Crystal structures of d-alanine-d-alanine ligase from Xanthomonas oryzae pv. oryzae alone and in complex with nucleotides

Doan, Thanh Thi Ngoc; Kim, Jin-Kwang; Ngo, H.P.T.; Tran, Huyen-Thi; Shin, Sun; Chung, Kyung Min; Huynh, Kim-Hung; Ahn, Yeh‐Jin; Kang, Lin‐Woo

doi:10.1016/j.abb.2014.01.009

Cited by 12 publications

(7 citation statements)

References 17 publications

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“…For instance, adenosine triphosphate (ATP) is used in generating universal chemical energy for cellular functions, guanosine triphosphate (GTP) is involved in the synthesis of DNA and proteins, and uridine monophosphate (UMP) is the central building block in the synthesis of RNA. , Although an abundance of information is available on solution binding studies and theoretical calculations predicting the binding modes of nucleotides, − structural reports of nucleotide complexes with synthetic receptors are indeed limited. − In 2008, Bianchi and co-workers reported the first structure of a nucleoside triphosphate complex with a synthetic receptor, showing hydrogen bonding and π–π stacking interactions between a thymidine 5′-triphosphate and a polyamine-based receptor . Several structures of nucleotides, nucleosides, or nucleobases as pure or mixed ligands with transition metal ions were also reported. − In particular, the central role played by nucleoside monophosphates (NMPs) in many biological events makes them attractive targets for mimicking their biological interactions. − For instance, as characterized by X-ray analysis, UMP was found within the cavity of a Bacillus subtilis orotidine 5′-monophosphate decarboxylase via hydrogen bonds and salt bridges between the nucleotide and the protein . However, to the best of our knowledge, a crystallographically characterized NMP complex with a macrocycle-based synthetic receptor has not been reported yet.…”

Section: Introductionmentioning

confidence: 99%

Supramolecular Assembly of Uridine Monophosphate (UMP) and Thymidine Monophosphate (TMP) with a Dinuclear Copper(II) Receptor

2017

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Understanding the intermolecular interactions between nucleotides and artificial receptors is crucial to understanding the role of nucleic acids in living systems. However, direct structural evidence showing precise interactions and bonding features of a nucleoside monophosphate (NMP) with a macrocycle-based synthetic molecule has not been provided so far. Herein, we present two novel crystal structures of uridine monophosphate (UMP) and thymidine monophosphate (TMP) complexes with a macrocycle-based dinuclear receptor. Structural characterization of these complexes reveals that the receptor recognizes UMP through coordinate–covalent interactions with phosphates and π–π stackings with nucleobases and TMP through coordinate–covalent interactions with phosphate groups. Furthermore, the receptor has been shown to effectively bind nucleoside monophosphates in the order of GMP > AMP > UMP > TMP > CMP in water at physiological pH, as investigated by an indicator displacement assay.

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Section: Introductionmentioning

confidence: 99%

Supramolecular Assembly of Uridine Monophosphate (UMP) and Thymidine Monophosphate (TMP) with a Dinuclear Copper(II) Receptor

2017

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“…Several metabolites involved in cell wall synthesis of M. leprae ’s cell wall were associated with up-regulated genes only during glycerol utilisation simulations. This is likely because cell wall components, such as arabinogalactan-decaprenyl phosphate [40], and d-alanyl-d-alanine, a peptide-glycan precursor [41], fatty-acid derived mycolates and arabinogalactan-peptidoglycan molecules are derived directly from glycerol metabolism.…”

Section: Resultsmentioning

confidence: 99%

GSMN-ML- a genome scale metabolic network reconstruction of the obligate human pathogenMycobacterium leprae

Borah

Kearney

Banerjee

et al. 2019

Preprint

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22 Leprosy, caused by Mycobacterium leprae, has plagued humanity for thousands 23 of years and continues to cause morbidity, disability and stigmatization in two 24 to three million people today. Although effective treatment is available, the 25 disease incidence has remained approximately constant for decades so new 26 approaches, such as vaccine or new drugs, are urgently needed for control.27 Research is however hampered by the pathogen's obligate intracellular lifestyle 28 and the fact that it has never been grown in vitro. Consequently, despite the 29 availability of its complete genome sequence, fundamental questions regarding 30 the biology of the pathogen, such as its metabolism, remain largely unexplored.31 In order to explore the metabolism of the leprosy bacillus with a long-term aim 32 of developing a medium to grow the pathogen in vitro, we reconstructed an in 33 silico genome scale metabolic model of the bacillus, GSMN-ML. The model was 2 34 used to explore the growth and biomass production capabilities of the pathogen 35 with a range of nutrient sources, such as amino acids, glucose, glycerol and 36 metabolic intermediates. We also used the model to analyze RNA-seq data 37 from M. leprae grown in mouse foot pads, and performed Differential Producibility 38 Analysis (DPA) to identify metabolic pathways that appear to be active during 39 intracellular growth of the pathogen, which included pathways for central carbon 40 metabolism, co-factor, lipids, amino acids, nucleotides and cell wall synthesis. 41The GSMN-ML model is thereby a useful in silico tool that can be used to 42 explore the metabolism of the leprosy bacillus, analyze functional genomic 43 experimental data, generate predictions of nutrients required for growth of the 44 bacillus in vitro and identify novel drug targets. 46Author Summary 47 Mycobacterium leprae, the obligate human pathogen is uncultivable in axenic 48 growth medium, and this hinders research on this pathogen, and the 49 pathogenesis of leprosy. The development of novel therapeutics relies on the 50 understanding of growth, survival and metabolism of this bacterium in the host, 51 the knowledge of which is currently very limited. Here we reconstructed a 52 metabolic network of M. leprae-GSMN-ML, a powerful in silico tool to study 53 growth and metabolism of the leprosy bacillus. We demonstrate the application 54 of GSMN-ML to identify the metabolic pathways, and metabolite classes that 55 M. leprae utilizes during intracellular growth. 56 57 Key words 58 Mycobacterium leprae; metabolism; metabolic network; genome scale model; 59 flux balance analysis; differential producibility analysis 60 61 Introduction 62 The mycobacterial genus includes two of the greatest scourges of humanity:63 Mycobacterium tuberculosis and M. leprae, responsible for tuberculosis (TB) and 64 leprosy respectively. Leprosy is one of the oldest plagues of mankind yet 65 remains prevalent in developing countries. In 1981, the World Health 66 Organization (WHO) recommended multidrug treatment (MDT) of d...

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“…Overall subunit structure Two high-resolution crystal structures have been determined, BpDdl:AMP and BpDdl:AMP:D-Ala-D-Ala, with statistics in Table 1. Ddl is a member of the ATP-grasp superfamily presents a characteristic and highly conserved fold [16,[25][26][27][28]. ATP-grasp proteins contain three well-defined domains [16].…”

Section: Resultsmentioning

confidence: 99%

Burkholderia pseudomallei d‐alanine‐d‐alanine ligase; detailed characterisation and assessment of a potential antibiotic drug target

et al. 2019

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Burkholderia pseudomallei is a serious, difficult to treat Gram‐negative pathogen and an increase in the occurrence of drug‐resistant strains has been detected. We have directed efforts to identify and to evaluate potential drug targets relevant to treatment of infection by B. pseudomallei. We have selected and characterised the essential enzyme d‐alanine‐d‐alanine ligase (BpDdl), required for the ATP‐assisted biosynthesis of a peptidoglycan precursor. A recombinant supply of protein supported high‐resolution crystallographic and biophysical studies with ligands (AMP and AMP+d‐Ala‐d‐Ala), and comparisons with orthologues enzymes suggest a ligand‐induced conformational change occurring that might be relevant to the catalytic cycle. The detailed biochemical characterisation of the enzyme, development and optimisation of ligand binding assays supported the search for novel inhibitors by screening of selected compound libraries. In a similar manner to that observed previously in other studies, we note a paucity of hits that are worth follow‐up and then in combination with a computational analysis of the active site, we conclude that this ligase represents a difficult target for drug discovery. Nevertheless, our reagents, protocols and data can underpin future efforts exploiting more diverse chemical libraries and structure‐based approaches.

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Crystal structures of d-alanine-d-alanine ligase from Xanthomonas oryzae pv. oryzae alone and in complex with nucleotides

Cited by 12 publications

References 17 publications

Supramolecular Assembly of Uridine Monophosphate (UMP) and Thymidine Monophosphate (TMP) with a Dinuclear Copper(II) Receptor

Supramolecular Assembly of Uridine Monophosphate (UMP) and Thymidine Monophosphate (TMP) with a Dinuclear Copper(II) Receptor

GSMN-ML- a genome scale metabolic network reconstruction of the obligate human pathogenMycobacterium leprae

Burkholderia pseudomallei d‐alanine‐d‐alanine ligase; detailed characterisation and assessment of a potential antibiotic drug target

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