Download Chapter 20-Amino Acid Metabolism

Chapter 20-Amino Acid Metabolism
→ The major source of amino acids is the diet. Humans can only synthesize 11 of the 20 common amino acids.
The other 9 (H I L K M F T W V) are essential. Arginine is essential only during growth. Tyr is not essential,
but only because it can be readily synthesized from the essential Phe.
→ No special storage compartment- all are in functional proteins- last to use as energy source
→Many of the amino acids can be synthesized from pyruvate,PEP (glycolysis), 3-phosphoglycerate (glycolysis)
or TCA cycle intermediates (see figure 16.14)
Example:
Pyruvate ⇔ alanine in 1 step
a-ketoglutarate ⇔ Glu →→→Arg
→ The amino acids are degraded by 20 different pathways that converge to just 7 metabolic intermediates (see
figure 21.13). These intermediates enter the TCA cycle to produce energy or be converted into glucose.
→Gly and three carbon to pyruvate
→4 carbon to oxaloacetate
→5 carbon to a-ketoglutarate
Amino Acid Transferases:
Can transfer amino groups between all the amino acids (except T and K). This involves the transfer of
an a-amino group from an amino acid to the a-keto position of an aketo acid.
Ala ⇔ pyruvate
Asp ⇔oxaloacetate
Glu ⇔ a-ketoglutarate
These reactions resemble redox reactions in that there must always be an amino donor and an amino acceptor.
Usually these reactions are coupled to glutamate/ a-ketoglutarate. These reactions are catalyzed by
aminotransferases.
Transport of nitrogen:
→ Apoptosis- programmed cell death- and protein turnover (majority of proteins turn over every few
days) lead to an excess of NH3 as proteins are degraded. Free NH3 is toxic . Most NH3 is transported in blood
as Gln or Ala (from the alanine cycle) to the liver.
Urea Cycle
Urea is produced in a 5 step process in the liver. The urea cycle was proposed by Krebs. Nitrogens in urea
come from NH3 and Asp. See figure 21.12 in book for the urea cycle. The urea cycle requires 4 ATP/cycle.
→Step 1: Carbamoyl phosphate is formed from ammonia, bicarbonate and ATP.
→Step 2: citrulline is formed from ornithine and carbamoyl phosphate by the enzyme ornithine
transcarbamoylase.
→Step 3: :arginosuccinate is formed from citrulline and Aspartic acid via a citrullyl- AMP intermediate by the
enzyme argininosuccinate synthetase. (This step requires 2 ATP)
→Step 4: Argininosuccinate is converted to fumarate (TCA int ermediate) and arginine by the enzyme
argininosuccinate lyase.
→Step 5: Arginine is hydrolyzed to form ornithine and urea by the enzyme arginase. The ornithine can then
combine with carbmoyl phosphate to begin the cycle again.
→ Note the "linking" of the Urea Cycle and the TCA cycle (the so-called Krebbs "bicycle").
→Steps 1 and 2 occur in the mitochondria, and steps 3-5 occur in the cytosol. There is a citruline/ornithine
exchange transpoter in the inner mitochondrial membrane.
→The urea then travels to the kidneys for filtration and excretion.
→The main regulation is controlled by need and diet. A high protein diet and starvation activate the cycle.
N-acetylglutamate activates carbamoyl phosphate synthase.
Metabolic Disorders:
NH3 is toxic because excess NH3 converts a-ketoglutarate to Glu. This results in a break in the TCA
cycle, reduced ATP, and leads to coma and death.
→The therapy to treat any metabolic disorders that result in a decrease in the urea cycle are (1) limit
protein intake, (2) remove excess NH3 with a compound the will bind the NH3 and be excreted, and (3) replace
TCA cycle intermediates.
Tyrosine Biosynthesis
Phe is converted to Tyr by phenylalanine hydroxylase. This is the biosynthetic pathway for making Tyr,
and this is the first step in the degradation of Phe.
→Phenylketonuria- autosommal recessive disorder in which phenylalanine hydroxylase is deficient.
The Phe can be degraded so it is converted to phenylpyruvate (transaminase reaction) which build up in the
body and causes irreversible brain damage.
Amino Acid Derivatives
→ Dopamine (neurotransmitter)- excess dopamine is responsible for psychotic symptoms and
schizophrenia, while lowered production of dopamine is a factor in Parkinson’s disease.
→Norpinephrine (neurotransmitter)
→Epinephrine (adrenaline) (neurotransmitter)
These three processes occur in the brain (see figure 26.50 for structures)
Tyr
Tyr
→Melanin- skin pigment
→thyroid hormone- stimulates β-oxidation in cells
Trp
→Seratonin- neurotransmitter in brain- causes contraction of smooth muscles of arterioles and
bronchioles (sleep inducing)
→Melatonin –produced in the brain- sleep inducing
→↑ amino acids in blood ↓ Trp to brain ↑ wakefulness
→↑carbohydrates causes ↑ Trp to brain ↑ sleepiness
Gly
Glutamate
His
→inhibitory neurotransmitter
→converted to GABA-inhibitory neurotransmitter
→histamine (decarboxylation)