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AA degradation & Urea Cycle II


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What is the purpose of the urea cycle?
To get the nitrogen from AA degradation out of the body (it's toxic otherwise).
Where does the urea cycle occur?
In liver - cytosol and mitochondria
In what form is Ammonia transported to liver from extrahepatic tissues?
By 4 transport amino acids:
-Gln, Ala, Ser, Arg.
How is free intestinal ammonia delivered to the liver?
Via the hepatic portal vein
What happens to urea after its synthesis?
Released into blood and sent to kidney for excretion.
3 ways to get NH4+ into Liver Cytosol:
1. Extrahepatic tissues send glutamine (2 NH4 groups)
2. Liver AAs give NH3 to a-KG -> Glu (aminotransferase)
3. Muscle sends Alanine; gives NH3 to a-KG -> Glu + Pyruvate
Enzyme that converts Glutamine to Glutamate Gln in liver mitochondria:
What is needed?
What is produced?
-Needs H2O
-Produces NH4+ and Glutamate
What happens to Glutamate in liver mitochondria?
Conversion to a-ketoglutarate
What enzyme catalyzes Glutamate -> a-KG in liver?
Glutamate dehydrogenase
What is special and unique about Glutamate dehydrogenase?
It can use either NAD or NADP
What regulates the activity of Glutamate Dehydrogenase?
Energy levels:
-ADP/GDP activate NH3 release
-ATP/GTP inhibit it.
What is free NH4+ in mitochondria used for?
Urea synthesis
What is the first step of urea synthesis?
Synthesis of Carbamoyl Phosphate
What enzyme accomplishes step 1?
Carbamoyl Phosphate Synthetase
So what do you know by the term Synthetase?
It requires 2 ATP
What is required to activate Carbamoyl Phosphate Synthetase?
What makes N-acetylglutamate?
What activates it?
Acetylglutamate Synthase (does not require ATP) -> activated by Arginine from Urea cycle
What are the substrates for making Carbamoyl Phosphate?
-NH3 (from glu/gln)
-HCO3- (from respiration)
-ATP (2)
What is the real first step of the urea cycle?
Synthesis of Citrulline
What is citrulline made from?
Carbamoyl Phosphate + Ornithine
How does Ornithine get into the mitochondrial matrix?
Via a specific transporter
How does Citrulline get out of the mito matrix?
By another specific transporter
What enzyme makes Citrulline?
Ornithine Transcarbamoylase
Any requirements for this first step?
Nope; just releases a phosphate.
What is involved in the 2nd step in Urea cycle?
2 reactions, one intermediate
What is step 2a of urea cycle?
Citrulline + ATP makes an activated Citrullyl-AMP intermediate
What enzyme catalyzes steps 2a/2b?
Argininosuccinate Synthetase
What does the name synthetase tell you right away?
It will use ATP
What happens to the Citrullyl-AMP intermediate?
AMP gets replaced by Aspartate to make Argininosuccinate.
Where does the Aspartate come from?
Oxaloacetate shuttling in the mitochondria during the TCA cycle.
What enzyme acts on Argininosuccinate? What does it produce?
Argininosuccinate Lyase; produces Fumurate and Arginine
Where does Aspartate in the liver mitochondria come from again?
-Fed state: from OAA in TCA.
-Starving: from Alanine -> OAA -> THEN to Aspartate.
So what happens to the Citrullyl-AMP intermediate?
It combines with Asp to make Argininosuccinate, w/ release of AMP.
And what happens to Argininosuccinate?
Argininosuccinate Lyase cleaves it into Fumarate + Arginine
What is the other product of Argininosuccinate Lyase?
What happens to the Arginine produced in step 3 of urea cycle?
It has 2 Options:
-Go to TCA cycle
-Continue in the Urea cycle
What acts on Arginine in step 4 of the urea cycle? Products?
Arginase - makes Urea and Ornithine
What does Urea do after release from Arginine?
The blood transports it from liver to kidney for excretion.
What happens to the ornithine produced by arginase?
It goes back to Mitosol for re-entry into the cycle.
What happens to some of the newly made urea?
Goes back into the intestine (via diffusion) and cleaves to CO2 + Ammonia
What enzyme causes intestinal cleavage of ammonia?
Urease in intestinal bacteria.
How do the intermediates in the urea cycle get to the next enzyme?
They are directly channeled from one active site to the next.
How many ATP are used in the urea cycle?
What substrates are used by the urea cycle (total)?
1 NH4+
1 HCO3-
1 H2O
1 Aspartate
What products are given off by the urea cycle (total)?
1 Urea
2 Pi
1 PPi
1 Fumarate
What are the most direct sources of ammonia for the urea cycle?
-Free ammonia
What shunt links the TCA and Urea cycles?
Aspartate:Argininosuccinate Shunt
Why is ALANINE the source of ASPARTATE during starving, exercise, or diabetes crisis?
B/c the TCA cycle is not running to make OAA; have to get it some other way.
What are the 2 types of regulating the Urea cycle?
1. Availability of N-acetylglutamate to activate Carbamoyl Phosphate synthetase
2. Enzyme transcription
What happens to the urea cycle in starving people or those on hi-protein diets?
It goes unregulated to detoxify all the amino acid breakdown products.
How are extrahepatic tissues detoxified of ammonia?
By synthesis of AGGS:
Ala, Glu, Gln, Ser
What happens to AGGS?
Released to bloodstream, taken to liver, for Urea cycle.
What happens when ammonia levels are excessively high?
The tissues are depleted of Glutamate and a-KetoGlutarate as Glutamine is synthesized for NH3 transport.
Why are high levels of Glutamine and NH3 toxic?
They cause the brain to swell.
What are the amino acid neurotransmitters?
GABA and Glutamate
What enzyme defcncy would be indicated by LOW Citrulline levels and excess Carbamoyl Phosphate levels?
Ornithine Transcarbamylase
What is the treatment for this inborn error of metabolism?
Liver transplant
What are Sodium Benzoate and Sodium Phenylacetate?
Nitrogen waste medications
What is the mechanistic basis for nitrogen waste meds?
Benzoate and Phenylacetate form complexes with AA's and allow their excretion.
What makes Ornithine transcarbamoylase deficiency unique from all other urea cycle enzyme deficiencies?
It is X-linked (less severe in women)
How is Argininosuccinate Lyase deficiency treated?
by giving dietary Arginine.
Why is dietary Arginine sufficient for treating Argininosuccinate lyase defic?
B/c Argininosuccinate can be excreted - don't HAVE to break it down all the way to urea.
If Argininosuccinate can be excreted, why give arginine?
Because you have to keep the urea cycle going by regenerating Ornithine.
What major organ disease can lead to impaired urea synthesis?
Reyes disease - or any liver damage - this is the site of urea cycle.

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