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Purine, pyrimidine and porphyria disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Myoadenylate deaminase deficiency is a rare metabolic disorder that is characterised by a deficiency of the muscle enzyme adenosine monophosphate (AMP) deaminase enzyme. AMP deaminase and the purine nucleotide cycle have an important role in providing energy for skeletal muscles during exercise. There are two forms of myoadenylate deaminase deficiency, namely an acquired form and an inherited form. This summary will focus on the inherited form.
Central fatigue and central regulation of performance
Published in Shaun Phillips, Fatigue in Sport and Exercise, 2015
Ammonia is produced in the body in several ways. At rest, most ammonia is produced from the gastrointestinal tract via the breakdown of the amino acid glutamine and urea.28 Ammonia is also produced in the brain, kidneys, and skeletal muscle. Within skeletal muscle, ammonia is produced via the deamination (removal of an amine group) of adenosine monophosphate (AMP) as part of the purine nucleotide cycle (Figure 6.1). This indicates that skeletal muscle ammonia production will increase during intense muscle contraction. Indeed, at exercise intensities below 50–60% VO2max very little ammonia accumulation occurs, but accumulation rapidly increases as intensity rises above this level.29 During exercise, skeletal muscle oxidation of BCAA’s can increase ~4 fold over resting rates. If exercise is prolonged, BCAA oxidation increases further due to the depletion of glycogen stores.30 Greater oxidation of BCAA’s can also significantly increase ammonia production. Anything from 75–90% of the ammonia produced in muscle during exercise is retained in the muscle until completion of exercise, where it is gradually released and metabolised.31 This is beneficial, as rapid release from muscle could raise blood ammonia concentrations to levels that could cause significant health risks.
Adenylosuccinic acid: a novel inducer of the cytoprotectant Nrf2 with efficacy in Duchenne muscular dystrophy
Published in Current Medical Research and Opinion, 2021
Emma Rybalka, Craig A. Goodman, Dean G. Campelj, Alan Hayes, Cara A. Timpani
In clinical trials conducted by the late Dr. Charles Bonsett (1980–1990s), adenylosuccinic acid (ASA) was identified as a candidate therapeutic with strong translational potential as it attenuated DMD progression2. ASA is made endogenously by ASA synthetase from inosine in the purine nucleotide cycle (PNC), which is augmented during metabolic stress to recover degraded purines and stimulate the mitochondria to re-balance energy homeostasis4. Since DMD was considered a metabolic disease during that era (i.e. pre-discovery of DMD’s genetic origin), ASA’s mode of action (MOA) was attributed to its metabolic activity. Due to ASA’s high production cost, infusion difficulties, and the eventual inability to source sufficient quantities for long-term treatment, these trials were discontinued despite clinical data suggesting persistent efficacy long after treatment cessation2.
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.