Short, strong hydrogen bonds on enzymes: NMR and mechanistic studies

A. S. Mildvan, M. A. Massiah, Thomas K Harris, G. T. Marks, D. H T Harrison, C. Viragh, P. M. Reddy, I. M. Kovach

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The lengths of short, strong hydrogen bonds (SSHBs) on enzymes have been determined with high precision (±0.05 Å) from the chemical shifts (δ), and independently from the D/H fractionation factors (φ) of the highly deshielded protons involved. These H-bond lengths agree well with each other and with those found by protein X-ray crystallography, within the larger errors of the latter method (±0.2 to ± 0.8 Å) [Proteins 35 (1999) 275]. A model dihydroxynaphthalene compound shows a SSHB of 2.54 ± 0.04 Å based on δ = 17.7 ppm and φ = 0.56 ± 0.04, in agreement with the high resolution X-ray distance of 2.55 ± 0.06 Å. On ketosteroid isomerase, a SSHB is found (2.50 ± 0.02 Å), based on δ = 18.2 ppm and φ = 0.34, from Tyr-14 to the 3-O- of estradiol, an analog of the enolate intermediate. Its strength is ∼7 kcal/mol. On triosephosphate isomerase, SSHBs are found from Glu-165 to the 1-NOH of phosphoglycolohydroxamic acid (PGH), an analog of the enolic intermediate (2.55 ± 0.05 Å), and from His-95 to the enolic-O- of PGH (2.62 ± 0.02 Å). In the methylglyoxal synthase-PGH complex, a SSHB (2.51 ± 0.02 Å) forms between Asp-71 and the NOH of PGH with a strength of ≥4.7 kcal/mol. When serine proteases bind mechanism-based inhibitors which form tetrahedral Ser-adducts analogous to the tetrahedral intermediates in catalysis, the Asp...His H-bond of the catalytic triad becomes a SSHB [Proc. Natl Acad. Sci. USA 95 (1998) 14664], 2.49-2.63 Å in length. Similarly, on the serine-esterase, butyrylcholinesterase complexed with the mechanism-based inhibitor m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone, a SSHB forms between Glu-327 and His-438 of the catalytic triad, 2.61 ± 0.04 Å in length, based on δ = 18.1 ppm and φ = 0.65 ± 0.10. Very similar results are obtained with (human) acetylcholinesterase. The strength of this SSHB is at least 4.9 kcal/mol.

Original languageEnglish
Pages (from-to)163-175
Number of pages13
JournalJournal of Molecular Structure
Volume615
Issue number1-3
DOIs
StatePublished - Sep 26 2002
Externally publishedYes

Fingerprint

enzymes
Hydrogen
Hydrogen bonds
Nuclear magnetic resonance
hydrogen bonds
nuclear magnetic resonance
Enzymes
acids
Acids
inhibitors
Ketosteroids
Triose-Phosphate Isomerase
analogs
proteins
Butyrylcholinesterase
Isomerases
protease
X ray crystallography
X Ray Crystallography
Chemical shift

Keywords

  • Nucleic acids
  • Phosphoglycolohydroxamic acid
  • Short, strong hydrogen bonds

ASJC Scopus subject areas

  • Structural Biology
  • Organic Chemistry
  • Physical and Theoretical Chemistry
  • Spectroscopy
  • Atomic and Molecular Physics, and Optics

Cite this

Mildvan, A. S., Massiah, M. A., Harris, T. K., Marks, G. T., Harrison, D. H. T., Viragh, C., ... Kovach, I. M. (2002). Short, strong hydrogen bonds on enzymes: NMR and mechanistic studies. Journal of Molecular Structure, 615(1-3), 163-175. https://doi.org/10.1016/S0022-2860(02)00212-0

Short, strong hydrogen bonds on enzymes : NMR and mechanistic studies. / Mildvan, A. S.; Massiah, M. A.; Harris, Thomas K; Marks, G. T.; Harrison, D. H T; Viragh, C.; Reddy, P. M.; Kovach, I. M.

In: Journal of Molecular Structure, Vol. 615, No. 1-3, 26.09.2002, p. 163-175.

Research output: Contribution to journalArticle

Mildvan, AS, Massiah, MA, Harris, TK, Marks, GT, Harrison, DHT, Viragh, C, Reddy, PM & Kovach, IM 2002, 'Short, strong hydrogen bonds on enzymes: NMR and mechanistic studies', Journal of Molecular Structure, vol. 615, no. 1-3, pp. 163-175. https://doi.org/10.1016/S0022-2860(02)00212-0
Mildvan, A. S. ; Massiah, M. A. ; Harris, Thomas K ; Marks, G. T. ; Harrison, D. H T ; Viragh, C. ; Reddy, P. M. ; Kovach, I. M. / Short, strong hydrogen bonds on enzymes : NMR and mechanistic studies. In: Journal of Molecular Structure. 2002 ; Vol. 615, No. 1-3. pp. 163-175.
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N2 - The lengths of short, strong hydrogen bonds (SSHBs) on enzymes have been determined with high precision (±0.05 Å) from the chemical shifts (δ), and independently from the D/H fractionation factors (φ) of the highly deshielded protons involved. These H-bond lengths agree well with each other and with those found by protein X-ray crystallography, within the larger errors of the latter method (±0.2 to ± 0.8 Å) [Proteins 35 (1999) 275]. A model dihydroxynaphthalene compound shows a SSHB of 2.54 ± 0.04 Å based on δ = 17.7 ppm and φ = 0.56 ± 0.04, in agreement with the high resolution X-ray distance of 2.55 ± 0.06 Å. On ketosteroid isomerase, a SSHB is found (2.50 ± 0.02 Å), based on δ = 18.2 ppm and φ = 0.34, from Tyr-14 to the 3-O- of estradiol, an analog of the enolate intermediate. Its strength is ∼7 kcal/mol. On triosephosphate isomerase, SSHBs are found from Glu-165 to the 1-NOH of phosphoglycolohydroxamic acid (PGH), an analog of the enolic intermediate (2.55 ± 0.05 Å), and from His-95 to the enolic-O- of PGH (2.62 ± 0.02 Å). In the methylglyoxal synthase-PGH complex, a SSHB (2.51 ± 0.02 Å) forms between Asp-71 and the NOH of PGH with a strength of ≥4.7 kcal/mol. When serine proteases bind mechanism-based inhibitors which form tetrahedral Ser-adducts analogous to the tetrahedral intermediates in catalysis, the Asp...His H-bond of the catalytic triad becomes a SSHB [Proc. Natl Acad. Sci. USA 95 (1998) 14664], 2.49-2.63 Å in length. Similarly, on the serine-esterase, butyrylcholinesterase complexed with the mechanism-based inhibitor m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone, a SSHB forms between Glu-327 and His-438 of the catalytic triad, 2.61 ± 0.04 Å in length, based on δ = 18.1 ppm and φ = 0.65 ± 0.10. Very similar results are obtained with (human) acetylcholinesterase. The strength of this SSHB is at least 4.9 kcal/mol.

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