Mammalian Urea Cycle Enzymes

Jackson, Marian J.; Beaudet, Arthur L.; O’Brien, William E.

doi:10.1146/annurev.ge.20.120186.002243

Cited by 123 publications

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“…Some of the enzymes in this pathway are present in a variety of cell types, while expression of other enzymes is highly restricted. Phosphate-dependent glutaminase, ornithine aminotransferase (OAT), argininosuccinate synthase (ASS), argininosuccinate lyase (ASL) and aspartate aminotransferase are widely distributed in animal tissues [42][43][44][45], whereas CPS I, ornithine carbamoyltransferase (OCT) and N-acetylglutamate Step 4 is a spontaneous, non-enzymic reaction. Glutamyl-γ-semialdehyde is in chemical equilibrium with P5C.…”

Section: Arginine Synthesismentioning

confidence: 99%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,450

2,036

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Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of proteins but also of nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. Of the enzymes that catalyse rate-controlling steps in arginine synthesis and catabolism, argininosuccinate synthase, the two arginase isoenzymes, the three nitric oxide synthase isoenzymes and arginine decarboxylase have been recognized in recent years as key factors in regulating newly identified aspects of arginine metabolism. In particular, changes in the activities of argininosuccinate synthase, the arginases, the inducible isoenzyme of nitric oxide synthase and also cationic amino acid transporters play major roles in determining the metabolic fates of arginine in health and disease, and recent studies have identified

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Section: Arginine Synthesismentioning

confidence: 99%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,450

2,036

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“…The enzyme carbamyl-phosphate synthetase I (CPSI) catalyzes the rate-limiting step of the urea cycle, thereby controlling the availability of NO precursors. [20][21][22] A common SNP in the CPSI gene causes the substitution of asparagine (Asn) for threonine (Thr) at position 1405 (T1405N) in the critical cofactor-binding domain of the enzyme. 23 Summar et al studied urea cycle function and the prevalence of this SNP in relation to HVOD, ALI, and oxidant stress in 200 patients undergoing myeloablative HSCT at Vanderbilt Medical Center.…”

Section: Hepatic Veno-occlusive Disease and Acute Lung Injurymentioning

confidence: 99%

Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?

Kallianpur

2004

Bone Marrow Transplant

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Summary:The occurrence of toxic complications following hematopoietic stem cell transplantation (HSCT) is highly variable and dependent on a multitude of host, donor, and treatment factors. The increasingly broad indications for HSCT and the need to provide this treatment option to older and/or more debilitated patients emphasizes the importance of refining our methods of predicting and ameliorating these toxicities. Late complications (occurring after day 100) also pose a threat to quality of life after HSCT. Genetic polymorphisms in key molecular pathways in the host are likely to contribute significantly to the observed variability in the development HSCT-associated complications. Hepatic veno-occlusive disease and acute lung injury, two of the most serious organ toxicities that occur, represent useful paradigms for the identification of genetic polymorphisms in enzyme systems that modulate local and systemic responses to oxidant stress during transplant conditioning therapy. Ongoing studies in this area are providing clues to the prevention of adverse clinical outcomes based on the genetic milieu. This review of studies in HSCT that explore genetic risk factors for transplant complications indicates that significant progress is being made in this rapidly evolving area. However, further large-scale clinical and translational studies are needed before genomic screening can be widely used to individualize treatment. Bone Marrow Transplantation (2005) Clinicians are continually challenged by the need to predict the responses of individual patients to potentially toxic treatments. The increasing promise of cure for patients who undergo hematopoietic stem cell transplantation (HSCT) for life-threatening disorders is overshadowed by the very real threat of short-term, often fatal, complications resulting from the transplant regimen and graft-versushost disease (GVHD). However, significant variation is observed between similarly treated individuals in the development of complications. It is an appealing concept, therefore, and one to which many clinicians now subscribe, that a significant portion of this variability has a genetic basis. Identifying important genetic variables will allow for better prediction of HSCT-related outcomes, and in the process of identifying these susceptibilities, it may also be possible to gain sufficient knowledge of the underlying pathophysiology of these toxicities to develop targeted interventions.This review will focus on genomic screening of the host for the prediction of specific complications, touching briefly on selected donor factors. Other rapidly evolving areas that are not covered include molecular genetic testing to predict graft failure and disease relapse after HSCT. The role of clinical and biochemical risk factors in the pre-transplant evaluation of HSCT candidates has also been reviewed recently in this journal. 1 Importance of context-dependent genetic effectsThe study of uncommon disease-associated mutations has been invaluable to our understanding of basic pathophy...

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“…The steady-state degradation rates found in these experiments fall within the range of 0Á09± 0Á3ah, which is slower than the rates of the highly inducible enzymes such as tyrosine aminotransferase (EC 2.6.1.5) or tryptophan pyrrolase, but in line with many other liver enzymes (Waterlow et al 1978). The concentrations of the mRNA for these enzymes were found to increase with increases in their amounts and activity (Mori et al 1981;Morris et al 1987), which suggests regulation of gene expression and transcription (Jackson et al 1986), but later work indicated that the situation is more complicated, with different control mechanisms for the different enzymes (Ulbright & Snodgrass, 1993). How the activities of the two mitochondrial and three cytoplasmic enzymes are coordinated is, as far as I know, unknown.…”

Section: The Biochemical Evidencementioning

confidence: 99%

“…How the activities of the two mitochondrial and three cytoplasmic enzymes are coordinated is, as far as I know, unknown. The fact that four of the ®ve genes are on separate chromosomes (Jackson et al 1986) makes this coordination all the more remarkable. The suggestion that it is all brought about by glucocorticoids and glucagon working through cyclic AMP seems rather simplistic (de Groot et al 1984).…”

Section: The Biochemical Evidencementioning

confidence: 99%

The mysteries of nitrogen balance

Waterlow¹

1999

Nutr. Res. Rev.

113

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The ®rst part of this review is concerned with the balance between N input and output as urinary urea. I start with some observations on classical biochemical studies of the operation of the urea cycle. According to Krebs, the cycle is instantaneous and automatic, as a result of the irreversibility of the ®rst enzyme, carbamoyl-phosphate synthetase 1 (EC 6.3.5.5; CPS-I), and it should be able to handle many times the normal input to the cycle. It is now generally agreed that acetyl glutamate is a necessary co-factor for CPS-1, but not a regulator. There is abundant evidence that changes in dietary protein supply induce coordinated changes in the amounts of all ®ve urea-cycle enzymes. How this coordination is achieved, and why it should be necessary in view of the properties of the cycle mentioned above, is unknown. At the physiological level it is not clear how a change in protein intake is translated into a change of urea cycle activity. It is very unlikely that the signal is an alteration in the plasma concentration either of total amino-N or of any single amino acid. The immediate substrates of the urea cycle are NH 3 and aspartate, but there have been no measurements of their concentration in the liver in relation to urea production. Measurements of urea kinetics have shown that in many cases urea production exceeds N intake, and it is only through transfer of some of the urea produced to the colon, where it is hydrolysed to NH 3 , that it is possible to achieve N balance. It is beginning to look as if this process is regulated, possibly through the operation of recently discovered urea transporters in the kidney and colon. The second part of the review deals with the synthesis and breakdown of protein. The evidence on whole-body protein turnover under a variety of conditions strongly suggests that the components of turnover, including amino acid oxidation, are in¯uenced and perhaps regulated by amino acid supply or amino acid concentration, with insulin playing an important but secondary role. Molecular biology has provided a great deal of information about the complex processes of protein synthesis and breakdown, but so far has nothing to say about how they are coordinated so that in the steady state they are equal. A simple hypothesis is proposed to ®ll this gap, based on the self-evident fact that for two processes to be coordinated they must have some factor in common. This common factor is the amino acid pool, which provides the substrates for synthesis and represents the products of breakdown. The review concludes that although the achievement and maintenance of N balance is a fact of life that we tend to take for granted, there are many features of it that are not understood, principally the control of urea production and excretion to match the intake, and the coordination of protein synthesis and breakdown to maintain a relatively constant lean body mass.

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Mammalian Urea Cycle Enzymes

Cited by 123 publications

References 0 publications

Arginine metabolism: nitric oxide and beyond

Arginine metabolism: nitric oxide and beyond

Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?

The mysteries of nitrogen balance

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