1oum

OverviewOverview

Activation of prodrugs by Escherichia coli purine nucleoside phosphorylase, (PNP) provides a method for selectively killing tumor cells expressing a, transfected PNP gene. This gene therapy approach requires matching a, prodrug and a known enzymatic activity present only in tumor cells. The, specificity of the method relies on avoiding prodrug cleavage by enzymes, already present in the host cells or the intestinal flora. Using, crystallographic and computer modeling methods as guides, we have, redesigned E. coli PNP to cleave new prodrug substrates more efficiently, than does the wild-type enzyme. In particular, the M64V PNP mutant cleaves, 9-(6-deoxy-alpha-L-talofuranosyl)-6-methylpurine with a kcat/Km over 100, times greater than for native E. coli PNP. In a xenograft tumor, experiment, this compound caused regression of tumors expressing the M64V, PNP gene.

About this StructureAbout this Structure

1OUM is a Single protein structure of sequence from Escherichia coli with PO4 and TAL as ligands. Active as Purine-nucleoside phosphorylase, with EC number 2.4.2.1 Full crystallographic information is available from OCA.

ReferenceReference

Designer gene therapy using an Escherichia coli purine nucleoside phosphorylase/prodrug system., Bennett EM, Anand R, Allan PW, Hassan AE, Hong JS, Levasseur DN, McPherson DT, Parker WB, Secrist JA 3rd, Sorscher EJ, Townes TM, Waud WR, Ealick SE, Chem Biol. 2003 Dec;10(12):1173-81. PMID:14700625

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