Renal Biochemistry: Urea Cycle Flashcards
With respect to humans, NH3 is
TOXIC
Ammonia is converted to what in order to reduce the toxicity
Urea
What is the majority of urea comprised of
Nitrogen
In acid-base chemistry, Ammonia is considered a
Weak-Base
NH3 + H2O <=> NH4+ + OH-
Whats the difference between NH3 and NH4+ when it comes to permeability of a membrane.
NH3 can move through a membrane with ease b/c its uncharged.
NH4+ cannot pass through membrane b/c it charged.
What is the charge, acid-base activity, and the amount of nitrogens carried by urea
=> 0 charge
=> No acid-base activity
=> 2 nitrogens
Protein turnover is the same as saying
Protein degradation
Why is the urea cycle so important to human life.
Humans cannot store nitrogens. When protein turnover (degredation) occurs, there is an excess of amino acids. These amino acids carry nitrogens (amino group). A series of enzymatic rxns can remove these nitrogens from amino acids and the urea cycle can then package these nitrogens for excretion out of body.
Nitrogen in the body exists primarily as
NH3
Typically NH4+ b/c of pka~ 9.3 and physiological pH=7.4
In which organ does the urea cycle take place in
Liver
What are the two important rxns that cause ammonia to be RELEASED in mammals
(TRICK THINK OF RXN CASCADE)
Glutamine (1)=> Glutamate (2)=> a-Ketoglutarate
(1) Glutaminase
(2) Glutamate dehydrogenase
*Glutamine dehydrogenase is a reversible reaction
What are the three important rxns that cause ammonia to be FIXED in mammals
a-Ketoglutarate (1)=> Glutamate (2)=> Glutamine
(1) Glutamate Dehydrogenase
(2) Glutaminase
HCO3- + NH4+ +2 ATP (3) => Carbamoyl - P + 2 ADP + 2Pi
(3) Carbamoyl Phosphate Synthetase -1 (CPS1)
* DON’T GET BOGGED DOWN IN DETAILS, JUST KNOW NITROGEN IS AFFIXED TO CARBON DIOXIDE BY CPS1
Glutamine is remarkable because
It’s a nitrogen donor (typically 2 in rxn cascade)
NH3 in the kidney is useful b/c
It can help with excretion of H+ in urine
Why can’t NH3 be excreted directly.
NH3 draws water of body. Cause dehydration
Gluconeogenisis
Formation of new glucose “de novo”.
Requires a carbon skeleton.
What is a good carbon skeleton and how is it derived.
a-Ketoacid.
During a transamination reaction, amine group from an amino acid is released and the formation on a carbon skeleton occurs. Subsequently, that amine will the go and create a new amino acid.
Ex) Amino acid release NH3 and becomes a-ketoacid
NH3 gets affixed to a-ketoglutarate and forms glutamate
When excess nitrogens are found in the muscle/tissue, what can happen to these nitrogens
Amino groups from muscle & other tissues are transported out as glutamine
Glutamate (1)=> Glutamine (fixes 1 nitrogen)
(1) Glutamine synthase
When does gluconeogenisis activity go up
When in a fasting state
If gluconeogenisis goes up, so should
Urea cycle
Under metabolic acidosis, the kidney can
Activate glutaminase enzyme to excrete NH4+
How many nitrogens does glutamine carry?
Two nitrogens
Where does a the urea cycle reactions take place in the cell
1) Mitochondrial Matrix (minority)
2) Cytosol (majority)
What is the first step of the urea cycle
CPS1
What is the rate limiting/regulating step of the urea cycle
CPS1
What is the first source of nitrogen in the urea cycle
CPS1
What is the second source of nitrogen in the urea cycle
Aspartate
What ensures the spinning of the urea cycle
ATP hydrolysis
Last step of the urea cycle
Formation of urea by arginase
What is the role of fumarate in the urea cycle.
Fumarate => Malate => OAA => Aspartate
Aspartate can then can go feed back nitrogen into the urea cycle
*OAA => Aspartate is a transamination rxn
In the urea cycle, going from arginosuccinate => arginine causes the release of
Fumarate
What are the three feed forward mechanism of the urea cycle
1) Allosteric regulation by N-Acetylglutamate
2) Presence of NH4+
3) Metabollic reasosn
Explain the role of N-Acetylglutamate in the urea cycle.
The activity of CPS1 is regulated by N-Acetylglutamate
N-Acetylglutamate is a cofactor that binds to the allosteric sites of CPS1
High presence of Glutamate, Aspartate, and acetyl-coA drive N-Acetylglutamate production.
Once bound, N-Acetylglutamate helps drive the enzymatic activity of CPS1
Explain the role of NH4+ in the urea cycle.
High concentration of NH4+ drives the urea cycle forward.
Explain the role of metabolic processes in the urea cycle.
Fasting => Gluconeogensis => requires a-keto acid skeleton => excretion of nitrogens from amino acids is required => drives urea cycle
High protein diet (Excess of nitrogens)
Increased gene expression of urea cycle enzymes can drive the urea cycle forward.
Why is NH3 so toxic to humans
High levels of NH3 can do the following:
Conversion of a-Ketoglutarate to glutamate can mess up TCA cycle. Causes less ATP to be produced in body. Hurts brain.
Glutamate is converted to glutamine
can cause a reduction in other neurotransmitter circulation. Primarily GABA and Glutamate
