Protein Metabolism II - Madura 3/11/16 Flashcards
B1 carbon chain classification
ketoacids have been classified based on feeding diabetic mice diets high in specific a.a.s and checking their urine…
- ketogenic : yield acetoacetate (low egy yield)
- glucogenic : yield TCA cycle intermediates (high egy yield)
*all a.a.s can give rise to ketogenic pdts!
also classify them as essential and non-essential
B2 alt uses for amino acids
C donor molecules
1. Met + ATP → S-adenosylmethionine (SAM)
- binding adenosine makes the methyl group labile
- no high egy P in this compound (all three P groups are lost in rxn)
2. tetrahydrofolate (THF)
methyl needed for making methylated DNA/RNA, epi, phosphatidylcholine, melatonin
methyl donor rxn is irreversible
B2. utilization of SAM, fate of pdt
SAM donates methyl group → S-adenosyl-homocysteine
- S-adenosyl-homoCys drops the adenosine → homocysteine
- two fates:
- homoCys → Cys
* cofactor: pyridoxal phosphate (B6), needed in 2 indep steps - homoCys → Met
* cofactor: methylcobalamin (B12) - charged by methyl-THF
B2. THF
versatile intermediary in C mobilization
- how methyl group joins THF and what type of bond it forms determines the pathway it goes into
- N5 and N10 play key roles in binding C
- different sources of carbon form diff linkages of C which determine diff destinations for C
folic acid is key vitamin precursor of THF
C1 urea cycle disorders → ammonia tox
CPS1 defect or N-acetylglutamate synthase defect → ammonium buildup → ammonium toxicity
- low levels: symptoms similar to alcohol intox
- high levels: death
- chronic low dose: mental retardation
another potential pathway: kidney failure → urea buildup → urea into int lumen → bacterial urease metabolize to ammonium → moves into circ → ammonium tox
C3 phenylketonuria
phenylalanine → tyrosine [Phe hydroxylase]
- in PKU, get a buildup of Phe → conversion into other molecules → toxicity
- diff mutations with diff severity/penetrance
- mutations in genes expressing cofactor willalso interfere with Phe → Tyr
C4 Blue Diaper Syndrome
failure to absorb Trp in intestine
- Trp hydrolyzed by bacteria → indole [blue!]
cystinuria
defect in prox intestine transporter: impaired abs of cystine and dibasic a.a.s (Lys, Arg, ornithine)
- cystine stones in urinary tract
C6 polycystic kidney disease
autosomal dominant or spontaneous
diagnosis: high creatinine and urea in blood
failure to reabsorb amino acids → fluid-filled cysts develop off of nephron and keep growing
- cysts block the flow of urine → pools of urine (infection), increased incidence of HTN
- 20% develop kidney stones
halfway through Madura2, questions - answer them
synthesis of catecholamine neurotransmitters
step 1
catecholamine nts: dopamine, norepi, epi
- always 2 OH groups present
Phe → Tyr →→→ catecholamines!
- Phe→Tyr, catalyzed by Phe hydroxylase (tetrahydrobiopterin cofactor)
will/how will PKU affect levels of catecholamine neurotransmitters?
PKU messes with Phe hydroxylase
- can’t turn Phe → Tyr [Phe hydroxylase; tetrahydrobiopterin cofactor]
- Phe buildup, Tyr deficiency!
- could mess with catecholamine synthesis, but usually solved by dietary restriction (Phe)/supplementation (Tyr)
synthesis of catecholamine neurotransmitters
step 2, step 3
Tyr → DOPA (dihydroxyphenylalanine)
- catalyzed by Tyr hydroxylase (tetrahydrobiopterin cofactor)
DOPA → dopamine
- catalyzed by aromatic amino acid decarboxylase (pyridoxal phosphate cofactor)
dopamine and associated diseases
Parkinson’s disease
degeneration of substantia nigra cells → loss of dopaminergic neurons → loss of dopamine
tx: L-DOPA to increase dopamine levels
- efficacy drops over time due to progressive loss of dopaminergic cells
schoziphrenia
dopamine excess
synthesis of catecholamines: full set of sequential rxns
Phe → Tyr → DOPA → dopamine → norepi → epi
- sequential set of rxns
- mess with one step, will see downstream effects too (epistatic)
