Urea which is also known as carbamide is an organic compound with the following chemical formula (NH2)2CO. The molecule contains two amines residues attached by a carbonyl functional group. Urea is the primary end product of protein metabolism.
Urea has a very important and remarkable role in the metabolism of compounds with nitrogens and it is the main nitrogen-containing substance in the urine of mammals. It is a neutral compound that is solid, colorless, odorless, very soluble in water and not toxic or lethal to humans. Urea is employed around the world as fertilizers and as a source of nitrogen.
Urea cycle is known as ornithine cycle or Kreb's Henselit. It is a cycle of biochemical reactions occuring in animals and it was one of the first metabolic pathway divulged. Urea cycle is the main and most important end product of nitrogen metabolism in organisms such as in humans and mammals. Liver is the only site or organ for urea formation due to the presence of arginase enzyme in liver only.
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Urea formation is the pathway by which liver, and to some extent kidney, can convert toxic ammonia into non-toxic urea. The product that makes the oxidative deamination reactions is the ammonia; which is very toxic in even small amounts and has to be withdrew from the organisms and the body. Organisms convert ammonia to substances such as urea or uric acid, because they are less toxic, due to the reason that they can't easily or rapidly remove ammonia.
The first two reactions occur in mitochondria where other reactions occur in the cytoplasm.The urea cycle consists of five amino acids; two in the mitchondrialand three cystolic ( cytoplasm). the five amino acids sharing in the urea cycle are: N-acetylglutamate, ornithine, citrulline, aspartate and arginine. Two amino groups are converted by the cycle; one from NH4+, one from aspartic acid and another carbon atom from HCO3âˆ’ to the closely discharge, that is not toxic,product urea at the cost of the four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one ATP to AMP). Ornithine is the carrier in this cycle and it is used for these carbon and nitrogen atom.
However, the urea formation is described as following:
2 Ammonia(NH4+) + carbon dioxide (CO2)+ 3ATP ---> urea + water + 3 ADP
Aspartic acid is the source for one of the amine group comes while the other amine group comes from oxidative deamination of glutamic acid. Aspartic acid is rejuvenated from fumaric acid that is produced by the urea cycle during conversion. At the beginning, the fumaric acid undergoes reactions through a small part of the citric acid cycle to results an oxaloacetic acid which is then altered by transamination into aspartic acid.
Doctors or people who measure urea, they measure it as blood urea nitrogen (BUN). When BUN levels may be increased, it is a disease which causes a condition that is called uremia that is found in both renal failures; acute and chronic. Several diseases ruin the kidney and cause wrongly urine formation and excretion. Congestive heart failure (C.H.F.) directs to a decreased blood pressure and consequent decreased filtration rates through the kidneys. Thus, when we measure BUN, there is a chance that it might be elevated. Another reason for elevated BUN is the urinary tract obstructions which is, to some extent, very dangerous.
In worst situations, hemodialysis is used to take out the soluble urea and other waste and unwated products from the blood. Waste and unwanted products circularize through the dialyzing membrane because their concentration is lower in the dialyzing solution. Ions, such as Na+ and Cl- which are to stay in the blood, are maintained at the same concentration in the dialyzing solution - no net diffusion occurs.
High ammonia levels or even low levels are very toxic to humans. A full block of any step in the urea cycle is dangerous and lethal since there is no other known substitute pathway for the synthesis of urea. Partial block in a few of the reactions could be caused by inherited disorders from defective enzymes and produces in hyperammonemia which can cause diseases such as mental and physical retardation. A lot and extensive ammonia accumulation leads to extensive and very bad liver damage and death. Alcoholism, which is the reason for the liver cirrhosis, produces an interference in the enzymes which produce carbamyl phosphate in the very first step on the cycle itself.
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Uric Acid Excretion:
In animals that are able to excrete urea, water is a must and it is required to dissolve urea in urine. Actually, urea is a natural diuretic which induces and help the flow of urine. Animals such as birds and reptiles which must maintain their water, discharges nitrogen as uric acid as a solid mixed with little amounts of water. In birds and reptiles, converting ammonia and the synthesis of uric acid is a complicated and difficult energy requiring process.
In humans, the uric acid is not produced from ammonia but it is synthesized from adenine and guanine found in various nucleotides.
Uric acid is usually discharged in little amounts in the urine of humans. Uric acid concentrations may become elevated or increased in the kidney diseases and leukemia which is white blood cell cancer. Uric acid salts maybe positioned in the form of kidney and/or bladder stones.
Gout, which is a painful arthritic disorder, results from the deposition of uric acid salts in cartilage in the joints. Gout is probably and most likely caused by a different types of inborn errors of metabolism producing in excessive synthesis of uric acid. Management of gout isn't very hard and it could be put under control by diet and/or drugs. The drug that would work is called allopurinol which supresses the enzyme which produces uric acid.
Animals who live in the water such as fishes discharge ammonia. Moreover, even fish do not have big concentrations of ammonia in the blood, they have really low amount since it is discharged as the amide in glutamine.
Glutamine is brought to a membrane and a layer in their organs in the gills near the surrounding water where a hydrolysis of the glutamine to glutamic acid releases the ammonia.
Also, humans discharge little amounts of NH3 which is altered by the acid in the urine to NH4+ (ammonium ions). Therefore, ammonia is replaced only as a defense against an acidosis condition since the ammonia neutralizes the acid which has the effectuation of conserving bases in the blood.
Regulation of urea cycle
The key enzyme of urea cycle is carbamoyl phosphate synthetase 1. It is activated allosterically by N-acetylglutamate, Mn++, and Mg++ ions. N-acetylglutamate synthesis is stimulated by high protein diet and amino acids specially arginine. However, extremely regulated expression of different enzymes present in the urea cycle happens also in a lot of other tissues, where these enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver. In contrast, the urea cycle enzymes in nonhepatic cells are regulated by a broad range of pro- and antiinflammatory cytokines and other agents. Regulation of these enzymes is very largely transcriptional in virtually all cell types. This review accentuates the new information concerning the roles and regulation of urea cycle and arginine metabolic enzymes in liver and other of the cell types.
The synthesis of the enzyme carbamoyl phosphate and the urea cycle rely on the presence of N-acetylglutamic acid (NacGlu) which allosterically activates CPS1. Synthesis of NAcGlu by NAGS, is stimulated by Arg - allosteric stimulator of NAGS, and Glu - a results in the transamination reactions with one of NAGS's substrates, the both of which are increased when free amino acids are elevated. Therefore, Arg is not only a substrate for the urea cycle reactions but also is able to act as an activator for the urea cycle.
The concentrations of substrate:
The rest of the enzymes of the cycle are being in control by the concentrations of their substrates. Therefore, acquired deficiencies in the cycle enzymes other than ARG1 do not produce in remarkable decrease in urea production (the complete decrease and the lack of any of these cycles enzyme will lead to death presently after being born). Rather, the lack of the enzyme's substrate builds up, increasing the rate of the lacking reaction back to normal.
The anomalous substrate buildup is with a cost, however, the concentrations of the substrate become increased all the way back up the cycle to NH4+, resulting in hyperammonemia (elevated [NH4+]P).
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Although the root cause of ammonia toxicity is not fully understood, a high [NH4+] puts a huge strain on the ammonia-clearing system, specifically in the brain (mental retardation and lethargy are the symptoms of urea cycle enzyme deficiencies). This clearing system involves GLUD1 and GLUL, which decrease the 2OG and Glu pools. The brain is the most sensitive organ to the depletion and breaking down of these pools. Depletion of 2OG decreases the rate of TCAC, whereas Glu is both a neurotransmitter and a precursor to GABA, another neurotransmitter.
Relation between tricarboxylic acid cycle and urea cycle:
-Co2 and ATP needed for urea cycle produced from TCA cycle.
-Fumurate produced from urea cycle can be oxidized in TCA cycle.
-Aspratate can give oxaloacetate and vice versa (transamination)