“…9 The enzyme catalyses the transformation of 5aminoimidazole-4-carboxyribonucleotide (CAIR) and L-aspartate to SAICAR in the presence of adenosine triphosphate (ATP) and Mg 2+ cofactors. 10,11 It is known that bacteria rely on the de novo pathway for their survival, as the pathway plays a crucial role in the synthesis of nucleic acid and nucleotide phosphate precursors for energy metabolism. Several studies in the past have shown that purine biosynthesis is vital for bacterial growth and persistence in the gut, blood and lungs.…”
Section: Introductionmentioning
confidence: 99%
“…The enzyme catalyzes the transformation of 5-aminoimidazole-4-carboxyribonucleotide (CAIR) and l -aspartate to phosphoribosylaminoimidazole-succinocarboxamide (SAICAR) in the presence of adenosine triphosphate (ATP) and Mg 2+ cofactors (Scheme ). , …”
Mycobacterium abscessus has emerged as a challenging threat to individuals with cystic fibrosis, particularly children. It is often impossible to treat the infection caused by this mycobacterium due to its intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in M. abscessus to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthase (PurC) from Mycobacterium abscessus (Mab) was identified as
“…9 The enzyme catalyses the transformation of 5aminoimidazole-4-carboxyribonucleotide (CAIR) and L-aspartate to SAICAR in the presence of adenosine triphosphate (ATP) and Mg 2+ cofactors. 10,11 It is known that bacteria rely on the de novo pathway for their survival, as the pathway plays a crucial role in the synthesis of nucleic acid and nucleotide phosphate precursors for energy metabolism. Several studies in the past have shown that purine biosynthesis is vital for bacterial growth and persistence in the gut, blood and lungs.…”
Section: Introductionmentioning
confidence: 99%
“…The enzyme catalyzes the transformation of 5-aminoimidazole-4-carboxyribonucleotide (CAIR) and l -aspartate to phosphoribosylaminoimidazole-succinocarboxamide (SAICAR) in the presence of adenosine triphosphate (ATP) and Mg 2+ cofactors (Scheme ). , …”
Mycobacterium abscessus has emerged as a challenging threat to individuals with cystic fibrosis, particularly children. It is often impossible to treat the infection caused by this mycobacterium due to its intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in M. abscessus to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthase (PurC) from Mycobacterium abscessus (Mab) was identified as
“…The enzyme catalyses the eighth step of the de novo purine biosynthesis pathway in bacteria and fungi, mediating the ligation of l -aspartate with 5-amino-1-(5-phospho- d -ribosyl) imidazole-4-carboxylate (CAIR) in the presence of adenosine 5′-triphosphate (ATP) and Mg 2+ to form SAICAR, as shown in figure 1 a . The importance of de novo purine biosynthesis in maintaining the viability of cells and differences in the structural architecture of bacterial and human PurC orthologues makes it an ideal target for antimicrobial agents [19–21], as further illustrated in the electronic supplementary material, figure S1. Figure 1.( a ) Schematic depiction of the enzyme reaction catalysed by PurC (SAICAR synthetase) in the bacterial purine biosynthesis pathway.…”
Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by the three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted by the development of synchrotron radiation sources. Structures of known drugs or inhibitors were used to guide the development of leads. The growth of high-throughput screening during the late 1980s and the early 1990s in the pharmaceutical industry of chemical libraries of hundreds of thousands of compounds of molecular weight of approximately 500 Da was impressive but still explored only a tiny fraction of the chemical space of the predicted 10
40
drug-like compounds. The use of fragments with molecular weights less than 300 Da in drug discovery not only decreased the chemical space needing exploration but also increased promiscuity in binding targets. Here we discuss advances in X-ray fragment screening and the challenge of identifying sites where fragments not only bind but can be chemically elaborated while retaining their positions and binding modes. We first describe the analysis of fragment binding using conventional X-ray difference Fourier techniques, with
Mycobacterium abscessus
SAICAR synthetase (PurC) as an example. We observe that all fragments occupy positions predicted by computational hotspot mapping. We compare this with fragment screening at Diamond Synchrotron Light Source XChem facility using PanDDA software, which identifies many more fragment hits, only some of which bind to the predicted hotspots. Many low occupancy sites identified may not support elaboration to give adequate ligand affinity, although they will likely be useful in drug discovery as ‘warm spots’ for guiding elaboration of fragments bound at hotspots. We discuss implications of these observations for fragment screening at the synchrotron sources.
This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.
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