Structures and mechanisms of Nudix hydrolases

A. S. Mildvan, Z. Xia, H. F. Azurmendi, V. Saraswat, P. M. Legler, M. A. Massiah, Sandra B Gabelli, Mario Antonio Bianchet, L. W. Kang, Mario L Amzel

Research output: Contribution to journalArticle

Abstract

Nudix hydrolases catalyze the hydrolysis of nucleoside diphosphates linked to other moieties, X, and contain the sequence motif or Nudix box, GX 5EX 7REUXEEXGU. The mechanisms of Nudix hydrolases are highly diverse in the position on the substrate at which nucleophilic substitution occurs, and in the number of required divalent cations. While most proceed by associative nucleophilic substitutions by water at specific internal phosphorus atoms of a diphosphate or polyphosphate chain, members of the GDP-mannose hydrolase sub-family catalyze dissociative nucleophilic substitutions, by water, at carbon. The site of substitution is likely determined by the positions of the general base and the entering water. The rate accelerations or catalytic powers of Nudix hydrolases range from 10 9- to 10 12-fold. The reactions are accelerated 10 3-10 5-fold by general base catalysis by a glutamate residue within, or beyond the Nudix box, or by a histidine beyond the Nudix box. Lewis acid catalysis, which contributes ≥10 3-10 5-fold to the rate acceleration, is provided by one, two, or three divalent cations. One divalent cation is coordinated by two or three conserved residues of the Nudix box, the initial glycine and one or two glutamate residues, together with a remote glutamate or glutamine ligand from beyond the Nudix box. Some Nudix enzymes require one (MutT) or two additional divalent cations (Ap 4AP), to neutralize the charge of the polyphosphate chain, to help orient the attacking hydroxide or oxide nucleophile, and/or to facilitate the departure of the anionic leaving group. Additional catalysis (10-10 3-fold) is provided by the cationic side chains of lysine and arginine residues and by H-bond donation by tyrosine residues, to orient the general base, or to promote the departure of the leaving group. The overall rate accelerations can be explained by both independent and cooperative effects of these catalytic components.

Original languageEnglish (US)
Pages (from-to)129-143
Number of pages15
JournalArchives of Biochemistry and Biophysics
Volume433
Issue number1
DOIs
StatePublished - Jan 1 2005

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Divalent Cations
Substitution reactions
Catalysis
Glutamic Acid
Polyphosphates
Diphosphates
Water
Guanosine Diphosphate Mannose
Lewis Acids
Nucleophiles
Hydrolases
Glutamine
Nucleosides
Histidine
Glycine
Phosphorus
Oxides
Lysine
Tyrosine
Arginine

Keywords

  • Catalytic power
  • Divalent cation activators
  • General base catalysis
  • Lewis acid catalysis
  • Mutagenesis studies
  • NMR
  • Nudix enzymes
  • Nudix sequence motif
  • Pulsed EPR
  • Solution structures
  • X-ray structures

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Mildvan, A. S., Xia, Z., Azurmendi, H. F., Saraswat, V., Legler, P. M., Massiah, M. A., ... Amzel, M. L. (2005). Structures and mechanisms of Nudix hydrolases. Archives of Biochemistry and Biophysics, 433(1), 129-143. https://doi.org/10.1016/j.abb.2004.08.017

Structures and mechanisms of Nudix hydrolases. / Mildvan, A. S.; Xia, Z.; Azurmendi, H. F.; Saraswat, V.; Legler, P. M.; Massiah, M. A.; Gabelli, Sandra B; Bianchet, Mario Antonio; Kang, L. W.; Amzel, Mario L.

In: Archives of Biochemistry and Biophysics, Vol. 433, No. 1, 01.01.2005, p. 129-143.

Research output: Contribution to journalArticle

Mildvan, AS, Xia, Z, Azurmendi, HF, Saraswat, V, Legler, PM, Massiah, MA, Gabelli, SB, Bianchet, MA, Kang, LW & Amzel, ML 2005, 'Structures and mechanisms of Nudix hydrolases', Archives of Biochemistry and Biophysics, vol. 433, no. 1, pp. 129-143. https://doi.org/10.1016/j.abb.2004.08.017
Mildvan AS, Xia Z, Azurmendi HF, Saraswat V, Legler PM, Massiah MA et al. Structures and mechanisms of Nudix hydrolases. Archives of Biochemistry and Biophysics. 2005 Jan 1;433(1):129-143. https://doi.org/10.1016/j.abb.2004.08.017
Mildvan, A. S. ; Xia, Z. ; Azurmendi, H. F. ; Saraswat, V. ; Legler, P. M. ; Massiah, M. A. ; Gabelli, Sandra B ; Bianchet, Mario Antonio ; Kang, L. W. ; Amzel, Mario L. / Structures and mechanisms of Nudix hydrolases. In: Archives of Biochemistry and Biophysics. 2005 ; Vol. 433, No. 1. pp. 129-143.
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