Nitrogen Metabolism II Flashcards
Give an overview of the urea cycle
-approx. 90% of nitrogen in urine is in the form of urea
- One nitrogen of urea derived from ammonia, the other from Aspartate
- (Both nitrogens from glutamate, from oxidative deamination and transamination, respectively)
- CO2 provides C and O of urea
- Urea is produced in the liver and transported to kidney for excretion in urine
Describe the distribution of N-containing compounds in urine
Urea- 86%
Creatinine- 5%
NH4+ - 3%
Other- 6%
List the steps of the urea cycle
- Formation of carbamoyl phosphate
- Formation of citrus line
- Synthesis of Arg ink Succinate
- Cleavage of arginosuccinate
- Cleave of arginine to urea and ornithine
Describe the first step of the urea cycle
Formation of carbamoyl phosphate
- catalyzed by mitochondrial carbamoyl phosphate synthetase I (CPS I)
- rate limiting step
- 2 ATPs needed to combine ammonia (from oxidative deamination) and CO2 to form carbamoyl phosphate
- Requires N-Acetyl glutamate
Describe the second step of the urea cycle
Formation of citrulline
- catalyzed by mitochondrial ornithine transcarbamoylase
- combines ornithine and carbamoyl phosphate
- release of high energy phosphate drives reaction
- citrulline is transported to the cytoplasm
Describe the third step of the urea cycle: synthesis of arginisuccinate
- catalyzed by arginosuccinate synthase
- citrulline condenses with Aspartate to form arginosuccinate
- source of second nitrogen atom in urea
- requires ATP, the third and final ATP needed for urea synthesis
Describe the 4th step of the urea cycle: cleave of arginosuccinate
- catalyzed by arginosuccinate lyase
- form fumarate and arginine
- fumarate can be used to make malate (and glucose), or Aspartate via oxaloacetate
- arginine is the intermediate precursor of urea
Describe the final step of the urea cycle
Cleavage of arginine to urea and ornithinine
- catalyzed by arginase
- arginase only found in liver
Explain the fate of urea
- urea is transported to the kidney where it is excreted in urine
- small part of urea is converted to NH3 and CO2 in the intestine by bacterial urease —> NH3 excreted in feces
- In kidney failure, this becomes a significant source of hyperammonia
- treatment with neomycin decreases urease-producing bacteria
Give the overall stoichiometry of the urea cycle
Aspartate + NH3 + 3ATP —> urea+ 2Pi + 2ADP+ PPi + AMP
4 high energy P-bonds are consumed
🔼G= big and neg —> irreversible
The urea cycle is linked to which cycle?
The TCA cycle
What kind of diet activates the urea cycle and why?
the urea cycle is activated by protein-rich diets, particularly glutamate and arginine
N-Acetylglutamate is an essential allosteric activator of CPS1
Formation of N-Acetylglutamate is dependent on:
- Glutamate
- Arginine
Explain the positive feedback of urea cycle
- Regulation of CPS1 by N-acetylglutamate
- synthesis of N-acetylglutamate dependent on [GLU]
- Synthesis of N-acetylglutamate is stimulated by ARG (produced by urea cycle)
- Regulation by substrate concentration (a.a.)
- the rate of NH 4+ production
- Induction (synthesis) of the cycle enzymes with increase in protein metabolism
- fasting and high protein diet
- increased gene expression
Liver has a large capacity to dispose of NH4+
Give an overview of the metabolism of ammonia
- NH3 is produced by all tissues during the metabolism of N-containing compounds
- NH3 extremely toxic to CNS, can cause coma and death
- Must have mechanism for removing NH3 from periphery to liver without increasing plasma NH3 levels
Explain the sources of ammonia amino acids and glutamine
- Amino acids
- produced in many tissues from sequential action of transaminases and glutamate dehydrogenase
- especially liver
- skeletal muscle protein degradation during fasting and exercise
- Glutamine -via renal glutaminase
- most ammonia excreted in urine as NH4+
- important for acid-base balance
- Glutamine - via intestinal (mucousal cell) glutaminase
- glutamine from blood or digestion
