urea cycle

what is urea?

the end product of protein metabolism (amino acid metabolism). the nitrogen of amino acids

what is the nitrogen of amino acids converted to?

ammonia, which is toxic to the body

what is the urea cycle?

the process of converting ammonia to urea and detoxifying it so it can be exerted in the urine. it accounts for 80-90% of nitrogen containing substances in the urine

what leads up to the urea cycle?

muscles → protein → amino acid → ammonia → urea

where is urea synthesized?

in the liver, and then transported to kidneys for excretion in the urine

how many nitrogen groups (NH2) are in urea?

two, one derived from free ammonia (NH₃), the other derived from aspartate, which is from step 3 in the urea cycle

how many steps is urea synthesis?

it is a five step cyclic process with five distinct enzymes, with two present in the mitochondria and the other localized in the cytosol

what are the enzymes of urea that are present in the mitochondria?

1. carbamoyl phosphate synthetase (CPS I)

2. ornithine transcarbamylase (OTC)

what are the enzymes of urea that are present in the cytosol?

1. arginosuccinate synthetase

2. arginosuccinate lyase

3. arginase

all amino acid have a chiral carbon except for what?

glycine

what is the significance of chiral carbons in the urea cycle?

if they weren’t chiral enzymes wouldn’t be able to distinguished between stereoisomers. chirality makes amino acid metabolism, including the funneling of nitrogen into the urea cycle, highly specific and efficient.

what occurs during the first step of the urea cycle?

mitochondrial enzyme carbamoyl phosphate synthase I (CPS I) catalyzes the condensation of NH4+ ions with CO2 to form carbamoyl phosphate. this step consumes 2 ATP, is irreversible and rate limiting

CPS I requires what to be activated?

N-acetylglutamate

how does CPS II differ from CPS I?

it is a cytosol enzyme involved in pyrimidine synthesis that accepts an amino group from glutamine and does not require N-acetylglutamate for activation

what are ornithine and citrulline?

basic amino acids involved in the urea cycle that lack codons in the genetic code, thus, unable to make or be incorporated in proteins

what occurs during the second step of the urea cycle?

citrulline is synthesized from carbamoyl phosphate and Ornithine

what is regenerated and reused in the urea cycle?

ornithine, making it comparable to that of oxaloacetate in the citric acid cycle

where is citrulline produced in step 2 transported to?

the cytosol. it is shuttled out of the mitochondria

what occurs during the third step of the urea cycle?

cytosol enzyme arginosuccinate synthetase condenses citrulline with aspartate to produce arginosuccinate

when is the second amino group of urea incorparated?

during step 3, provided by aspartate.

what does step 3 require?

1 ATP which is cleaved to produce AMP and pyrophosphate (PPi), which is immediately broken down into an inorganic phosphate (Pi)

what occurs during the fourth step of the urea cycle?

cytosol enzyme argininosuccinate lyase (or argininosuccinase) cleaves arginosuccinate to give arginine and fumarate.

what is the immediate precursor for urea?

arginine

fumarate released in step 4 of the urea cycle serves what purpose?

it provides a connecting link with the TCA cycle, gluconeogenesis, etc

what occurs during the fifth step of the urea cycle?

arginase cleaves arginine to yield urea and ornithine. orthenine is regenerated and reenters the mitochondria for its reuse in the urea cycle

what is arginase activated by?

Co2+ and Mn2+

where is arginase primarily found?

the liver. In contrast, the other four enzymes of the urea cycle are also present in various extrahepatic tissues. Because of this distribution, arginine synthesis can occur to varying degrees in many tissues, but only the liver can ultimately produce urea

what is the overall reaction and energetics of the urea cycle?

it is an overall irreversible process, consuming 4 ATP. two ATP are utilized for the synthesis of carbamoyl phosphate in the first step, and one ATP is converted to AMP and PPi to produce arginosuccinate in step 3, which is equivalent to 2 ATP.

what is the regulatory enzyme of the urea cycle?

carbamoyl phosphate synthase I (CPS I), which catalyzes the first reaction and is the rate limiting step or the committed step in urea synthesis

what is CPS I allosterically activated by?

N acetyl glutamate (N AG).

the rate of urea synthesis in the liver is correlated with what?

the concentration N-acetylglutamate

high concentrations of what increases N AG?

arginine, so the consumption of a high protein meal increases the level of N AG in the liver, leading to enhanced urea synthesis

what enzymes are localized in the mitochondria?

carbamoyl phosphate synthase I and glutamate dehydrogenase

CPS I and glutamate dehydrogenase coordinate with each other for what?

the formation of NH3 and its utilization for the synthesis of carbamoyl phosphate

the remaining enzymes of urea cycle are mostly controlled by what?

their respective substrates

what are the 3 different ways the urea cycle is linked to the TCA cycle?

1. urea cycle produces fumarate, which is converted to malate in the TCA cycle, which is then converted to oxaloacetate. oxaloacetate can undergo transamination to form aspartate, which re-enters the urea cycle by combining with citrulline to form argininosuccinate. it can also combine with acetyl-CoA to form citrate and get oxidized, or serve as a precursor for gluconeogenesis

2. TCA cycle produces ATP → helps supply energy for the urea cycle, which consumes 4 high-energy bonds per urea.

3. CO₂ from TCA cycle is used in the urea cycle to make carbamoyl phosphate.

what are TCA and the urea cycle considered?

bicyclic intermediates where energy flows between them allowing efficient nitrogen disposal and energy use.

what is hyperammonemia?

a condition characterized by excessive ammonia in blood, which if untreated, can lead to renal failure and mental retardation. other symptoms associated with it is vomiting, lethargy, irritability, and ataxia