Download 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
• 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
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%), ammonia, uric acid or
creatinine in urine with small amounts in fecal matter
(undigested)
Positive Nitrogen Balance
Negative Nitrogen Balance
1. Stress
2. Decreased Intake
3. Lack of an essential AA
Specificity of Some Proteolytic Enzymes
Enzyme
Occurrence
pH optimum
Major site of action
Trypsin
Intestine
7.5 to 8.5
Arginyl, lysyl bonds
Chymotrypsin
Intestine
7.5 to 8.5
Pepsin
Stomach
1.5 to 2.5
Aromatic amino acyl
bonds (Phe, Trp, Tyr)
Wide range of specificity
Carboxypeptidas e Intestine
7.5 to 8.5
C-terminal amino acid
Aminopeptidase
Intestinal
mucosa
N-terminal amino acid
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.
Sterospecific Transport Systems
for Amino Acids
Amino acid specificity
Amino acids transported
1. Small neutral amino
acids
Alanine, serine, throenine
2. Large neutral and
aromatic amino acids
Isoleucine, leucine, valine,
tyrosine, tryptophan,
phenylalanine
Arginine, lysine, omithine,
cystine
3. Basic amino acids
4. Proline, glycine
5. Acidic amino acids
Human disease
Hartnup disease
Cystinuria
Glycinuria
Glutamic and aspartic 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.
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]
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,
glutamine used)
3 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.
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
Nucleotides
Blood cell
PL
Sugar
DNA
Protein synthesis
Biogenic amines
Protein
Neurotransmitters
Carnitine
Heart
Creatine phosphate « 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
Summary of Protein Metabolism
a) α keto 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
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
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  absorption of nicotinate present in
corn → niacin
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 (phenylketonuria) 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
Glycogenic and Ketogenic
Amino Acids
Glycogenic
Glycogenic
and Ketogenic
Ketogenic
Alanine, Arginine
Asparagine, Aspartate
Cysteine, Glutamate
Glutamine, Glycine
Histidine, Methionine
Proline, Serine
Threonine, Valine
Isoleucome
Phenytolanine
Tryptophen
Tyrosine
Leucine
Lysine
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)
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
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?
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).
(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 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, 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
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.
1. Sweet corn protein
is deficient in
1. Tryptophan
2. Glutamic acid
3. Lysine
4. Arginine
2. Is tryptophan an EAA?
YES
3. Pellagra is caused by
a deficiency in
A. Pyridoxal phosphate
B. Ascorbic Acid
C. Niacin
D. Vitamin B12
E. Riboflavin
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