Human HAD phosphatases: structure, mechanism, and roles in health and disease

FEBS J. 2013 Jan;280(2):549-71. doi: 10.1111/j.1742-4658.2012.08633.x. Epub 2012 Jun 13.


Phosphatases of the haloacid dehalogenase (HAD) superfamily of hydrolases are an ancient and very large class of enzymes that have evolved to dephosphorylate a wide range of low- and high molecular weight substrates with often exquisite specificities. HAD phosphatases constitute approximately one-fifth of all human phosphatase catalytic subunits. While the overall sequence similarity between HAD phosphatases is generally very low, family members can be identified based on the presence of a characteristic Rossmann-like fold and the active site sequence DxDx(V/T). HAD phosphatases employ an aspartate residue as a nucleophile in a magnesium-dependent phosphoaspartyl transferase reaction. Although there is genetic evidence demonstrating a causal involvement of some HAD phosphatases in diseases such as cancer, cardiovascular, metabolic and neurological disorders, the physiological roles of many of these enzymes are still poorly understood. In this review, we discuss the structure and evolution of human HAD phosphatases, and summarize their known functions in health and disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Sequence
  • Female
  • Humans
  • Hydrolases / metabolism*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Phosphoric Monoester Hydrolases / chemistry*
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Protein Structure, Tertiary*
  • Protein Tyrosine Phosphatases / chemistry
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism
  • Sequence Homology, Amino Acid


  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Hydrolases
  • Phosphoric Monoester Hydrolases
  • EYA2 protein, human
  • Protein Tyrosine Phosphatases
  • 2-haloacid dehalogenase