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Structural aspects of the inhibition and catalytic mechanism of thymidylate synthase

100%

Hardy L. W.

Acta Biochimica Polonica

1995

tom 42

nr 4

Thymidylate synthase (TS) is a target for anticancer drugs, due to its unique role in the biosynthesis of an essential DNA precursor. The X-ray structures available for several bacterial enzymes have been used to design novel inhibitors of TS, to structurally analyze the binding mode of existing inhibitors, and to propose catalytic roles for amino-acid residues on the protein. The first part of this paper describes some aspects of structure-based drug design, including a recent result from the groups of Montfort and Maley emphasizing the importance of conformational changes in inhibitor binding. The second part of the paper describes the work of the author on the TS mechanism, especially the catalytic roles of active site amino acids Asnl77 and Glu58 in TS from Escherichia coli. An important function for Glu58 is proposed to be preventing the excessive stabilization of a covalent intermediate. The use of isotope effects to probe the mechanistic basis for stimulation of E. coli TS by magnesium ions, and to identify differences between the E. coli and human enzymes, is described. The hypothesis that N5 of tetrahydrofolate provides the basicity for deprotonation of the nucleotide is also discussed.

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Carbon isotope distribution along pine needles [Pinus nigra Arnold]

80%

Barszczowska L., Jedrysek M. O.

Acta Societatis Botanicorum Poloniae

2005

tom 74

nr 2

In this paper we show spatial carbon isotope variations in black pine (Pinus nigra Arnold) needles, collected in spring 2001 and autumn 2003, from trees at the coast of south-western Croatia island (Žirje) and southern Spain (Benalmadena near Malaga), respectively. Needles were segmented perpendicularly to the longer axis (base, middle and top) and each segment was analysed separately. d13C values in needles from Croatia varied between -26.65‰ to -24.43‰ (2 months old needles) and from -28.25‰ to -25.21‰ (1 year old needles), while d13C values in needles from Spain varied from -27.58‰ to -25.27‰. The difference between d13Cb (base) and d13Ct (top) in the same needle (D13Cb-t) varied from 1.85 to 2.05‰ (in young needles from Croatia), from 0,02 to 1,80‰ (young needles from Spain), and 1.16 to 2.32‰, (in old needles from Croatia). The average D13Cb-t values were 0.78‰ and 1.73‰ in Spain and Croatia, respectively. In each needle the base of the needle was always 13C-enriched as compared to the top of the same needle. This evidences that carbon isotopes are not retranslocated after its fixation into the leaf structure (after the growth process is over). Temperature variation was most probably negligible for the discovered intraneedle carbon isotope distribution. Although, the intraneedle carbon isotope inhomogeneity can be partly the result of seasonal variation in d13C of atmospheric CO2, most probably the remarkably high D13Cb-t values, and regular pattern, are predominantly resulting from isotopic and chemical composition of primary and secondary products contained in the growin part of needle and kinetic isotope fractionation during decomposition of storage materials at the base.

Ograniczanie wyników

1 Acta Biochimica Polonica

1 Acta Societatis Botanicorum Poloniae

1 Barszczowska L.

1 Hardy L. W.

1 Jedrysek M. O.

1 2005

1 1995

Wyniki wyszukiwania

Structural aspects of the inhibition and catalytic mechanism of thymidylate synthase

Carbon isotope distribution along pine needles [Pinus nigra Arnold]