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Argininosuccinic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The enzyme argininosuccinate lyase, or argininosuccinase (EC 4.3.2.1) (Figure 29.1), catalyzes the conversion of the argininosuccinate formed from citrulline and aspartate, to fumarate and arginine, the last compound of the urea cycle prior to the urea splitting off. The cDNA for the human gene has been cloned [11] and the gene has been localized to chromosome 7q11.21 [12]. Mutations have been defined [13–15], some of which have led to alternative splicing.
Amino acid disorders and urea cycle disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
This disorder is one of a group of conditions, known as the urea cycle disorders, in which the body’s ability to manage dietary protein is impaired. In argininosuccinic aciduria there is a deficiency or absence of the enzyme argininosuccinate lyase (ASL), which is an important part of the urea cycle. This leads to an accumulation of the amino acid argininosuccinic acid (hence the name), and may lead to a build-up of ammonia (and its related product glutamine) in the body, giving rise to the symptoms of the disorder.
L-citrulline
Published in Linda M. Castell, Samantha J. Stear (Nottingham), Louise M. Burke, Nutritional Supplements in Sport, Exercise and Health, 2015
Nikki A. Jeacocke, Stephen J. Bailey, Andrew M. Jones
L-citrulline is a non-essential α-amino acid (C6H13N3O3), found in a range of protein-rich foods of both animal and plant origin. Endogenously, L-citrulline is synthesised during the metabolism of L-ornithine by ornithine carbamoyltransferase, a key reaction in the breakdown of L-glutamine, and is a product of L-arginine oxidation via the nitric oxide synthase (NOS) enzymes (Wu and Morris, 1998). L-citrulline can be recycled back into L-arginine through the enzymatic activity of argininosuccinate synthase (yielding argininosuccinate) and subsequently argininosuccinate lyase (yielding L-citrulline). Oral supplementation of L-citrulline appears more effective at increasing circulating and muscle [L-arginine] and nitric oxide (NO) biomarkers than L-arginine supplementation (Schwedhelm et al., 2008; Wijnands et al., 2012). L-citrulline is also an intermediate in the urea cycle; it attenuates the rise in circulating ammonia during exercise (Takeda et al., 2011). The potential for L-citrulline to improve exercise performance may be linked to its ability to increase L-arginine content, and hence NO and creatine synthesis substrates, and to facilitate ammonia detoxification (Sureda and Pons, 2013). However, studies investigating the potential benefits of L-citrulline supplementation on athletic performance are limited.
Fumarate hydratase as a therapeutic target in renal cancer
Published in Expert Opinion on Therapeutic Targets, 2020
Priyanka Kancherla, Michael Daneshvar, Rebecca A. Sager, Mehdi Mollapour, Gennady Bratslavsky
In an effort to identify metabolic biomarkers, Zheng et al. aimed to develop a metabolic signature of FH-deficient renal cell carcinoma using an FH-deficient mouse model [78]. The authors identified the urinary metabolites most characteristic of FH loss to be fumarate, urobilin, a product of heme degradation, and 2-SC, as expected based on the known metabolic derangements associated with FH loss presented in this review. Additionally, argininosuccinate, a urea cycle metabolite, was also identified. This metabolic signature was replicated in the spent culture media of UOK262 cells compared to UOK262 cells with re-constituted FH expression. The authors suggest that the generation of argininosuccinate serves as a means by which FH-deficient cells excrete accumulated fumarate. Reversal of the urea cycle enzyme argininosuccinate lyase generates argininosuccinate from arginine and excess fumarate, causing cells to become dependent on exogenous arginine. The authors aim to exploit this weakness for therapeutic benefit. They demonstrated that arginine deprivation using pegylated arginine deiminase inhibited cellular proliferation in FH-deficient cells. Their findings suggest a role for argininosuccinate and arginine deprivation in the diagnosis and treatment of HLRCC [78].
Arginine-lowering enzymes against cancer: a technocommercial analysis through patent landscape
Published in Expert Opinion on Therapeutic Patents, 2018
Rakhi Dhankhar, Pooja Gulati, Sanjay Kumar, Rajeev Kumar Kapoor
L-asparaginase, which destroys the free source of aspargine, was approved by the Food and Drug Administration for the treatment of T-cell acute lymphoblastic lymphoma [5]. This success has drawn the attention of many research groups toward arginine. Arginine is a nonessential amino acid (essential for neonates) which is involved in various cellular functions like synthesis of nitric oxide, polyamines, nucleotides, proline, glutamate, and proteins [6]. In normal cells, arginine is synthesized in the urea cycle, enzyme argininosuccinate synthetase (ASS) catalyzes the reaction forming argininosuccinate from L-citrulline, and the enzyme argininosuccinate lyase (ASL) finally converts argininosuccinate into L-arginine (Figure 1) [1]. Several tumors including hepatocellular carcinoma (HCC), malignant melanoma, malignant pleural mesothelioma (MPM), and prostate and renal cancer are arginine auxotrophic, due to variable loss or downregulation of ASS [7]. These cancerous cells rely upon exogenous arginine for survival and will die of starvation in presence of arginine-degrading enzymes.
Inherited hyperammonemias: a Contemporary view on pathogenesis and diagnosis
Published in Expert Opinion on Orphan Drugs, 2018
Evelina Maines, Giovanni Piccoli, Antonia Pascarella, Francesca Colucci, Alberto B. Burlina
Hyperammonemia due to defects in ammonia detoxification is usually differentiated in two types. Primary hyperammonemia is due to loss-of-function defects of any of the urea cycle enzymes. These comprise three mitochondrial enzymatic defects (carbamoylphosphate synthetase 1 deficiency [CPS1D, OMIM #237300], ornithine transcarbamylase deficiency [OTCD, OMIM #311250], N-acetylglutamate synthase deficiency [NAGSD, OMIM #237310]), three cytosolic enzymatic defects (citrullinemia type 1 or argininosuccinate synthetase deficiency [ASSD, OMIM #215700], argininosuccinic aciduria or argininosuccinate lyase deficiency [ASLD, OMIM #207900], arginase 1 deficiency or argininemia [ARG1D, OMIM #207800]), and two mitochondrial transport defects (hyperornithinemia-hyperammonemia-homocitrullinuria syndrome [HHH, OMIM #238970]) and citrullinemia type 2 or citrin deficiency (Citrin-D, OMIM #605814 and #603471) [4,5].