Irreversible inhibition of S-adenosylmethionine decarboxylase of trypanosoma bru cei bru cei by S-adenosylmethionine analogues

Babu L. Tekwani, Cyrus J. Bacchi, John A. Secrist, Anthony E. Pegg

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

S-Adenosylmethionine analogues designed as active-site directed inhibitors were tested in vitro for their effects on S-adenosylmethionine decarboxylase (AdoMetDC) of Trypanosoma brucei brucei. These analogues contained a tertiary nitrogen atom in place of the sulfonium and had a side chain of variable length ending in a reactive group (hydrazino-, aminooxy-, hydrazido- or a methylnitrosourea). The hydrazino- derivatives were the most potent inhibitors with ic50 values in the range of 40-100 nM. The most active compound (ic50 of 0.04 μM) was 5'-deoxy-5'-[(2-hydrazinoethyl)-methylamino] adenosine (MHZEA). Addition of MHZEA produced a time-dependent inactivation with an apparent Ki, of 0.4 μM, and the enzyme half-life at a saturating concentration of MHZEA was 0.4 min. Increasing the length of the side chain or changing the methyl group attached to the nitrogen to an ethyl group reduced the potency. Replacement of the hydrazino moiety with an aminooxy group resulted in about a 30- to 35-fold decrease in inhibition potency. However, the relative order of activities of these aminooxy analogues was similar to that found in the hydrazino series with 5'-deoxy-5'-[(2-arninooxyethyl) methylamino]adenosine (MAOEA), which had an ic50 of 1.3 μM, being the most active. The hydrazido analogs were even less effective with 5'-deoxy-5'-[(3-hydrazino-3-oxopropyl)-methylamino] adenosine, the best inhibitor, having an ic50, value of 8.7 μM. The methylnitrosourea derivatives were inactive. The inactivation of trypanosomal AdoMetDC with MHZEA or MAOEA was irreversible and was greatly stimulated by putrescine, a known activator of the enzyme, indicating that the compounds bind to the active site and form a covalent bond with the enzyme. These inhibitors may have considerable potential as chemotherapeutic agents against trypanosomiasis and other protozoal infections and may also be useful in studying the role of AdoMetDC in the regulation of polyamine levels in these organisms.

Original languageEnglish (US)
Pages (from-to)905-911
Number of pages7
JournalBiochemical Pharmacology
Volume44
Issue number5
DOIs
StatePublished - Sep 1 1992

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Adenosylmethionine Decarboxylase
Trypanosoma
S-Adenosylmethionine
Adenosine
Inhibitory Concentration 50
Methylnitrosourea
Nitrogen
Enzyme Activators
Derivatives
Catalytic Domain
Covalent bonds
Putrescine
Polyamines
Enzymes
Trypanosoma brucei brucei
Trypanosomiasis
Half-Life
Atoms
Infection
5'-deoxy-5'-(N-methyl-N-(2-(aminooxy)ethyl)amino)adenosine

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

@article{a1e85e35529a4328bb1c7edaa4394e26,
title = "Irreversible inhibition of S-adenosylmethionine decarboxylase of trypanosoma bru cei bru cei by S-adenosylmethionine analogues",
abstract = "S-Adenosylmethionine analogues designed as active-site directed inhibitors were tested in vitro for their effects on S-adenosylmethionine decarboxylase (AdoMetDC) of Trypanosoma brucei brucei. These analogues contained a tertiary nitrogen atom in place of the sulfonium and had a side chain of variable length ending in a reactive group (hydrazino-, aminooxy-, hydrazido- or a methylnitrosourea). The hydrazino- derivatives were the most potent inhibitors with ic50 values in the range of 40-100 nM. The most active compound (ic50 of 0.04 μM) was 5'-deoxy-5'-[(2-hydrazinoethyl)-methylamino] adenosine (MHZEA). Addition of MHZEA produced a time-dependent inactivation with an apparent Ki, of 0.4 μM, and the enzyme half-life at a saturating concentration of MHZEA was 0.4 min. Increasing the length of the side chain or changing the methyl group attached to the nitrogen to an ethyl group reduced the potency. Replacement of the hydrazino moiety with an aminooxy group resulted in about a 30- to 35-fold decrease in inhibition potency. However, the relative order of activities of these aminooxy analogues was similar to that found in the hydrazino series with 5'-deoxy-5'-[(2-arninooxyethyl) methylamino]adenosine (MAOEA), which had an ic50 of 1.3 μM, being the most active. The hydrazido analogs were even less effective with 5'-deoxy-5'-[(3-hydrazino-3-oxopropyl)-methylamino] adenosine, the best inhibitor, having an ic50, value of 8.7 μM. The methylnitrosourea derivatives were inactive. The inactivation of trypanosomal AdoMetDC with MHZEA or MAOEA was irreversible and was greatly stimulated by putrescine, a known activator of the enzyme, indicating that the compounds bind to the active site and form a covalent bond with the enzyme. These inhibitors may have considerable potential as chemotherapeutic agents against trypanosomiasis and other protozoal infections and may also be useful in studying the role of AdoMetDC in the regulation of polyamine levels in these organisms.",
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Irreversible inhibition of S-adenosylmethionine decarboxylase of trypanosoma bru cei bru cei by S-adenosylmethionine analogues. / Tekwani, Babu L.; Bacchi, Cyrus J.; Secrist, John A.; Pegg, Anthony E.

In: Biochemical Pharmacology, Vol. 44, No. 5, 01.09.1992, p. 905-911.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Irreversible inhibition of S-adenosylmethionine decarboxylase of trypanosoma bru cei bru cei by S-adenosylmethionine analogues

AU - Tekwani, Babu L.

AU - Bacchi, Cyrus J.

AU - Secrist, John A.

AU - Pegg, Anthony E.

PY - 1992/9/1

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N2 - S-Adenosylmethionine analogues designed as active-site directed inhibitors were tested in vitro for their effects on S-adenosylmethionine decarboxylase (AdoMetDC) of Trypanosoma brucei brucei. These analogues contained a tertiary nitrogen atom in place of the sulfonium and had a side chain of variable length ending in a reactive group (hydrazino-, aminooxy-, hydrazido- or a methylnitrosourea). The hydrazino- derivatives were the most potent inhibitors with ic50 values in the range of 40-100 nM. The most active compound (ic50 of 0.04 μM) was 5'-deoxy-5'-[(2-hydrazinoethyl)-methylamino] adenosine (MHZEA). Addition of MHZEA produced a time-dependent inactivation with an apparent Ki, of 0.4 μM, and the enzyme half-life at a saturating concentration of MHZEA was 0.4 min. Increasing the length of the side chain or changing the methyl group attached to the nitrogen to an ethyl group reduced the potency. Replacement of the hydrazino moiety with an aminooxy group resulted in about a 30- to 35-fold decrease in inhibition potency. However, the relative order of activities of these aminooxy analogues was similar to that found in the hydrazino series with 5'-deoxy-5'-[(2-arninooxyethyl) methylamino]adenosine (MAOEA), which had an ic50 of 1.3 μM, being the most active. The hydrazido analogs were even less effective with 5'-deoxy-5'-[(3-hydrazino-3-oxopropyl)-methylamino] adenosine, the best inhibitor, having an ic50, value of 8.7 μM. The methylnitrosourea derivatives were inactive. The inactivation of trypanosomal AdoMetDC with MHZEA or MAOEA was irreversible and was greatly stimulated by putrescine, a known activator of the enzyme, indicating that the compounds bind to the active site and form a covalent bond with the enzyme. These inhibitors may have considerable potential as chemotherapeutic agents against trypanosomiasis and other protozoal infections and may also be useful in studying the role of AdoMetDC in the regulation of polyamine levels in these organisms.

AB - S-Adenosylmethionine analogues designed as active-site directed inhibitors were tested in vitro for their effects on S-adenosylmethionine decarboxylase (AdoMetDC) of Trypanosoma brucei brucei. These analogues contained a tertiary nitrogen atom in place of the sulfonium and had a side chain of variable length ending in a reactive group (hydrazino-, aminooxy-, hydrazido- or a methylnitrosourea). The hydrazino- derivatives were the most potent inhibitors with ic50 values in the range of 40-100 nM. The most active compound (ic50 of 0.04 μM) was 5'-deoxy-5'-[(2-hydrazinoethyl)-methylamino] adenosine (MHZEA). Addition of MHZEA produced a time-dependent inactivation with an apparent Ki, of 0.4 μM, and the enzyme half-life at a saturating concentration of MHZEA was 0.4 min. Increasing the length of the side chain or changing the methyl group attached to the nitrogen to an ethyl group reduced the potency. Replacement of the hydrazino moiety with an aminooxy group resulted in about a 30- to 35-fold decrease in inhibition potency. However, the relative order of activities of these aminooxy analogues was similar to that found in the hydrazino series with 5'-deoxy-5'-[(2-arninooxyethyl) methylamino]adenosine (MAOEA), which had an ic50 of 1.3 μM, being the most active. The hydrazido analogs were even less effective with 5'-deoxy-5'-[(3-hydrazino-3-oxopropyl)-methylamino] adenosine, the best inhibitor, having an ic50, value of 8.7 μM. The methylnitrosourea derivatives were inactive. The inactivation of trypanosomal AdoMetDC with MHZEA or MAOEA was irreversible and was greatly stimulated by putrescine, a known activator of the enzyme, indicating that the compounds bind to the active site and form a covalent bond with the enzyme. These inhibitors may have considerable potential as chemotherapeutic agents against trypanosomiasis and other protozoal infections and may also be useful in studying the role of AdoMetDC in the regulation of polyamine levels in these organisms.

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