Carbonic anhydrase inhibitors: The very weak inhibitors dithiothreitol, β-mercaptoethanol, tris(carboxyethyl)phosphine and threitol interfere with the binding of sulfonamides to isozymes II and IX

Alessio Innocenti; Mika Hilvo; Andrea Scozzafava; Mikaela Lindfors; Henri R. Nordlund; Markku S. Kulomaa; Seppo Parkkila; Claudiu T. Supuran

doi:10.1016/j.bmcl.2008.02.008

Carbonic anhydrase inhibitors: The very weak inhibitors dithiothreitol, β-mercaptoethanol, tris(carboxyethyl)phosphine and threitol interfere with the binding of sulfonamides to isozymes II and IX

Alessio Innocenti, Mika Hilvo, Andrea Scozzafava, Mikaela Lindfors, Henri R. Nordlund, Markku S. Kulomaa, Seppo Parkkila, Claudiu T. Supuran (Corresponding Author)

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Abstract

The inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) with dithiothreitol, 2-mercaptoethanol, tris(carboxyethyl)phosphine (reducing agent frequently added to enzyme assay buffers) and threitol has been investigated. The agents were very weak inhibitors of isozymes CA II and CA IX, but unexpectedly, strongly influenced the binding of the low nanomolar sulfonamide inhibitor acetazolamide (5-acetamido-1,3,4-thiadiazole-2-sulfonamide). Acetazolamide affinity for all investigated CAs diminished orders of magnitude with increasing concentrations of these agents in the assay system. DTT and similar derivatives should not be added to the assay buffers used in monitoring CA activity/inhibition, as they lead to under-estimation of the binding constants, by a mechanism probably involving the formation of ternary complexes.

Original language	English
Pages (from-to)	1898-1903
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2008.02.008
Publication status	Published - 2008
MoE publication type	A1 Journal article-refereed

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10.1016/j.bmcl.2008.02.008

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Innocenti, A., Hilvo, M., Scozzafava, A., Lindfors, M., Nordlund, H. R., Kulomaa, M. S., Parkkila, S., & Supuran, C. T. (2008). Carbonic anhydrase inhibitors: The very weak inhibitors dithiothreitol, β-mercaptoethanol, tris(carboxyethyl)phosphine and threitol interfere with the binding of sulfonamides to isozymes II and IX. Bioorganic and Medicinal Chemistry Letters, 18(6), 1898-1903. https://doi.org/10.1016/j.bmcl.2008.02.008

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title = "Carbonic anhydrase inhibitors: The very weak inhibitors dithiothreitol, β-mercaptoethanol, tris(carboxyethyl)phosphine and threitol interfere with the binding of sulfonamides to isozymes II and IX",

abstract = "The inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) with dithiothreitol, 2-mercaptoethanol, tris(carboxyethyl)phosphine (reducing agent frequently added to enzyme assay buffers) and threitol has been investigated. The agents were very weak inhibitors of isozymes CA II and CA IX, but unexpectedly, strongly influenced the binding of the low nanomolar sulfonamide inhibitor acetazolamide (5-acetamido-1,3,4-thiadiazole-2-sulfonamide). Acetazolamide affinity for all investigated CAs diminished orders of magnitude with increasing concentrations of these agents in the assay system. DTT and similar derivatives should not be added to the assay buffers used in monitoring CA activity/inhibition, as they lead to under-estimation of the binding constants, by a mechanism probably involving the formation of ternary complexes.",

author = "Alessio Innocenti and Mika Hilvo and Andrea Scozzafava and Mikaela Lindfors and Nordlund, {Henri R.} and Kulomaa, {Markku S.} and Seppo Parkkila and Supuran, {Claudiu T.}",

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language = "English",

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Innocenti, A, Hilvo, M, Scozzafava, A, Lindfors, M, Nordlund, HR, Kulomaa, MS, Parkkila, S & Supuran, CT 2008, 'Carbonic anhydrase inhibitors: The very weak inhibitors dithiothreitol, β-mercaptoethanol, tris(carboxyethyl)phosphine and threitol interfere with the binding of sulfonamides to isozymes II and IX', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 6, pp. 1898-1903. https://doi.org/10.1016/j.bmcl.2008.02.008

Carbonic anhydrase inhibitors: The very weak inhibitors dithiothreitol, β-mercaptoethanol, tris(carboxyethyl)phosphine and threitol interfere with the binding of sulfonamides to isozymes II and IX. / Innocenti, Alessio; Hilvo, Mika; Scozzafava, Andrea et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 6, 2008, p. 1898-1903.

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

TY - JOUR

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AU - Innocenti, Alessio

AU - Hilvo, Mika

AU - Scozzafava, Andrea

AU - Lindfors, Mikaela

AU - Nordlund, Henri R.

AU - Kulomaa, Markku S.

AU - Parkkila, Seppo

AU - Supuran, Claudiu T.

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AB - The inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) with dithiothreitol, 2-mercaptoethanol, tris(carboxyethyl)phosphine (reducing agent frequently added to enzyme assay buffers) and threitol has been investigated. The agents were very weak inhibitors of isozymes CA II and CA IX, but unexpectedly, strongly influenced the binding of the low nanomolar sulfonamide inhibitor acetazolamide (5-acetamido-1,3,4-thiadiazole-2-sulfonamide). Acetazolamide affinity for all investigated CAs diminished orders of magnitude with increasing concentrations of these agents in the assay system. DTT and similar derivatives should not be added to the assay buffers used in monitoring CA activity/inhibition, as they lead to under-estimation of the binding constants, by a mechanism probably involving the formation of ternary complexes.

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Innocenti A, Hilvo M, Scozzafava A, Lindfors M, Nordlund HR, Kulomaa MS et al. Carbonic anhydrase inhibitors: The very weak inhibitors dithiothreitol, β-mercaptoethanol, tris(carboxyethyl)phosphine and threitol interfere with the binding of sulfonamides to isozymes II and IX. Bioorganic and Medicinal Chemistry Letters. 2008;18(6):1898-1903. doi: 10.1016/j.bmcl.2008.02.008

Carbonic anhydrase inhibitors: The very weak inhibitors dithiothreitol, β-mercaptoethanol, tris(carboxyethyl)phosphine and threitol interfere with the binding of sulfonamides to isozymes II and IX

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