New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C 8 substitution in structural analogues of S-adenosylmethionine

Diane E. McCloskey, Shridhar Bale, John A. Secrist, Anita Tiwari, Thomas H. Moss, Jacob Valiyaveettil, Wesley H. Brooks, Wayne C. Guida, Anthony E. Pegg, Steven E. Ealick

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C 8-substituted adenine analogues bound in the active site.

Original languageEnglish (US)
Pages (from-to)1388-1407
Number of pages20
JournalJournal of Medicinal Chemistry
Volume52
Issue number5
DOIs
StatePublished - Mar 12 2009

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Adenosylmethionine Decarboxylase
S-Adenosylmethionine
Adenine
Catalytic Domain
Enzymes
Decarboxylation
Aptitude
Group Processes
X Ray Crystallography
Biosynthetic Pathways
Polyamines
Ligands

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

McCloskey, Diane E. ; Bale, Shridhar ; Secrist, John A. ; Tiwari, Anita ; Moss, Thomas H. ; Valiyaveettil, Jacob ; Brooks, Wesley H. ; Guida, Wayne C. ; Pegg, Anthony E. ; Ealick, Steven E. / New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase : studies of adenine C 8 substitution in structural analogues of S-adenosylmethionine. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 5. pp. 1388-1407.
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abstract = "S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C 8-substituted adenine analogues bound in the active site.",
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New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase : studies of adenine C 8 substitution in structural analogues of S-adenosylmethionine. / McCloskey, Diane E.; Bale, Shridhar; Secrist, John A.; Tiwari, Anita; Moss, Thomas H.; Valiyaveettil, Jacob; Brooks, Wesley H.; Guida, Wayne C.; Pegg, Anthony E.; Ealick, Steven E.

In: Journal of Medicinal Chemistry, Vol. 52, No. 5, 12.03.2009, p. 1388-1407.

Research output: Contribution to journalArticle

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AU - McCloskey, Diane E.

AU - Bale, Shridhar

AU - Secrist, John A.

AU - Tiwari, Anita

AU - Moss, Thomas H.

AU - Valiyaveettil, Jacob

AU - Brooks, Wesley H.

AU - Guida, Wayne C.

AU - Pegg, Anthony E.

AU - Ealick, Steven E.

PY - 2009/3/12

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