AST, SGOT)
c) Part of liver function test in lab panels (High blood Levels indicate Injury to liver)
Generally aminotransferases require Pyridoxal Phosphate (Vit B6) in its coenzyme form


PLP is a Cofactor for MANY rxns:
Especially rxns involving AAparticularly those that involve rxns @ atoms attached to -Carbon
Intermediate of rxns involving PLP: by attaching to the Amino group, it (along with the enzyme for which it is
a cofactor) can shift the double bond btw the amino group & -Carbon resulting in removal of hydrogen or
the carboxyl or of the amino group itself (depending on enzyme involved). For example: removal of carboxyl
group will generate the corresponding Amine (such as Histamine from Histidine) in a decarboxylase rxn
Activation of the C-R bond is observed in some aldolases. & PLP facilitates breakage of the C-H & C-N
bonds in transaminases.

Glutamate Dehydrogenase: most important enzyme for removal of N.
In the process of AA degradation, there must be net removal of N which eventually finds its way to urea
Transaminases provide shuffling of N from 1 AA to another, but do not provide net removal of N from AA pool
GDH is allosterically controlled & does NOT use PLP
(-)inhibited by High concentrations of ATP & GTP & -KG
(+)activated by High concentrations of ADP & GDPunder low energy conditions, -KG is supplied to the
TCA cycle & the whole process of deamination is accelerated.
Deamination of Glutamate by Glutamate Dehydrogenase usually occurs in Mito, using NAD+ as cofactor
Summary of N removal: coupling Transamination to Glutamic Dehydrogenase we get net removal of N from AAvia
Amino groups are transferred by specific transaminases coupled to ketoglutaric acid to generate glutamate, which in turn
is acted upon by GDH to remove nitrogen as Ammonia

Other ways to Remove N from AA
1) Glutamate Dehydrogenase (NAD-dependent)-most important
2) Glycine Synthase-minor pathway (the others below are quantitatively less important low N removed)
3) Serine Dehydratase: 1 of 2 pathways for Serine Metabolism (PLP-dependent)
4) Threonine Dehydratase: 1 of 3 pathways for Threonine metabolism (PLP-dependent)
5) Histidine Urocanate: conversion of His to Uro is the 1
st
step in the Only pathway for His metabolism. (Note:
PLP is not involved in this rxn)
There are other minor pathways found only in kidneys: L-Amino Acid Oxidase & D-Amino Acid Oxidase, both involve
Flavoprotein (No PLP!)

Transport of N in Circulation
Although AA catabolism is taking place in various tissues, we do NOT find significant amounts of Glutamate
or Ammonia in the circulation during a fast (amino is bad for you it brings decay)
In fasting rate Glutamine & Alanine are found in bloodunder conditions where much muscle protein is being
catabolized (disuse atrophy) the amount of Glutamine Synthetase increases significantly
In normal absorptive man there is continuous exchange of AA among organs, particularly for the return to Amino
Acid Nitrogen to liver
Most important AA of the group = Glutamine & Alaninethe Nitrogen of Amino A cid breakdown will be
transaminated to KG to make Glutamate

Glutamine Synthetase: will add Ammonia to Glutamate making Glutamine (in most tissues)
ATP Required
Amount of enzyme increases when muscle catabolism is occurring
This is an important process Ammonia is toxic to the Central Nervous System, so it must be immediately
converted to safer substance. In non-hepatic tissues the linked rxns of Glutamate Dehydrogenase & Glutamine
Synthetase remove 2 Ammonia (NH4+) molecules from the tissues as a way of ridding the tissues of N waste.
In muscle Pyruvate is converted to Alanine by Transaminase

Glucose-Alanine Cycle
Alanine can release Nitrogen Atom in the Liver by using:
(1) Another transaminase Rxn and
(2) The Glutamate Dehydrogenase Rxn
G-A Cycle as follows In muscle tissue there is plenty of Pyruvate around due to glucose metabolism.
Glutamate transfers amino group to Pyruvate to make Alanine & the remaining -KG goes into TCA cycle
Alanine carries a N atom to liverremaining Pyruvate is converted to glucosewhich is returned to muscle

Kidney Production of Ammonia (NH4+) for Excretion
Ammonia is secreted by the kidney @ the distal tubule as an Ammonium Ionthe ion is removed from kidney cell by a
Sodium-Ammonium Antiporter (Na+/NH4+). This follows successive removal of amino groups from Glutamine via
Glutaminase & Glutamate Dehydrogenase

Flow of N from AA to Urea in Liver
Once Glutamine reached the liver, the N is released from Glutamine in the form of Ammonia via Glutaminase.
(Glutamate Dehydrogenase can also work here, releasing Ammonia)
Amino Acid flow from muscle to liver
Alanine & glutamine
Liver
Transfers N to Glutmate via Glutaminase/Transaminases
Transfers Glu-N to Aspartate via Aspartate Transaminase (Transamination Route)
Transfers Glu-N to NH3 via Glutmate Dehydrogenase (Trans-deamination Route)
Transfers N to Urea

UREA CYCLE
Occurs only in the liver, partly in the Cytosol & partly in the Mito
Carbon atom of urea derived from CO2 (transported in circulation as Bicarb ions = more soluble)
Mito membrane has transporters for Ammonia, Bicarbonate, Ornithine, & Citrulline
1) Carbamoyl Phoshphate Synthetase-I (mito): catalyzes 1
st
step in the mito involving the fixing of both CO2 &
NH4+ into a metabolite called Carbamoyl Phosphate. Rxn utilizes 2 equivalents of ATP
2) Ornithine Transcarbamoylase (mito): converts ornithine/carbamoyl phosphate to citrulline releasing Pi
3) Argininosuccinate Synthetase (cytosol): converts aspartate/citrulline to Argininosuccinate (Using 1 ATP)
4) Argininosuccinase/Lyase (cyto): converts argininosuccinate to arginine & fumarate (returns to TCA cycle)
5) Arginase (cyto): converts arginine to Ornithine (back to mito) & Urea Released
Note:
Rxns where N enters the cycle & require ATP (step 1synthesis of Carbamoyl Phosphate & step 3
synthesis of Argininosuccinate
Also 1 nitrogen atom comes in as Aspartate the piece remaining after N removal is Fumurate, which enters
TCA & is converted to MalateOXA
A standard Transaminase rxn converts OXA to Aspartate, which can enter the Urea Cycle
Cycle as written uses 3 ATPs but in terms of ATP (High Energy) equivalents it is using 4because
Argininosuccinate Synthetase generates AMP instead of ADP. To return AMP to ATP requires 2 high
energy equivalents

5 enzymes=5 inborn Errors of metabolism in Urea Cycle all produce Hyperammonia. High blood NH4+ levels are toxic to CNS
Enzyme Disorder
Carbamoyl Phosphate Synthetase I Type I Congenital Hyperammonia
Ornithine Transcarbamoylase Type II Congenital Hyperammonia
Argininosuccinate Synthetase Citrullinemia
Argininosuccinate Lyase Argininosuccinate Aciduria
Arginase Arginemia

Allosteric Regulation of Carbamoyl Phosphate Synthetase-I (CPS-I)
Regulation of Urea Cyclecontrol is exerted @ 2 levels
1) Short-term: CPS-I is allosterically (+)activated by N-acetyl-glutamatethe synthesis of acetylglutmate is
allosterically controlled by the level of arginine (increased activity when Arginine level is high)
When proteins are degraded either in the liver or in the gut followed by transport in the circulation to the liver,
Arginine (& other AAs) will be @ higher concentrations.
Arginine will allosterically activate (+) Acetylglutamate Synthetase which in turn will activate (+)
CPS-Iprepparing the liver cell for metabolism of AAs
2) Long-term: the amount of all enzymes of the urea cycle are influenced by the amount of protein metabolized for
energy This controls the transcription of the urea cycle enzymes. Regulation @ this level takes 24-36 hours
Urea & TCA Cycles
The key Relationship:
1 of the urea N is supplied to the urea cycle as aspartic acidwhich is formed from the TCA cycle intermediate
OXA by simple transamination.
Carbons are then returned to TCA as Fumarateproduct of Argininosuccinate Lyase Rxn 4
The N for Aspartate comes from the following: Glutamine is returning to liver by circulation & is acted upon by
Glutaminase to produce Glutamatewhich then participate in the abundant Glutamic-OXA transaminase rxn to
produce Aspartic Acid for the Argininosuccinate Synthetase step in the cycle
Not only does Glutamate get formed from Glutamine, recall that the breakdown of most AAs, particularly
the abundant Alanine, occurs by way of Transamination w/ ketoglutarate to form Glutamate

Ammonia Detoxification by the Liver
Liver is very effective @ eliminating Ammonia from Blood
Portal blood Ammonia = 300uM
Systemic blood Ammonia = 20uM
Periportal Hepatocytes
Urea Synthesis
Perivenous Hepatocytes
Glutamine Synthesisvery low Km for Ammonia (high binding affinity)