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