14: Amino Acids Metabolism Flashcards
Why is ammonia toxic, what are the symptoms and how it is treated?
Seen in Liver Failure & inborn errors of metabolism.
Effects are on the nervous system: dizziness, coma, convulsions. Also seen are Irritability, Vomiting, Lethargy & confusion, Respiratory distress, Migraines.
What is the biochemistry behind ammonia toxicity?
- Brain glutamate dehydrogenase forms glutamate from α-ketoglutarate and NH3, lowering brain pools of α-KG; hence, flux through the TCA cycle is reduced.
- Increased glutamate leads to increased glutamine from the excess NH3. Brain pools of Glutamate decrease. Glutamate is a neurotransmitter in the brain and is a precursor of γ- aminobutyric acid (GABA). GABA Levels in the brain fall, GABA is an inhibitory neurotransmitter in the brain.
- Glutamine leaves brain neurons in exchange for tryptophan. Trp is converted to serotonin (5-hydroxy-tryptamine), a neurotransmitter. High serotonin is thought to be an important factor in coma associated with liver failure.
Summary: Uncontrolled changes in the levels of 3 neurotransmitters (glutamate, GABA and serotonin) in the brain.
What is glucogenic and ketogenic?
Amino acids may be categorized by the final product of the pathways of their degradation, which can be glucogenic or ketogenic.
Ketogenic = amino acids are degraded to either acetyl coenzyme A or acetoacetyl CoA, which give rise to KETONE bodies.
Glucogenic = amino acids are degraded to pyruvate or citric acid cycle intermediates, which can give rise to GLUCOSE via formation of phosphoenolpyruvate.
Where do the carbon backbones of individual aa come from and end up?
Glucogenic amino acids can provide an excellent source of glucose after glycogen stores are gone. Remember that certain organs like the brain are highly dependent on glucose as an energy source.
Remember that the carbons in ketones and acetyl-CoA can not be converted into glucose, only into fatty acids.
Leucine and Lysine are the only ketogenic = LL
all the Ts [tryptophan, tyrosin, threonine] + Phenylalanine & Isoleucine are ketogenic and glugogenic = TTTIP
all others are glucogenic only
See rxn D pg. 6
What is Maple Syrup Urine disease and the biochemistry behind it?
BCAA’s = Valine, leucine, and isoleucine. All three keto acids are recognized by a common enzyme, branched-chain keto acid dehydrogenase, which catalyzes the oxidative decarboxylation of these molecules.
Maple syrup urine disease (branched chain ketoaciduria) is caused by a defect in
BRANCHED-CHAIN KETO ACID DEHYDROGENASE. The build up of these keto acids give the urine a characteristic odor for which the disease is named. Treatment includes dietary RESTRICTION of these BCAA’S. In addition some patients will respond to high doses of THIAMINE.
I Love Vermont Maple Syrup
[Isoleucine Leucine Valine] metabolism blocked in Maple Syrup disease.
What are the different types of PKU, how is it treated?
Tyrosine is formed by the hydroxylation of phenylalanine
Enzyme: Phenylalanine hydroxylase
Cofactor: Tetrahydrobiopterin
PKU- Phenylketonuria is a genetic disorder associated with the inability to catalyze the hydroxylation of phenylalanine and the subsequent accumulation of toxic derivatives of phenylalanine such as phenylpyruvate = mutation in the gene for enzyme phenylalanine hydroxylase (PAH). If not diagnosed early, severe mental retardation will occur in infants.
Treatment- phenylalanine restricted diet until the age of at least 16y/o.
Atypical PKU- caused by a defect in the dihydrobiopterin reductase, no treatment
For women with phenylketonuria, it is essential for the health of their children to maintain low Phe levels before and during pregnancy.[33] Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta.
Tyrosine is an essential amino acid in patients with PKU.
What is tetrahydrobiopterin?
Cofactor for Phenylalanine hydroxylase that does Phe to Tyr: This really a two step reaction that uses BH4 as a cofactor. The NADH is then used by another enzyme BH2 reductase to convert it back.
Tetrahydrobiopterinis oxidized to dihydrobiopterin during this reaction and must be regenerated by another enzyme, dihydrobiopterin reductase, which uses NADH as a reductant.
What is Alkaptonuria?
Homogentisate is converted to 4-maleylacetate by Homogentisate oxidase.
Defect in homogentisate 1,2-dioxygenase enzyme = Alkaptonuria
Homogentisate is secreted in the urine and causes the urine to darken upon exposure to the air. Cause no other symptoms, but later in life it may lead to arthritis. This is oxidized to a black color, and is deposited in the bones and cartilage, hence the increased risk of arthritis. Can be diagnosed by looking at the ear lobes with a light.
ALKA = BLACK
What is so important about serine?
Serine is a major source of 1- carbon groups through the serine hyroxy methyl transferase reaction.
Hence we can funnel 1-carbon groups directly from glycolysis to where we need them.
Why do we need arginine for growth?
When we synthesize arginine, we make ornithine and then run it through the urea cycle. You can synthesize arginine, but during growth or positive nitrogen balance you need extra, since in the liver it constantly be degraded to ornithine and urea.
Why is tryptophan so important?
Tryptophan is an important precursor of the neurotransmitter serotonin and can contribute to the pool of pyridine nucleotide coenzymes (niacin). Deficiency of tryptophan can lead to a niacin deficiency (Pellagra = 4D’s).
