Structural and computational dissection of the catalytic mechanism of the inorganic pyrophosphatase from Mycobacterium tuberculosis

Pratt, Andy C.; Dewage, Sajeewa W.; Pang, A.H.; Biswas, Tapan; Barnard-Britson, Sandra; Cisneros, G. Andrés; Tsodikov, Oleg V.

doi:10.1016/j.jsb.2015.08.010

Cited by 16 publications

(36 citation statements)

References 51 publications

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“…4 and 5D). Their active site is composed of four conserved acidic residues that coordinate two metal ions that activate a water molecule, followed by proton abstraction by one of the conserved acidic residues (117). All previously structurally characterized members in the PDB database contain an additional β hairpin between the first and the second strands of the core fold.…”

Section: Resultsmentioning

confidence: 99%

Polyvalent Proteins, a Pervasive Theme in the Intergenomic Biological Conflicts of Bacteriophages and Conjugative Elements

et al. 2017

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Intense biological conflicts between prokaryotic genomes and their genomic parasites have resulted in an arms race in terms of the molecular “weaponry” deployed on both sides. Using a recursive computational approach, we uncovered a remarkable class of multidomain proteins with 2 to 15 domains in the same polypeptide deployed by viruses and plasmids in such conflicts. Domain architectures and genomic contexts indicate that they are part of a widespread conflict strategy involving proteins injected into the host cell along with parasite DNA during the earliest phase of infection. Their unique feature is the combination of domains with highly disparate biochemical activities in the same polypeptide; accordingly, we term them polyvalent proteins. Of the 131 domains in polyvalent proteins, a large fraction are enzymatic domains predicted to modify proteins, target nucleic acids, alter nucleotide signaling/metabolism, and attack peptidoglycan or cytoskeletal components. They further contain nucleic acid-binding domains, virion structural domains, and 40 novel uncharacterized domains. Analysis of their architectural network reveals both pervasive common themes and specialized strategies for conjugative elements and plasmids or (pro)phages. The themes include likely processing of multidomain polypeptides by zincin-like metallopeptidases and mechanisms to counter restriction or CRISPR/Cas systems and jump-start transcription or replication. DNA-binding domains acquired by eukaryotes from such systems have been reused in XPC/RAD4-dependent DNA repair and mitochondrial genome replication in kinetoplastids. Characterization of the novel domains discovered here, such as RNases and peptidases, are likely to aid in the development of new reagents and elucidation of the spread of antibiotic resistance.IMPORTANCE This is the first report of the widespread presence of large proteins, termed polyvalent proteins, predicted to be transmitted by genomic parasites such as conjugative elements, plasmids, and phages during the initial phase of infection along with their DNA. They are typified by the presence of multiple domains with disparate activities combined in the same protein. While some of these domains are predicted to assist the invasive element in replication, transcription, or protection of their DNA, several are likely to target various host defense systems or modify the host to favor the parasite's life cycle. Notably, DNA-binding domains from these systems have been transferred to eukaryotes, where they have been incorporated into DNA repair and mitochondrial genome replication systems.

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Section: Resultsmentioning

confidence: 99%

Polyvalent Proteins, a Pervasive Theme in the Intergenomic Biological Conflicts of Bacteriophages and Conjugative Elements

et al. 2017

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“…Family III is unexplored and found in some bacterial species. The latter seems to be modified to dehalogenase of haloalkanes, which operate by a separate mechanism [12].…”

Section: Inorganic Pyrophosphatase: Overviewmentioning

confidence: 99%

“…The hydrolysis reaction is based on the activation of a nucleophile group, the generation of a nucleophilic Figure 2 and Figure 3). This mechanism is well described in Escherichia coli, provided by three divalent metal ions located in the catalytic site of the enzyme: M1 and M2 ions present before the substrate binding site, they are involved in the positioning of the substrate and the activating of a water molecule for the nucleophilic attack; M3 ion coordinates the positioning of pyrophosphate in the active site [12].…”

Section: Soluble Pyrophosphatasesmentioning

confidence: 99%

“…The active site containing a water molecule (Wc) and the divalent metal ion M2: a) that captures pyrophopshate PPi with the M1 and M3 ions; b) The nucleophile complex formed following proton-abstraction by an aspartate residue Asp (Asp 67 in the PPase from Escherichia coli, Asp54 in the PPase from Mtb tuberculosis) attack the electrophilic active phosphate group of PPi; c) upon hydrolysis; d) a new water molecule binds phosphate and the other group dissociates, giving a complex that releases the phosphate (Pi) attacked [12]. The nucleophilic water molecule is named Wn and represented by the red atom in c; the electrophilic phosphorus is at the bottom of each figure.…”

Section: Soluble Pyrophosphatasesmentioning

confidence: 99%

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Inorganic Pyrophosphatases: Study of Interest

Daouda¹,

Bouchra²,

Roman³

et al. 2017

ABB

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Inorganic pyrophosphatases are enzymes that catalyze the hydrolysis of inorganic pyrophosphate to orthophosphate. These enzymes are divided into two groups: the soluble pyrophosphatases and the membrane pyrophosphatases. They vary in structure and each has a determined catalysis mechanism. Soluble pyrophosphatases are ubiquitous enzymes and play a key role in regulating the rate of pyrophosphate and balance in this sense, the biosynthetic reactions. Membrane pyrophosphatases are ion pumps, producing a proton or sodium gradient, and provide critical energy reserves to organisms, especially during stress conditions. Several studies have shown that these enzymes are involved in numerous disorders (diseases, fault cell growth•••). However they are potential targets for the development of agents against parasites. This article consists of a description of the different types, structures, catalytic properties of inorganic pyrophosphatases and their involvement in cellular metabolism.

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“…Extensive structural and biochemical studies had been reported on Family I PPases from Escherichia coli (E-PPase) [37][38][39] and Saccharomyces cerevisiae (Y-PPase) [40][41][42][43][44][45]. X-ray crystallographic studies had also been carried out on soluble PPases from other species, including Thermus thermophilus (T-PPase) [46], Pyrococcus horikoshii (Pho-PPase) [47], human parasites Plasmodium falciparum (Pf-PPase) and Toxoplasma gondii (Tg-PPase) [48], Mycobacterium tuberculosis (Mt-PPase) [36,49], Trypanosoma brucei brucei (also called vacuolar soluble protein TbbVSP1) [50], and S. japonicum (Sj-PPase, not published).…”

Section: Introductionmentioning

confidence: 99%

Crystallographic and Modeling Study of the Human PPA1 (Inorganic Pyrophosphatase 1): a Potential Anti-cancer Drug Target

Niu

Zhu

et al. 2020

Preprint

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Inorganic pyrophosphatases (PPases) catalyze the hydrolysis of pyrophosphate to phosphates. PPases play essential roles in growth and development, and are found in all kingdoms of life. Human possess two PPases, PPA1 and PPA2. PPA1 is present in all tissues, acting largely as a housekeeping enzyme. Besides pyrophosphate hydrolysis, PPA1 can also directly dephosphorylate phosphorylated JNK1. Upregulated expression of PPA1 has been linked to many human malignant tumors. PPA1 knockdown induces apoptosis and decreases proliferation. PPA1 is emerging as a potential prognostic biomarker and target for anti-cancer drug development. In spite of the biological and physiopathological importance of PPA1, there is no detailed study on the structure and catalytic mechanisms of mammalian origin PPases. Here we report the crystal structure of human PPA1 at a resolution of 2.4Å. We also carried out modeling studies of PPA1 in complex with JNK1 derived phosphor-peptides. The monomeric protein fold of PPA1 is similar to those found in other family I PPases. PPA1 forms a dimeric structure that should be conserved in animal and fungal PPases. Analysis of the PPA1 structure and comparison with available structures of PPases from lower organisms suggest that PPA1 has a largely pre-organized and relatively rigid active site for pyrophosphate hydrolysis. Results from the modeling study indicate the active site of PPA1 has the potential to accommodate double-phosphorylated peptides derived from JNK1. In short, results from the study provides new insights into the mechanisms of human PPA1 and basis for structure-based anti-cancer drug developments using PPA1 as the target.

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Structural and computational dissection of the catalytic mechanism of the inorganic pyrophosphatase from Mycobacterium tuberculosis

Cited by 16 publications

References 51 publications

Polyvalent Proteins, a Pervasive Theme in the Intergenomic Biological Conflicts of Bacteriophages and Conjugative Elements

Polyvalent Proteins, a Pervasive Theme in the Intergenomic Biological Conflicts of Bacteriophages and Conjugative Elements

Inorganic Pyrophosphatases: Study of Interest

Crystallographic and Modeling Study of the Human PPA1 (Inorganic Pyrophosphatase 1): a Potential Anti-cancer Drug Target

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