Krebs Henseleit ornithine cycle

Fig. 6.11. The (Krebs-Henseleit) ornithine cycle. Numbers refer to enzymes as follows. (1) Carbamyl phosphate synthetase (E.C.2.7.2.a). (2) Ornithine transcarbamylase (E.C.2.1.3.3). (3) Arginino-succinate synthetase (E.C.6.3.4.5). (4) Arginino-succinate lyase (E.C.4.3.2.1). (5) Arginase (E.C.3.5.3.1). (After Smyth, 1969.)...

On an average Western diet, adnlt hnmans excrete around 30 g of nrea per day but this can easily triple on a protein-rich diet. The reactions and the concept of a cycle were discovered by Krebs Henseleit (1932). Snbseqnent work clari-hed the details of what has become known as the ornithine or the nrea cycle. 

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). 

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)... 

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. 

Recent advances in the understanding of the mechanism of the biosynthesis of urea have been concerned with (1) the elucidation of the enzymatic steps, (2) the nature of the ammonia or amino group acceptors and donors, (3) the mechanism of CO2 fixation, and (4) the nature of the energy coupling reactions. The outline of the over-all ornithine cycle as originally proposed by Krebs and Henseleit remains essentially intact and may be considered as consisting of three over-all enzymatic steps as follows ... 

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. 

The formation of arginine from ornithine, via citruUine, has long been known. In fact, the ornithine cycle of Krebs and Henseleit was one of the first biosynthetic pathways ever proposed. 

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

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. 

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 ... 

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. 

It was suggested, by Krebs and Henseleit more than thirty years ago, that urea is formed (primarily in liver tissue), by a cycle of reactions between the basic amino acids, ornithine, citruUine and arginine. The original scheme, given in Figure 41, is now known to be oversimplified. Other intermediates are involved, and enzymes catalysing the individual steps in the reaction have been purified and partly characterised. The reactions involved are as follows ... 

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

---