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
Sources of nitrogen:
From ____ amino acids performed by glutamate dehydrogenase or glutaminase.
From ____ amino acids, via aspartate amino transferase
Deamination
Transamination
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+
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
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