China
Africa
Explore chapters and articles related to this topic
Adenylosuccinate lyase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The enzyme adenylosuccinate lyase (adenylosuccinase, ASL; EC 4.3.2.2) catalyzes the eighth step in the de novo synthesis of purines in which succinylaminoimidazolecarboxamide ribotide (SAICAR, SAICAMP) is converted to aminoimidazolecarboxamide ribotide (AICAR, AICAMP, ZMP) (Figure 71.1) [4, 5]. The same enzyme catalyzes the conversion of adenylosuccinate to adenosine monophosphate (AMP) in the cycle of purine nucleotide conversions that yield adenine nucleotides [6]. Deficient activity of the enzyme was documented in 1988 by Jaeken and colleagues [4]. The human gene has been mapped to chromosome 22q1.3.1.-1.3.2 [7]. The human cDNA has been cloned, and the nature of the point mutation was defined in the initial family reported [1, 2]. A majority of the 30 different mutations initially delineated were missense, most of them in compound heterozygotes. The most common mutation, p.R426H, was found in 17 families from many countries [3, 8] many on single alleles. More than 50 patients have now been reported [3]. Mutations have continued to be missense, many on single alleles.
Purine, pyrimidine and porphyria disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Adenylosuccinate lyase deiciency is a rare disorder characterised by a deiciency or an absence of the enzyme adenylosuccinate lyase. This enzyme catalyses two separate steps in the pathways of purine nucleotide synthesis. ADSL deficiency results in a blockage in these pathways and the build-up of two unusual chemical compounds, succinylaminoimidazole carboxamide riboside (SAICAR) and adenylo-succinic acid (AMPS), in the body. Both have a toxic efect on the brain and cause the symptoms of this condition. There are four forms of this disorder.
In the quest for new targets for pathogen eradication: the adenylosuccinate synthetase from the bacterium Helicobacter pylori
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Ante Bubić, Natalia Mrnjavac, Igor Stuparević, Marta Łyczek, Beata Wielgus-Kutrowska, Agnieszka Bzowska, Marija Luić, Ivana Leščić Ašler
In the second step, adenylosuccinate lyase cleaves adenylosuccinate to form AMP. AdSS operates at a branch point of the de novo synthesis of purines and the purine nucleotide cycle, the so-called salvage pathway, which makes this enzyme a challenging subject to study1. AdSS activity has been observed in all the tissues investigated, except in erythrocytes1. There are over 700 reviewed protein entries for the gene name “purA” in the UniProt database (July 2018) from all domains of life. Two AdSS enzymes were identified in vertebrates: acidic (pI ∼ 6) and basic (pI ∼ 9), presumably the former associated with the biosynthesis of purines and the latter with the purine nucleotide cycle2. Regulation of activity of these two isoforms is complex and different (as judged by different reactions with inhibitors), and is dependent on the isozyme content and levels in a given tissue, as well as substrate and product levels1. As AdSS operates at a regulatory point in the metabolism of purines, its substrate binding sites are quite specific3.
Understanding the structural insights of enzymatic conformations for adenylosuccinate lyase receptor in malarial parasite Plasmodium falciparum
Published in Journal of Receptors and Signal Transduction, 2021
Adenylosuccinate lyase is a housekeeping gene that is present in many organisms, especially in the plasmodium family. It plays a crucial role in cellular replication, purine nucleotide cycle. Recent studies on Plasmodium falciparum have suggested that the C–N bond cleavage is the rate-limiting step, through uni-bi mechanism kinetic mechanism. The reaction pathway involves cleavage of adenylosuccinate to AMP and fumarate and examining these complexes is core important to understand the structural aspect of adenylosuccinate lyase. In forward reaction, the adenylosuccinate is cleaved into adenosine monophosphate and fumarate as shown in Figure 4. Since, there have been several studies performed to understand the reaction mechanism of adenylosuccinate lyase, and as of now, the structural insights of those complexes are not well studied. By this, we examined the docked complex of adenylosuccinate bound protein and AMP with fumarate bound protein (Figure 5). The 2 D interactions of adenylosuccinate bound protein and AMP with fumarate bound protein are provided in Supplementary Figure S2. The protein amino acids Asp92, Glu97, Ser125 and Arg338 shows direct hydrogen bonding interactions with adenylosuccinate (reactant), while in the product, the amino acids Asn90, Asp92, Gln250, Arg338, Ser343, Arg347 are directly interacting with AMP through hydrogen bonds and the amino acids His91, Lys94, Glu97, His120, Ser125 are directly interacting with fumarate through hydrogen bonds. Dynamical Cross-Correlation Map (DCCM) predicted by dynamut is provided in the heat map for the reactant and product of adenylosuccinate lyase complex in Figure 6(a,b). Here the Ser 125 is playing the dual role of proton acceptor and donor in the reaction transfer mechanism and the Glu 250 and Glu97 provides marginal base support as reaction activator. While in the reactant, the His amino acid as electrostatic stabilizer does not play any direct role, but the His120 comes forward to hold the fumarate and plays the imperial role in separating the fumarate form the adenylosuccinate. The other amino acids like Lys, Arg, Asn are contributing to the binding and transfer of reactant into product with the intermediate steps.