A novel family of phospholipase D homologues that includes phospholipid synthases and putative endonucleases: Identification of duplicated repeats and potential active site residues

Ponting, Chris P.; Kerr, Iain

doi:10.1002/pro.5560050513

Cited by 303 publications

(243 citation statements)

References 70 publications

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“…The majority of the sequence identity between Tdp1 and the members of the PLD family is restricted to two copies of an active site signature motif H(X)K(X 4 )D, also referred to as an HKD motif [29], which has been implicated in the catalytic mechanism of these enzymes [30,31]. Two such motifs are present in the N-and C-terminal domains of human Tdp1, both of which contain the conserved histidine and lysine residues ( 263 HTK 265 and 495 HIK 497 ) but lack the aspartate residues that exist in other HKD motifs ( Fig.…”

Section: Biological Functions and Catalytic Mechanismmentioning

confidence: 99%

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Dexheimer¹,

Antony²,

Marchand³

et al. 2008

ACAMC

143

203

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3′-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3′-end DNA alterations including 3′-phosphoglycolates and 3′-abasic sites indicating it may function as a general 3′-DNA phosphodiesterase and repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human TDP1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.

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Section: Biological Functions and Catalytic Mechanismmentioning

confidence: 99%

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Dexheimer¹,

Antony²,

Marchand³

et al. 2008

ACAMC

143

203

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“…This bacteria-specific transesterification is catalyzed by the enzyme cardiolipin synthase, i.e. Cls-I, which belongs to the phospholipase D (PLD) superfamily that includes type I phosphatidylserine synthases, poxvirus envelope proteins, phospholipases D, and nucleases (8). In contrast, eukaryotes synthesize CL from cytidine diphosphate-diacylglycerol (CDP-DAG) and PG thereby forming CL and cytidine monophosphate (see Fig.…”

Section: Cardiolipin (Cl)mentioning

confidence: 99%

A Eukaryote-like Cardiolipin Synthase Is Present in Streptomyces coelicolor and in Most Actinobacteria

Sandoval-Calderón

Geiger

Guan

et al. 2009

Journal of Biological Chemistry

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Cardiolipin (CL) is an anionic membrane lipid present in bacteria, plants, and animals, but absent from archaea. It is generally thought that bacteria use an enzyme belonging to the phospholipase D superfamily as cardiolipin synthase (Cls) catalyzing a reversible phosphatidyl group transfer from one phosphatidylglycerol (PG) molecule to another PG to form CL and glycerol. In contrast, in eukaryotes a Cls of the CDP-alcohol phosphatidyltransferase superfamily uses cytidine diphosphate-diacylglycerol (CDP-DAG) as the donor of the phosphatidyl group, which is transferred to a molecule of PG to form CL. Searching the genome of the actinomycete Streptomyces coelicolor A3(2) we identified a gene coding for a putative Cls of the CDP-alcohol phosphatidyltransferase superfamily (Sco1389). Here we show that expression of Sco1389 in a CL-deficient Rhizobium etli mutant restores CL formation. In an in vitro assay Sco1389 condenses CDP-DAG with PG to form CL and therefore catalyzes the same reaction as eukaryotic cardiolipin synthases. This is the first time that a CDP-alcohol phosphatidyltransferase from bacteria is shown to be responsible for CL formation. The broad occurrence of putative orthologues of Sco1389 among the actinobacteria suggests that CL synthesis involving a eukaryotic type Cls is common in actinobacteria.

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“…The PLD enzymes catalyze phosphoryl transfer reactions from a donor to an acceptor, to either water or an alcohol (19). The phospholipases and the nucleases in this family use water to hydrolyze phosphodiester bonds, whereas the phospholipid synthases use an alcohol in a transesterification reaction to make a new phosphodiester.PLD proteins are characterized by a conserved sequence motif called HXK (17,19), and they use the conserved histidine in the motif for nucleophilic attack on the target phosphorus. They follow a two-step mechanism (18,20): in the first step, they attack the phosphorus to form a covalent phosphohistidine intermediate and release the alcohol; in the second, the intermediate is attacked by either another alcohol or water to yield, respectively, the transesterification or the hydrolysis product (21,22).…”

mentioning

confidence: 99%

“…The N-terminal half of BfiI (13,14) is similar to Nuc, an EDTA-resistant nuclease from Salmonella typhimurium (15,16) that belongs to the phospholipase D (PLD) superfamily. The PLD superfamily is a diverse group of proteins that includes phospholipases, phospholipid synthases, bacterial toxins, phosphodiesterases (PDEs), and nucleases (17,18). The PLD enzymes catalyze phosphoryl transfer reactions from a donor to an acceptor, to either water or an alcohol (19).…”

mentioning

confidence: 99%

Site-specific DNA transesterification catalyzed by a restriction enzyme

Sasnauskas¹,

Connolly

Halford

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Most restriction endonucleases use Mg 2؉ to hydrolyze phosphodiester bonds at specific DNA sites. We show here that BfiI, a metal-independent restriction enzyme from the phospholipase D superfamily, catalyzes both DNA hydrolysis and transesterification reactions at its recognition site. In the presence of alcohols such as ethanol or glycerol, it attaches the alcohol covalently to the 5 terminus of the cleaved DNA. Under certain conditions, the terminal 3 -OH of one DNA strand can attack the target phosphodiester bond in the other strand to create a DNA hairpin. Transesterification reactions on DNA with phosphorothioate linkages at the target bond proceed with retention of stereoconfiguration at the phosphorus, indicating, uniquely for a restriction enzyme, a twostep mechanism. We propose that BfiI first makes a covalent enzyme-DNA intermediate, and then it resolves it by a nucleophilic attack of water or an alcohol, to yield hydrolysis or transesterification products, respectively.I n the presence of Mg 2ϩ , type II restriction endonucleases (REases) hydrolyze specific phosphodiester bonds in DNA to yield 5Ј-phosphate and 3Ј-hydroxyl termini (1). The stereochemical pathway for phosphodiester hydrolysis by four such enzymes, EcoRI, EcoRV, SfiI, and HpaII (2-4), have been determined. All proceed with inversion of configuration at the scissile phosphate, which implies an odd number of chemical steps in the hydrolytic reaction, and it is most simply accounted for by a direct in-line displacement of the 3Ј-leaving group by water (5-7). High-resolution structures are available for many more REases than have been analyzed stereochemically (1). Their active sites are generally similar, with several carboxylates to act as ligands for Mg 2ϩ in spatially equivalent positions (1). All such enzymes probably act in the same way, by using water to attack the scissile phosphate, to invert its configuration.Endonucleases from the transposase-retroviral integrase family, like MuA or HIV-integrase, catalyze at a single active site two sets of reactions on DNA (4, 8, 9). The first, the endonucleolytic cleavage of the 3Ј end of the transposon or viral DNA, is mechanistically similar to the hydrolysis reactions of REases. The second, termed DNA strand transfer, is a single-step transesterification in which the newly liberated 3Ј-OH group attacks and becomes linked to a phosphate group in the target DNA (9, 10).We ask here whether the BfiI REase can catalyze transesterification reactions in addition to DNA hydrolysis. BfiI cleaves DNA at specified positions downstream from an asymmetric recognition sequence (11). Unlike other REases, it functions without metal ions (12). The N-terminal half of BfiI (13, 14) is similar to Nuc, an EDTA-resistant nuclease from Salmonella typhimurium (15, 16) that belongs to the phospholipase D (PLD) superfamily. The PLD superfamily is a diverse group of proteins that includes phospholipases, phospholipid synthases, bacterial toxins, phosphodiesterases (PDEs), and nucleases (17, 18). The PLD enzymes catal...

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A novel family of phospholipase D homologues that includes phospholipid synthases and putative endonucleases: Identification of duplicated repeats and potential active site residues

Cited by 303 publications

References 70 publications

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

A Eukaryote-like Cardiolipin Synthase Is Present in Streptomyces coelicolor and in Most Actinobacteria

Site-specific DNA transesterification catalyzed by a restriction enzyme

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