Specific adenosine phosphorylase from hepatopancreas of gastropod Helix pomatia

Trembacz, H.; Jeżewska, Maria

doi:10.1016/0305-0491(93)90270-f

Cited by 6 publications

(2 citation statements)

References 20 publications

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“…The PNP-1 from Sulfolobus solfataricus accepts MTAdo as a substrate in addition to adenosine (Ado), inosine (Ino) and guanosine (Guo) [19]. The PNP-1 from Helix pomatia cleaves Ado exclusively [20] and the PNP-1 from Plasmodium falciparum only cleaves Ino and methylthioinosine [21]. The second group (PNP-2) consists of vertebrate PNP's.…”

Section: Description Of Pnp Family Structuresmentioning

confidence: 99%

PNP Anticancer Gene Therapy

Zhang¹,

Parker²,

Sorscher³

et al. 2005

CTMC

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Escherichia coli purine nucleoside phosphorylase (PNP) catalyzes the cleavage of 9-(2-deoxy-beta-D-ribofuranosyl)-6-methylpurine (MeP-dR), while human PNP does not. MeP-dR is well tolerated while the cleavage product, 6-methylpurine (MeP), is highly cytotoxic. This clinical profile suggests an anticancer gene therapy strategy in which solid tumors are transfected with the gene for E. coli PNP. Tumor cells expressing E. coli PNP will liberate MeP and be killed. Furthermore, MeP released from the cell via the purine transport system will enter nearby cells, resulting in bystander killing of tumor cells. To reduce toxicity resulting from activation of MeP-dR by intestinal tract flora, we redesigned the E. coli PNP active site to cleave prodrugs that are not cleaved by wild type E. coli PNP. It is possible that the variation of substrate specificity among enzymes that cleave nucleosides will have broader application in the gene therapy approach to prodrug activation. Here we review progress in the development of E. coli PNP anticancer gene therapy. We also review the structural basis for activity of nucleoside phosphorylases and suggest future directions for the development of activating enzymes for suicide gene therapy.

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Section: Description Of Pnp Family Structuresmentioning

confidence: 99%

PNP Anticancer Gene Therapy

Zhang¹,

Parker²,

Sorscher³

et al. 2005

CTMC

View full text Add to dashboard Cite

show abstract

“…B. anthracis is genetically and phenotypically related to B. cereus (Ivanova et al, 2003;Read et al, 2003). Other organisms in which a distinct adenosine phosphorylase has been identified are Schistosoma mansoni (Miech et al, 1975), Acholeplasma laidlawii (McElwain et al, 1988), Helix pomatia (Trembacz & Jezewska, 1993) and Fasciola hepatica (Trembacz & Jezewska, 1998).…”

Section: Introductionmentioning

confidence: 99%

Structural basis of the substrate specificity ofBacillus cereusadenosine phosphorylase

Dessanti

Zhang

Allegrini

et al. 2012

Acta Crystallogr D Biol Cryst

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Purine nucleoside phosphorylases catalyze the phosphorolytic cleavage of the glycosidic bond of purine (2 0 -deoxy)nucleosides, generating the corresponding free base and (2 0 -deoxy)-ribose 1-phosphate. Two classes of PNPs have been identified: homotrimers specific for 6-oxopurines and homohexamers that accept both 6-oxopurines and 6-aminopurines. Bacillus cereus adenosine phosphorylase (AdoP) is a hexameric PNP; however, it is highly specific for 6-aminopurines. To investigate the structural basis for the unique substrate specificity of AdoP, the active-site mutant D204N was prepared and kinetically characterized and the structures of the wild-type protein and the D204N mutant complexed with adenosine and sulfate or with inosine and sulfate were determined at high resolution (1.2-1.4 Å ). AdoP interacts directly with the preferred substrate through a hydrogen-bond donation from the catalytically important residue Asp204 to N7 of the purine base. Comparison with Escherichia coli PNP revealed a more optimal orientation of Asp204 towards N7 of adenosine and a more closed active site. When inosine is bound, two water molecules are interposed between Asp204 and the N7 and O6 atoms of the nucleoside, thus allowing the enzyme to find alternative but less efficient ways to stabilize the transition state. The mutation of Asp204 to asparagine led to a significant decrease in catalytic efficiency for adenosine without affecting the efficiency of inosine cleavage.

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Adenosine phosphorylase and other enzymes of purine salvage in Pulmonata snails and their Trematoda parasites

Trembacz

Jeżewska

1994

Comparative Biochemistry and Physiology Part B: Comparative Bio

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Specific adenosine phosphorylase from hepatopancreas of gastropod Helix pomatia

Cited by 6 publications

References 20 publications

PNP Anticancer Gene Therapy

PNP Anticancer Gene Therapy

Structural basis of the substrate specificity ofBacillus cereusadenosine phosphorylase

Adenosine phosphorylase and other enzymes of purine salvage in Pulmonata snails and their Trematoda parasites

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