Protein Metabolism II: Nitrogen Flashcards
control point of urea cycle
carbomoyl phosphate synthase I: mitochondria
uses 2/3 ATPs used in cycle
allosteric activation via n-acetyltransglutamate (synthesis dependent on Argenine)
allosteric activator of control enzyme in urea cycle
n-acetyltransglutamate
n-acetylglutamate synthase activated by arginine
Glutamine
Glu Dehydrogenase= control point
controls the direction of nitrogen removal/ incorporation of AA
Glu Synthase: Glutamate–> Glutamine for transport in liver to urea cycle
Alanine
transport in muscle; alanine/glucose cycle
pyruvate –> alanine: transport to liver
alanine –> pyruvate: gluconeogenesis back to muscle
Arginine
crosstalk and alternative reactions to urea cycle
NO synthase: Arginine –> citrulline + NO
Arginase: Arginine –> ornithine: produces creatine phosphate for muscle energy
Ketogenic
no net production of glucose
lysine & leucine are only ketogenic because their breakdown gives Acetyl CoA (2 carbons)
glucogenic
produces pyruvate or kreb cycle intermediates
oxaloacetate in kreb cycle from aspartate transamination
MSUD
deficient a-keto dehydrogenase
blocked oxidative carboxylation of branched AA (isoleucine, leucine, valine)
CNS deficits, Intelectual Disability, Death
buildup a-ketoacids in urine: sweet smelling
increased a-ketoacids in blood: especially leucine
MSUD Tx
restrict dietary leucine, isoleucine, valine
thiamine supplementation
hyperammonemia
acquired or hereditary from urea cycle enzyme deficiencies
excess NH4 depletes a-ketoglutarate –> Inhibition of TCA cycle
Ammonia Intoxication symptoms
tremor (asterixis) slurred speech somnolence vomiting cerebral edema blurred vision
hyper ammonemia treatment
limit dietary protein
Benzoate/ phenylbutarate: bind to AA and lead to excretion
Lactulose: acidify GI tract to trap NH4 for excretion
how to differentiate N-acetylglutamate deficiency from carbamoyl phosphate synthetase I deficiency?
Increased ornithine with normal urea cycle suggest n-acetylglutamate deficiency
ornithine transcarbamylase deficiency
most common urea cycle disorder (x-linked recessive)
usually presents first few days of life
increased orotic acid in blood/urine
decreased BUN
hyperammonemia symptoms
NO megaloblastic anemia bc different from orotic acuduria
Neomycin (oral)
can be used to treat hyper ammonia by reducing number of urease producing bacteria in the gut
Phenylbutyrate (prodrug)
phenylacetate (active drug)
combines with glutamine to form phenylacetylglutamine to be excreted in urine
assists in nitrogen clearance from blood
Tyrosine products
prohormone T4 and active hormone T3
TSH
stimulated iodide (I-) uptake and release of T3, T4 TBG (thyroxin binding globulin): transports T3, T4
rate limiting step in porphyrin production
aminolevulinate synthase: gly + sucinyl CoA –> Ala
mitochondria
decreased by Heme & glucose
increased by p450 inducers
enzymes effected in lead poisoning
aminolevulinate dehydrase (cytosol) 2ALA --> Porphobilinogen
ferrochelatase (mitochondria)
Protoporphyrin IV –> heme
Bilirubin in blood
via albumin
bilirubin in Liver
bilirubin –> bilirubin diglucuronide (conjugated bilirubin)
Bilirubin in intestine
bilirubin diglucuronide –> sterobilin
Relationship between Heme and aminotransferases
decreased heme = increased ALA synthase
Increased heme = decreased ALA synthase
*??Negative feedback
Lead poisoning substrates & symptoms
substrates in blood: protoporphyrin, ALA
microcytic anemia, GI/Kidney disease
Children: mental deterioration
Adults: headache, memory loss, demyelination
Acute Intermittent Porphyria
enzyme: porphobininogen deaminase
substrate: porphobilinogen, als, coporphobilinogen (urine)
Symptoms: 5Ps Painful Abdomen Port wine colored urine Polyneuropathy Psychological disturbances Precipitated by drugs, ETOH, Starvation
hepatic
treatment for Acute Intermittent Porphyria
glucose and Heme to inhibit ALA synthetase
drug relationship to porphyrias
Cytochrome P-450 inducers precipitate attacks because P-450 reduces Heme, which increases ALA synthase synthesis
results in increase of heme precursors
*relates to hepatic porphyrias
Prophyria Cutanea Tarda
most common prophyria
Enzyme: uroporphyrinogen decarboxylase
Substrate: uroporphyrin (red-brown urine)
Blistering cutaneous photosensitivity
mixed hepatic/ erythropoietic
