Urea Cycle Flashcards
The urea cycle is how the body gets rid of excess ____. The enzymes of the urea cycle convert nitrogen from ____ and ____ to urea, which can be excreted in the urine.
Nitrogen
Ammonium
Aspartate
_____ is a hallmark of disorders of the urea cycle
Hyperammonemia
The nitrogen that we eat can not be used as ____. Healthy adults are in nitrogen ____, over 24 hours they excrete as much nitrogen as they consume.
Fuel
Balance
Cachexia, anorexia, and Kwashiorkor causes ____ nitrogen balance
Negative
Nitrogen balance equation:
____% of nitrogen is excreted in the urine in the form of urea.
90
The intracellular amino acid pool depends on the balance between protein ____ and proteins ____, and uptake of amino acids from the circulating pool
Degradation
Synthesis
In a solution with a pH of 9.3 there will be equal concentrations of ___ __ and ___. They are toxic. Neuronal cells are particularly vulnerable. Symptoms of ammonia toxicity are ___, ___, ___ , etc.
Ammonium ion (NH4+)
Ammonia (NH3)
Lethargy, headache, seizures
____ can not cross membranes. ____ can cross the membranes.
Ammonium
Ammonia
Protein digestion and amino acid turnover:
Dietary protein is digested down to a single ___ ___ in the gut and intestinal epithelial cells. Amino acids enter the blood and are transported to the ____.
Amino acid
Liver
Transport of amino acids from the gut lumen into intestinal epithelial cells is by ____ ___ ___. Transport of amino acids across other membranes is by ___ ___.
Secondary active transport
Facilitated diffusion
Key amino acids and their transamination/deamination partners:
Nitrogen metabolism in the Fed state:
Insulin promotes the storage pathway for amino acids, which is ___ ___. Gluconeogenesis amino acid can also be converted to ___ ___ and stored as _____.
Protein synthesis
Fatty acids
Triacylglycerol
Nitrogen metabolism in the fasted state: (breakdown of stored fuels)
In muscle cells, side chains from ___ ___ amino acids are used as a fuel in the TCA cycle. Other amino acids enter the circulation. ____ is a key glucogenic amino acid.
Branched chain
Alanine
The ___/____ cycle allows amino acids to be used as fuel by muscle cells. _____ acts as the universal amine acceptor, forming glutamate. Glutamate donates the amine to ____, forming ___.
Alanine is transported to the liver . Alanine’s carbon is used for gluconeogenesis and the ____ is converted to ___.
Alanine/glucose
Alpha ketoglutarate
Pyruvate
Alanine
Nitrogen
Urea
Glutamine transports ammonium nitrogen to the liver:
____ ____ and ___ ___ can add a free ammonium to glutamate to fix it as glutamine. These reactions require energy in the liver. The reactions are reversible to release free ____.
Glutamate dehydrogenase (GDH)
Glutamine synthase
Ammonium
Glutamate can be converted to alpha ketoglutarate by ___ ____. This enzyme can use either NAD plus or NADP plus as the electron acceptor/donor.
Glutamate dehydrogenase
Alanine donates nitrogen to the urea cycle through ____ ____ which converts alpha ketoglutarate to glutamate.
Then, glutamate dehydrogenase makes _____ or aspartate amino transferase makes _____.
Alanine aminotransferase
Ammonium
Aspartate
The urea cycle overview:
_____ plays a similar role as oxaloacetate in the TCA cycle. Nitrogen enters the cycle as free ___ and as ___.
Ornithine
Ammonium
Aspartate
Another picture of the urea cycle:
The liver has a high capacity to fix ____ as urea. The availability of ____ is the main regulator of urea cycle flux (feedforward regulation).
Nitrogen
Substrates
The urea cycle is also modulated by allosteric regulation of ____ and transcriptional regulation of urea cycle ____.
CPS-1
Enzymes
Sources of nitrogen:
From ____ amino acids performed by glutamate dehydrogenase or glutaminase.
From ____ amino acids, via aspartate amino transferase
Deamination
Transamination
Urea cycle disorders manifest as ____ and _____. Neurons are particularly sensitive. Glutamate depletion prevents synthesis of ___. Symptoms include:
Hyperammonaemia
Hyperglutaminaemia
Neurotransmitters
Refusal to eat, protein aversion, seizures, irritability, lethargy, ataxia, tremors, and FTT
The urea cycle may be dysfunctional to an inherited mutation in one of the genes encoding urea cycle enzymes, resulting in ____, increased ammonium. The urea cycle may also be dysfunctional secondary to ___ ___.
Hyperammonemia
Liver damage
To measure free ammonia in a patient, incubate blood with recombinant ___, ____, and ____. NADPH absorbs UV light, so absorption ____ as it oxidizes. The decrease in light absorption is proportional to the concentration of ___.
GDH, alpha ketoglutarate, NADPH
Decreases
NH4+
Measuring free ammonium in the blood urea nitrogen (BUN) uses a ____ to measure decrease in NAPDH
Spectrophotometer
The urea cycle regulation by arginine:
Arginine ____ synthesis of N-acetyl-glutamate (NAG). NAG acts as an ___ ____ of carbamoyl phosphate synthetase I.
Increases
Allosteric activator
When arginine builds up, it increases ____ synthesis which activates _____. Arginine also increases ___ activity.
NAG
CPS-1
Arginase
There are ___ enzymes of the urea cycle. ___ disorders that all manifest as elevated NH4+
Seven
Seven
Diagnosing disorders of the urea cycle: Orotic acid:
Carbamoyl phosphate is a substrate for both ____ ____ in the urea cycle and ____ ____ ____ in Pyrimidine synthesis.
Elevated urinary __ ___ is a characteristic of urea cycle disorders downstream of CPS-1
Ornithine transcarbamoylase (OTC)
Aspartate carbamoyl transferase
Orotic acid
If ornithine transcarbamoylase (OTC) is mutated, there will be highly elevated urinary ___ ___.
Orotic acid
If there is a mutation in ____, there will be small or no elevation in urinary Orotic acid
Arginase
If there is a mutation in CPS-1, there will be ___ ____ in urinary Orotic acid
No elevation
In arginosuccinate synthase deficiency, ____ becomes elevated. The classical form presents in neonates as ____, ___ ___, ___ ___, and death.
Citrulline
Lethargy
Poor feeding
Neurological symptoms
In hyperammonaemia, hyperornithaemia, homocitrullinaemia syndrome (HHH syndrome), the ornithine/citrulline anti porter ____ is defective.
SLC25A15
Clinical decision making for a newborn with hyperammonaemia:
Treatment of inherited urea cycle disorders:
The goal is to decrease blood ___ by eating a low ___ diet.
NH4+
Protein
Treatment:
____ and ___ ___ are used to make amino acids excretable in the urine. These drugs are considered nitrogen scavengers.
Phenylbutyrate
Benzoic acid
Benzoic acid is first linked to ____ _ to activate it. It then can bond to glycine to make ___ ___, which is soluble enough to be secreted in the urine.
Coenzyme A
Hippuric acid
Phenylbutyrate is oxidized to ____, which is linked to coenzyme A. Coenzyme A is then displaced by ____ to make phenylacetylglutamine, which is soluble enough to be excreted in the urine.
Phenylacetate
Glutamine
Treatment of disorders:
____ can be used to regenerate ornithine in the case of arginosuccinate lyase deficiency. ___ also Allosterically activates NAG synthetase.
Arginine
Arginine
Arginine can also be converted into the polyamines, ____ (3 nitrogens) and ____ (4 nitrogens). Both can be eliminated by the urine.
spermidine
Spermine
_________ is an analog of N-acetyl-glutamate. It can be used to treat NAG Synthase deficiency.
N-carbamoyl-glutamate
Clinical case:
Arginosuccinate synthetase deficiency
(Aka citrullinemia)
Diagnostic flow for argininosuccinate synthetase deficiency:
In HHH syndrome, the rational for arginine treatment is to generate ____ (and creatine) which can be urinated out to eliminate nitrogen.
Spermine
____ nitrogen balance is taking in more nitrogen than they are losing. Such as in pregnancy.
____ nitrogen balance is losing more nitrogen than you are taking in. Can happen in trauma or lack of nutrition.
Positive
Negative
The urea cycle is generally happening in the ___ state.
Fasted
____ and ___ are the main transporters of nitrogen
Alanine
Glutamine
Normally, we don’t have a lot of ___ ___ around. Only during nucleotide synthesis is ___ ___ present
Orotic acid
Orotic acid
Review
If patient presents with elevated ammonium, elevated ornithine, and elevated homocitrullinuria. No Orotic acid was measured:
_____ syndrome
HHH
