Krebs-Henseleit urea cycle

The Krebs-Henseleit Urea Cycle (Figure 20.13, Figure 21.2, Diagram)... 

This is an enzyme of the Krebs—Henseleit urea cycle which occurs almost exclusively in liver. It is currently considered to be a good specific indicator of hepatic cell damage. In acute carbon tetrachloride poisoning in swine serum levels are elevated 400-fold. In dogs, the elevation is greater (2000-fold). It may be assayed radiochemically [516] or... 

Ammonia is one end product of the metabolism of all the amino acids and of most other nitrogenous substances. It is a very toxic substance, relatively low concentrations in the blood causing serious neurological signs. Ammonia is converted to non-toxic urea by the Krebs-Henseleit urea cycle (Figure 6.3),... 

Arginine and ornithine are readily interconvertible in the hver through the agency of the Krebs-Henseleit urea-forming cycle. This subject is treated in the chapter. Nitrogen Metabolism of Amino Acids, and need not be dwelt on here. The subsequent steps of the catabolism of these two amino acids, then, are through the degradation of ornithine. 

In 1937 Krebs found that citrate could be formed in muscle suspensions if oxaloacetate and either pyruvate or acetate were added. He saw that he now had a cycle, not a simple pathway, and that addition of any of the intermediates could generate all of the others. The existence of a cycle, together with the entry of pyruvate into the cycle in the synthesis of citrate, provided a clear explanation for the accelerating properties of succinate, fumarate, and malate. If all these intermediates led to oxaloacetate, which combined with pyruvate from glycolysis, they could stimulate the oxidation of many substances besides themselves. (Kreb s conceptual leap to a cycle was not his first. Together with medical student Kurt Henseleit, he had already elucidated the details of the urea cycle in 1932.) The complete tricarboxylic acid (Krebs) cycle, as it is now understood, is shown in Figure 20.4. 

The first suggestion that substrates in carbohydrate oxidation might exert catalytic effects on the oxidation of other intermediates (cf.earlier demonstration of such action in the urea cycle by Krebs and Henseleit, 1932 see Chapter 6) arose from the work of Szent-Gyorgi (1936). He demonstrated that succinate and its 4C oxidation products catalytically stimulated the rate of respiration by muscle tissues. He also observed that reactions between the 4C intermediates were reversible and that if muscle was incubated with oxaloacetate, fumarate and malate made up 50-75% of the products, 2-oxoglutarate 10-25% and, significantly, 1-2% of the C was converted to citrate. These observations were... 

Lohman discovered ATP in muscles. Krebs and Henseleit. The urea cycle. Svedberg began studies with the ultracentrifuge. 

In ureotelic organisms, the ammonia deposited in the mitochondria of hepatocytes is converted to urea in the urea cycle. This pathway was discovered in 1932 by Hans Krebs (who later also discovered the citric acid cycle) and a medical student associate, Kurt Henseleit. Urea production occurs almost exclusively in the liver and is the fate of most of the ammonia channeled there. The urea passes into the bloodstream and thus to the kidneys and is excreted into the urine. The production of urea now becomes the focus of our discussion. 

The urea cycle Urea is synthesized in the liver by the urea cycle. It is then secreted into the bloodstream and taken up by the kidneys for excretion in the urine. The urea cycle was the first cyclic metabolic pathway to be discovered by Hans Krebs and Kurt Henseleit in 1932,5 years before Krebs discovered the citric acid cycle (see Topic LI). The overall reaction of the pathway is ... 

Production of urea by cestodes suggests the existence of the urea (Krebs-Henseleit) cycle, which is shown in Fig. 6.11. One of the key enzymes, arginase, has been widely reported in cestodes (796, 185-187). However, some of the other enzymes, notably carbamyl phosphate synthetase and ornithine transcarbamyl, are either absent or present in only low amounts (39) and it is doubtful if a complete cycle operates in cestodes. It is likely that the urea excreted by tapeworms comes from the activity of arginase alone. The uric acid produced and excreted by cestodes probably arises from the breakdown of purines (39). 

Urea is synthesized via the urea cycle (Fig. 18-1). In 1932, Krebs and Henseleit pubEshed data demonstrating that ornithine stimulates the synthesis of urea without stoichiometric consumption of this intermediate. This apparent catalytic function was determined to be the result of the cycEc nature of the pathway. This was a revolutionary idea since metabolic pathways were conceptualized as purely linear prior to the pubEcation of these observations. In the foUowing sections, we discuss the biochemical processes involved in urea formation. 

In terrestrial vertebrates, urea is synthesized by the urea cycle (Figure 23.16). The urea cycle, proposed by Hans Krebs and Kurt Henseleit in 1932, was the first cyclic metabolic pathway to be discovered. One of the nitrogen atoms of the urea is transferred from an amino acid, aspartate. The other nitrogen atom is derived directly from free NH4 +, and the carbon atom comes from HCO3 (derived by hydration of CO2 see Section 9.2). 

Fig. 3.12 Diagram showing the ammonia detoxification process in the urea cycle (= ornithine cycle) (H.A. Krebs, K. Henseleit, 1932) (A.L. Lehnesigee, 1979)...

The urea cycle, also called ornithine cycle, was first described by H.A. Krebs and K. Henseleit in 1932. (quot. 51) The principle of ammonia detoxification in the urea cycle is based on the conversion of ammonium and bicarbonate in the mitochondria under ATP consumption into carbamoyl phosphate (by means of carbamoyl phosphate synthetase). It enters the urea cycle, which is localized mainly - yet with a low affinity for ammonium - in the periportal zone of the liver lobule. In the urea cycle alone, about two thirds of the amino nitrogen of ammonia are irretrievably lost to the organism (= definitive ammonia detoxification), (s. fig. 3.12)... 

As early as 1932, H.A. Krebs and K. Henseleit established that of the investigated amino acids, only ornithine was able to effect a real increase in the synthesis of urea from ammonia (although arginine also displayed low efficacy), (quot. 57) Thus it seemed possible to raise the turnover of ammonia in the metabolism process by using intermediates of the urea cycle. (127) (s. tab. 15.6) (s. fig. 3.10) To this end, ornithine aspartate (oral and parenteral route), arginine malic... 

As early as 1932, H.A. Krebs and K. Henseleit discovered in their investigation of the amino acids that ornithine, even in small amounts, was capable of increasing urea synthesis from (toxic) ammonia. Otherwise, only arginine had a slight effect in this respect. (138) The following table shows which of the amino adds involved in the urea cycle are available for therapeutic purposes ... 

A26. About 80% of the excreted nitrogen is in the form of urea, which is also largely made in the liver, in a series of reactions that are distributed between the mitochondrial matrix and the cytosol. The series of reactions that form urea is known as the Urea Cycle or the Krebs-Henseleit Cycle. 

In ureotelic organisms the urea cycle disposes of approximately 90% of surplus nitrogen. As shown in Figure 15.1, urea is formed from ammonia, C02, and aspartate in a cyclic pathway referred to as the urea cycle. Because the urea cycle was discovered by Hans Krebs and Kurt Henseleit, it is often referred to as the Krebs urea cycle or the Krebs-Henseleit cycle. 

The urea cycle was proposed in 1932 by Hans Krebs and a medical student, Kurt f ] Henseleit, based on their laboratory observations. It was originally called the Krebs-Henseleit cycle. Subsequently, Krebs used this concept of metabolic cycling to explain a second process that also bears his name, the Krebs (or TCA) cycle. 

The first M.c. to be recognized was the Urea cycle (see), described by Krebs and Henseleit in 1932. This may be considered as an anabolic cycle since it results in the energy-dependent synthesis of urea but with respect to its metabolic role in the degradation of protein and detoxication of ammonia, it is catabolic. However, under certain conditions, it also provides arginine for protein synthesis, and anaplerosis occurs by the synthesis of ornithine from glutamate. 

Discovery of the ornithine or urea cycle (Krebs and Henseleit)... 

Figure 6.3. Conversion of ammonia to urea by the Krebs-Henseleit cycle (also known as the urea or ornithine cycle). (Courtesy Blackwell, Oxford.)...

The ornithine cycle [Eq. (8)-(ll)] was proposed by Krebs and Henseleit (1932) to explain urea formation from ammonium derived from amino acid catabolism in the mammalian liver. Since the promulgation of the ornithine cycle was partly based on the natural occurrence of citrulline in juice of the watermelon Citrullus vulgaris) (Wada, 1930), it is not surprising that citrulline is an intermediate in arginine formation in higher plants. 

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