The role of phosphate in the action of thymidine phosphorylase inhibitors: Implications for the catalytic mechanism

Harsh V. Jain; Roshni Rasheed; Thomas I. Kalman

doi:10.1016/j.bmcl.2010.01.076

The role of phosphate in the action of thymidine phosphorylase inhibitors: Implications for the catalytic mechanism

Harsh V. Jain
, Roshni Rasheed
, Thomas I. Kalman

Chemistry

SUNY Buffalo

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

The design and synthesis of 5-fluoro-6-[(2-aminoimidazol-1-yl)methyl]uracil (AIFU), a potent inhibitor of thymidine phosphorylase (TP) with K_i-values of 11 nM (ecTP) and 17 nM (hTP), are described. Kinetic studies established that the type of inhibition of TP by AIFU is uncompetitive with respect to inorganic phosphate (or arsenate). The results obtained suggest that AIFU and other zwitterionic thymine analog inhibitors of TP act as transition state analogs, mimicking the anionic thymine leaving group, consistent with an S_N2-type catalytic mechanism, and anchored by their protonated side chains to the enzyme-bound phosphate by electrostatic and H-bonding interactions.

Original language	English
Pages (from-to)	1648-1651
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	5
DOIs	https://doi.org/10.1016/j.bmcl.2010.01.076
State	Published - Mar 1 2010

Keywords

Enzyme mechanism
Inhibition kinetics
Thymidine phosphorylase
Transition state analog

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10.1016/j.bmcl.2010.01.076

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title = "The role of phosphate in the action of thymidine phosphorylase inhibitors: Implications for the catalytic mechanism",

abstract = "The design and synthesis of 5-fluoro-6-[(2-aminoimidazol-1-yl)methyl]uracil (AIFU), a potent inhibitor of thymidine phosphorylase (TP) with Ki-values of 11 nM (ecTP) and 17 nM (hTP), are described. Kinetic studies established that the type of inhibition of TP by AIFU is uncompetitive with respect to inorganic phosphate (or arsenate). The results obtained suggest that AIFU and other zwitterionic thymine analog inhibitors of TP act as transition state analogs, mimicking the anionic thymine leaving group, consistent with an SN2-type catalytic mechanism, and anchored by their protonated side chains to the enzyme-bound phosphate by electrostatic and H-bonding interactions.",

keywords = "Enzyme mechanism, Inhibition kinetics, Thymidine phosphorylase, Transition state analog",

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TY - JOUR

T1 - The role of phosphate in the action of thymidine phosphorylase inhibitors

T2 - Implications for the catalytic mechanism

AU - Jain, Harsh V.

AU - Rasheed, Roshni

AU - Kalman, Thomas I.

PY - 2010/3/1

Y1 - 2010/3/1

N2 - The design and synthesis of 5-fluoro-6-[(2-aminoimidazol-1-yl)methyl]uracil (AIFU), a potent inhibitor of thymidine phosphorylase (TP) with Ki-values of 11 nM (ecTP) and 17 nM (hTP), are described. Kinetic studies established that the type of inhibition of TP by AIFU is uncompetitive with respect to inorganic phosphate (or arsenate). The results obtained suggest that AIFU and other zwitterionic thymine analog inhibitors of TP act as transition state analogs, mimicking the anionic thymine leaving group, consistent with an SN2-type catalytic mechanism, and anchored by their protonated side chains to the enzyme-bound phosphate by electrostatic and H-bonding interactions.

AB - The design and synthesis of 5-fluoro-6-[(2-aminoimidazol-1-yl)methyl]uracil (AIFU), a potent inhibitor of thymidine phosphorylase (TP) with Ki-values of 11 nM (ecTP) and 17 nM (hTP), are described. Kinetic studies established that the type of inhibition of TP by AIFU is uncompetitive with respect to inorganic phosphate (or arsenate). The results obtained suggest that AIFU and other zwitterionic thymine analog inhibitors of TP act as transition state analogs, mimicking the anionic thymine leaving group, consistent with an SN2-type catalytic mechanism, and anchored by their protonated side chains to the enzyme-bound phosphate by electrostatic and H-bonding interactions.

KW - Enzyme mechanism

KW - Inhibition kinetics

KW - Thymidine phosphorylase

KW - Transition state analog

UR - https://www.scopus.com/pages/publications/76649116193

U2 - 10.1016/j.bmcl.2010.01.076

DO - 10.1016/j.bmcl.2010.01.076

M3 - Article

C2 - 20138520

AN - SCOPUS:76649116193

SN - 0960-894X

VL - 20

SP - 1648

EP - 1651

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 5

ER -

The role of phosphate in the action of thymidine phosphorylase inhibitors: Implications for the catalytic mechanism

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Keywords

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