Flashcards in Unit 6 - Amino Acid Metabolism Deck (39):
what are effects of ammonia intoxication of inborn errors of metabolism?
primarily on nervous system, leading to dizziness, coma, and convulsions
what are possible mechanisms of ammonia toxicity? (3 main neurotransmitters)
1. brain glutamate dehydrogenase forms glu from a-KG and NH3, lowering brain pools of a-KG, so flux thru TCA is reduced
2. increased glu causes increased gln from excess NH3, causing brain pools of glu to decrease, so less GABA can be made
3. gln leaves brain neurons in exchange for trp, which is converted to serotonin, which is important in liver failure-associated coma
thus uncontrolled changes in nt glu, GABA, and serotonin
what are symptoms of ammonia toxicity?
irritability, vomiting, lethargy/confusion, respiratory distress, migraines
how are AA carbon skeletons degraded?
1. removal of nitrogen
2. disposal of C skeletons to harvest energy
how are AA categorized in regards to degradation?
1. ketogenic: degraded to either ACoA or acetoacetylCoA to make ketone bodies
2. glucogenic: degraded to pyruvate or TCA intermediates to give rise to glucose via formation of PEP
-provide excellent source of glucose after glycogen stores are gone
what can carbons in ketones and ACoA be converted into?
fatty acids, NOT glucose
which amino acids are ketogenic, glucogenic, and both?
K: leucine, lysine
G: alanine, serine, cysteine, glycine, arginine, histidine, glutamine, proline, glutammate, valine, methionine, aspartate, asparagine
B: isoleucine, phenylalanine, threonine, tryptophan, tyrosine
what 5 AA are converted to pyruvate? how? which one is the major one?
1. alanine: ala + a-KG pyruvate + glu
2. serine: ser --serine dehydratase--> NH4 + pyruvate
3. cysteine: cys --> --> --> pyruvate + H2S
-uses multi-step desulfhydrase
4. threonine: thr --> --> gly in important RXN
5. glycine: gly ser in important RXN
-serine hydroxylmethyl transferase
first three are 3-C AA; gly 2C; thr 4C
what is alanine transaminase used for?
serum marker for liver damage
what 2 AA are converted to OAA? how?
asn and asp
1. asn + H2O --asparaginase--> asp + NH4+
2. asp + a-KG glu + OAA
why is threonine an essential AA?
its conversion to glycine (and eventual pyruvate) is one way, via threonine dehydrogenase
what 5 AA are converted to glutamate, which is then converted to alpha-ketoglutarate?
2. histidine - uses THF, and in one direction, so essential (multistep RXN)
last 2 are linked together
why is extra arginine needed during growth or positive N2 balance?
liver constantly degrades it to ornithine and urea
what are the 3 branched AA, and how/what are they converted to? what happens to these products?
val, leu, and ile converted to corresponding alpha-keto acid by branched chain AA transaminase
-keto acids are recognized by common branched-chain keto acid dehydrogenase that uses lipoamide, B1 pyrophosphate, FAD, and NAD (like pyruvate dehydrogenase)
what does branched chain AA transaminase deficiency cause?
increased insulin sensitivity, increased PRO turnover (b/c more leucine), decreased fat and body weight, and increased energy
what does branched chain keto acid dehydrogenase defect do?
causes maple syrup urine disease (branched chain ketoaciduria)
-build up of keto acids gives urine a characterstic odor
-treated with restriction of these AA (with just a little b/c essential), and high doses of B1
what AA are catabolized to SCoA?
met, ile, and val
-different pathways to make mmCoA to make SCoA
how is tyr formed from phe?
hydroxylation via phe hydroxylase
-uses cofactor tetrahydrobiopterin (gets oxidized to dihydrobiopterin, and is regenerated by dihydrobiopterin reductase with NADH as reductant)
what is phenylketonuria?
genetic disorder that is now tested for at birth (1:15,000)
-cannot catalyze phe hydroxylation (phe hydroxylase defect), so accumulate toxic derivatives like phenylpyruvate
-if not diagnosed early, get severe mental retardation
-treat with phe-restricted diet until 16 years old (brain is no longer developing)
what is atypical PKU and maternal PKU?
A: caused by defect in dihydrobiopterin reductase (cannot regenerate tetrahydrobiopterin from dihydrobiopterin, so cannot hydroxylate phe)
M: caused by high in utero levels in mother with PKU, who are not being treated
what does dihydrobiopterin reductase do? what would a defect in this cause?
dihydrobiopterin + NADH + H+ --> NAD+ + tetrahydrobiopterin
-so BH4 can be used for phenylalanine hydroxylase again
-defects cause atypical PKU
what does homogentisate (homogentisic acid 1,2) oxidase do? what happens if there's a defect? how is it diagnosed?
homogentisate + O2 --> 4-maleyl-acetoacetic acid
-defects cause alkaptonuria, where homogentisate is secreted into urine, and darkens upon exposure to air to cause black urine
--black oxidation also deposited in bones and cartilage, causing increased risk of arthritis
--can be diagnosed by looking at the ear lobes with a light
catabolism of tryptophan
-what can deficiency cause?
trp is only used sparingly as a component of PRO, so catabolism isn't significant to make glucose
-but trp is used as serotonin precursor, and used as cofactor to make N3
-deficiency related to pellegra
--body conserves it b/c not abundant in food sources
catabolism of lysine
complex, and eventually leads to ACoA production (so ketogenic AA)
-not very highly degraded
what are the 11 nonessential AA that can be made in mammals?
how is alanine made in the body?
made from pyruvate in transamination reaction (ala transaminase)
how is apsartate made in the body?
made from OAA in transamination RXN (asp transaminase)
how is asn made in the body?
amidation of aspartate
what are the 3 methods to add NH3 to molecules?
2. asp --> fumarate
3. gln --> glu
how is glu made in the body?
-reductive amination of alpha-KG by glu dehydrogenase
-transamination of a-KG by almost any other AA
how is gln made in the body?
amidation of glu
-also picks up free ammonia
how is arg made in the body?
formed during urea cycle from ornithine, which is made from glu
how is pro made in the body?
formed in 2 steps from glu
how is ser made in the body?
formed in 3 steps from 3-phosphoglycerate (intermediate of glycolysis)
what is serine a major source of? what does this do?
1-carbon groups via serine hydroxy-methyl transferase reaction
-funnels 1-C groups directly from glycolysis to where we need them
how is gly made in the body?
made from serine in reversible reaction via serine hydroxymethyltransferase, with B6 and THF as cofactors
how is cys made in the body?
from serine and methionine, so only nonessential if met is provided in diet
how is tyr made in body? what about PKU patients?
from phe, so only nonessential if phe is provided in diet
-tyr is essential if PKU