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112 Cards in this Set
- Front
- Back
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where does the urea cycle occur?
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liver
(hepatocytes) |
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what is hyperammonemia?
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elevated ammonia in the blood
normal levels are 10-40umol/L |
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what is the normal level for blood urea nitrogen (BUN)?
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6-20 mg/dL
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what is the central molecule of nitrogen homeostasis (the primary nitrogen donor and acceptor)?
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glutamate
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what does it mean to "fix nitrogen"
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convert gaseous nitrogen to biomolecules
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what does the body use to regulate the pH of blood and urine?
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conversion of ammonia to ammonium via addition of a proton
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what is urea?
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a water soluble nitrogen waste product excreted in the urine
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what is creatinine clearance test?
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test which compares the level of creatinine in urine with that of creatinine in blood
(could also test volume of blood plasma that is cleared of creatinine per unit time) |
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what is uric acid?
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insoluble primary waste nitrogen product of purine bases
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what happens under metabolic acidotic contitions to adjust the pH?
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liver drives glutamate and ammonia into glutamine, which it then releases
kidney releases NH3 from glutamine NH3 attaches a proton pH increases |
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what are the three ubiquitous enzymes responsible for converting ammonia into amino acids?
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glutamate dehydrogenase (GDH)
glutamine synthetase glutaminase |
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what is the reaction catalyzed by GDH?
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glutamate dehydrogenase converts alpha-ketoglutarate and ammonia to glutamate and back
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what is required for the forward reaction of GDH?
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NADPH
proton ammonium alpha-ketoglutarate |
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what is required for the reverse reaction of GDH?
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NAD
glutamate |
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what are the allosteric activators of the forward reaction of GDH?
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ATP
GTP |
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under what conditions does the GDH reaction proceed in the forward direction?
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sufficient energy levels in cell
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under what conditions does the GDH reaction proceed in the reverse direction?
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low energy levels in cell
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what are the allosteric activators of the GDH reaction in the reverse direction?
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ADP
GDP |
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what is the important benefit to the reverse reaction of GDH?
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fill up TCA cycle
shunt energy into electron transport chain |
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what is the gateway molecule between free ammonia and amino groups of most amino acids?
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glutamate
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what reaction is catalyzed by glutamine synthetase?
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conversion of glutamate to glutamine
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what reaction is catalyzed by glutaminase?
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conversion of glutamine to glutamate
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what are glutamine synthetase and glutaminase responsible for?
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transport of tissue ammonia to liver and kidney
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which waste nitrogen product is eliminated via liver?
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urea
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which waste nitrogen product is eliminated via the kidneys?
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ammonia
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what is the advantage of glutamate as a nitrogen-waste-product collector?
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can tie up two moles of nitrogen per one mole of glutamate
nontoxic to the body |
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what is the role of glutamine in the circulation?
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to ferry ammonia to and from various tissues
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how does liver control flow of ammonia into glutamine or urea?
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compartmentalizing glutamate synthetase and glutaminase
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what amino acids do not participate in aminotransferase reactions?
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threonine
lysine |
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what is the nitrogen balance?
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ratio of amount of nitrogen ingested to the amount of nitrogen excreted
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what is positive nitrogen balance?
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more nitrogen is ingested than is excreted
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what is negative nitrogen balance?
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more nitrogen is excreted than is ingested
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when would one expect a patient to have a positive nitrogen balance?
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in growing state
growing children pregnancy convalescing adults refeeding after starvation |
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what is the definition of convalescing?
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Recover one's health and strength over a period of time after an illness or operation
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when would one expect a patient to have a negative nitrogen balance?
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starvation
disease states diet deficient in an essential amino acid |
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where is excreted nitrogen from in a well fed state?
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excess protein digestion
normal turnover |
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what do transamination reactions provide for the biosynthesis of urea?
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intermediates
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what does the oxidative deamination reaction of glutamate provide for the biosynthesis of urea?
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free NH3
alpha-ketoglutarate for energy |
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what are the four steps required for the biosynthesis of urea?
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transamination
oxidative deamination of glutamate ammonia transport urea cycle reactions |
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what are the six enzymes of the urea cycle?
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carbamoyl phosphate synthetase I
ornithine transcarbamylase argininosuccinate synthetase argininosuccinate lyase arginase N-acetylglutamate synthetase |
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what is the function of carbamoyl phosphate synthetase I (CPS I)?
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convert bicarb and ammonium to carbamoyl phosphate
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what are the two intermitochondrial enzymes of the urea cycle?
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CPS I
OTC |
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what is the function of ornithine transcarbamylase (OTC)?
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convert carbamoyl phosphate to citrulline
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what is the function of argininosuccinate synthetase (AS)?
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convert citrulline to argininosuccinate
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what is the function of argininosuccinate lyase (AL)?
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convert argininosuccinate to arginine
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what is the function of arginase?
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convert arginine to ornithine, releasing urea
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what is CPS II active in?
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nucleotide metabolism
same function as CPS I, but it takes nitrogen from glutamate rather than free ammonia |
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what is the only x-linked enzyme in the urea cycle?
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ornithine transcarbamylase
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by how much can enzymatic action of urea cycle enzymes increase in response to excess nitrogen in liver?
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up to 20-fold
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what are the two major mechanisms by which urea cycle is controlled?
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N-acetylglutamate
arginine |
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without what molecule is CPS-I nonfunctional?
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N-acetylglutamate
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what is the function of N-acetylglutamate synthetase?
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convert glutamate and acetyl-CoA into N-acetylglutamate
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how can you increase the limited action of CPS-I in patients with CPS-I deficiency?
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administer N-acetylglutamate
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how does arginine regulate the urea cycle?
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allosteric activator of N-acetylglutamate synthetase, which produces N-acetylglutamate to activate CPS-I
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what are the four minor regulators of the urea cycle?
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availability of ammonia or amino acids to liver
concentration of intermediates protein in diet starvation |
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which type of urea cycle disorders are the most severe or dangerous? when do they usually set in?
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neonatal presenting classes
onset is usually 24-72 hours after birth |
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what are the four types of neonatal onset UCDs?
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CPSD
OTCD ASD ALD |
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what is the most common neonatal UCD?
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ornithine transcarbamylase deficiency (OTCD)
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when are UCDs most severe?
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when occuring in CPSD (or OTCD)
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why are the symptoms lessened by getting to citrulline?
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some NH3 has been covalently linked
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how common are UCDs?
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1/25,000 births
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what are the symptoms of neonatal UCDs?
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convulsions
ataxia lethargy vomiting poor feeding coma |
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what are the symptoms of adult onset UCDs?
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hyperactivity
enlarged liver avoidance of high protein foods |
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what is the screening for UCDs? the confirmation?
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serum ammonia level
liver biopsy |
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what is the prognosis for patients with neonatal UCDs?
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undiagnosed - 100% mortality
diagnosed - fair chance of survival earlier diagnoses lead to better chance of preventing mental retardation |
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what are the causes of hyperammonemia in newborns?
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UCDs
organic acidemias transient hyperammonemia of the neonate herpes simplex |
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why is the presentation time of neonatal UCDs so bad?
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24-72 hours after birth (sometimes several days later)
symptoms present when patients are already home, and by time symptoms are bad enough to warrant (in parents' minds) a trip to the hospital, it is too late |
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what is transient hyperammonemia in the neonate?
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temporary (self-relieving) situation in which newborn has elevated levels of serum ammonia, which manifests at birth or shortly after
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why are neonatal UCDs so hard to predict?
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occurs in full-term infants with no obstetric risk factors
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what are the most prevalent symptoms of neonatal UCDs?
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infants become lethargic and require stimulation to feed
seizures coma |
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what are additional symptoms of neonatal UCDs?
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vomiting
hypothermia hyperventilation |
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in neonatal UCDs, how is hyperventilation often misinterpreted?
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pulmonary disease
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what is interesting in the workup for sepsis in a patient with a neonatal UCD?
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unrevealing
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what would be the only lab that would be informative (other than serum ammonia) in a patient with neonatal UCD?
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low blood urea nitrogen
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how is the bulging fontanel often misdiagnosed in patients with neonatal UCDs?
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intracranial hemorrhage
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in patients with neonatal UCDs, what causes a bulging fontanel?
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excess glutamine in brain cells osmotically draw water into cells, causing them to expand (and burst)
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what will be revealed in the CT scan of a patient with neonatal UCD?
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cerebral edema
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what are deaths caused by neonatal UCDs generally attributed to?
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sepsis
intracranial hemorrhage |
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what is cerebral edema?
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excess accumulation of water in intracellular and/or extracellular spaces in the brain
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when diagnosing neonatal UCD, what are the stages?
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symptoms between 24-48hrs post-partum
no acidosis or ketosis observed suspect urea cycle defect assay plasma citrulline evaluate next stage based on plasma citrulline |
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in a patient with suspected UCD, what does absent or trace amounts of plasma citrulline indicate?
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assay urine orotic acid
low - CPS I deficiency high - OTC deficiency |
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in a patient with suspected UCD, with absent or trace amounts of plasma citrulline, what does a low urine orotic acid indicate?
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CPS I deficiency
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in a patient with suspected UCD, with absent or trace amounts of plasma citrulline, what does a high urine orotic acid indicate?
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OTC deficiency
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in a patient with suspected UCD, what does moderately elevated plasma citrulline (100-300uM) indicate?
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assay plasma argininosuccinic acid (ASA) and ASA anhydrides
high - AL deficiency |
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in a patient with suspected UCD, what does severel elevated plasma citrulline (>1000uM) indicate?
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AS deficiency
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what is urine orotic acid?
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orotic acid is an intermediate in nucleotide biosynthesis, produced from excess carbamoyl phosphate after it leaves the mitochondria in OTCD
excreted in urine, because it cannot be used properly (too much) |
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what is the normal value for serum citrulline?
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approx. 30uM
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when is hyperammonemia likely to be caused by a neonatal UCD?
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if symptoms present >24hrs after birth
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which neonatal UCD is diagnosed by exclusion?
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CPSD
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what is the most important part of treating neonatal UCDs longterm?
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must balance protein
(enough for growth/development, but not enough to cause hyperammonemia) |
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what is categorized as type I hyperammonemia?
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carbamoyl phosphate synthetase I deficiency
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what is characterized as type II hyperammonemia?
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ornithine transcarbamylase deficiency
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what enzyme is also known as arginosuccinase?
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argininosuccinate lyase
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what is the only way to lower life threatening hyperammonemia?
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hemodialysis
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what is the most important guide to therapy of UCDs?
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plasma glutamine levels
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why are drugs not an effective method of treating life threatening hyperammonemias?
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can keep ammonia levels low, however action is too slow to use for immediate care
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how are CPSD and OTCD treated?
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increased dietary intake of citrulline
Na-phenylbutyrate |
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how is ASD treated?
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arginine
Na-phenylbutyrate |
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how is ALD treated?
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arginine
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what is the benefit of phenylbutyrate over benzoate in UCD treatment?
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phenylbutyrate can detoxify 2 moles of waste nitrogen per mole
benzoate can detoxify only one mole of waste nitrogen per mole |
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through what mechanism does benzoate detoxify nitrogen?
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binds to glycine (holds one nitrogen)
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through what mechanism does phenylacetate detoxify nitrogen?
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binds to glutamine (holds two nitrogens)
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what is Buphenyl?
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oral drug containing Na-phenylbutyrate
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what is ammunol?
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injectable drug containing Na-benzoate and Na-phenylacetate
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what causes neural defects in hyperammonemia?
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inc. NH3
inc. glutamate production dec. a-KG dec. OAA dec. TCA cycle activity permanent cell damage |
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how does hyperammonemia cause seizures?
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inc. NH3
inc. glutamate inc. glutamine dec. GABA seizures |
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what is GABA?
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gamma-aminobutyric acid
an inhibitory neurotransmitter, without which neurons fire uncontrollably (seizure) |
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how does hyperammonemia cause edema?
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inc. NH3
inc. glutamate inc. glutamine inc. water edema |
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what are the broad theories for treating UCDs?
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limit protein intake (replace with alpha ketoacids)
remove excess ammonia replace missing intermediates from cycle (arginine or citrulline) |
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what is the function of levulose?
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acidifies the colon
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how can antibiotics be used to remove excess ammonia from a patient?
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kill intestinal bacteria that produce nitrogen, so that nitrogen cannot be absorbed by intestine, therefore it doesn't get into body
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how do sodium benzoate and sodium phenylacetate remove excess ammonia from a patient?
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bind up glycine and glutamine
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