Phosphatase Family PHP

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Phosphatase Classification: PHP Fold: PHP Superfamily: PHP Family

PHP is the only phosphatase known to be histidine-specific.


PHP is found throughout eukaryotes, though lost from fungi. It is usually single copy per genome, but four are found in Drosophila melanogaster. Three of them (janA, janB, con) arranged as tandem duplications which are conserved other flies of melanogaster group. The janA is canonical PHP, but the other three have substitution at conserved positions of canonical PHPs. The most conserved positions include:

  • Motif 1: 18 GxFKY 22
  • Motif 2: 45 RG 46
  • Motif 3: H 53
  • Motif 4: 75 GGGx[RK]IxH 81
  • Motif 5: 92 GxSxxxGxAxH 102

His-53 and Lys-21 are required for catalytic activity (see below).


PHP has a single domain: catalytic domain. The structure of the domain has been solved and a potential enzymatic mechanism proposed (see figure 4 in [1]): (i) the substrate binds to the protein by forming four H-bonds; (ii) His-53 acts as a general base to activate a water molecule, which in turn functions as a nucleophile to attack the phosphate substrate; and (iii) the positively charged amine group of Lys-21 helps in stabilizing the transition state during catalysis.


Several substrates have been reported, including beta subunit of heterotrimeric G proteins [2], the metabolic enzyme adenosine 5’-triphosphate-citrate lyase (ACL) [3], and the Ca2+-activated K+ channel KCa3.1 [4]. These are known or suspected substrates of the nucleoside diphosphate kinases (NDK).

Its role in neuronal cells is particularly interesting. Human PHP (PHPT1) is widely expressed across different tissues, most abundantly in cerebellum and pituitary, according to RNA-seq data from GTEx. In C. elegans, PHP is expressed exclusively in neurons [5]. In human cells, the overexpression of PHPT1 decreases the activity of adenosine 5’-triphosphate-citrate lyase (ACL) and reduces the viability of neuronal cells [6].


  1. Gong W, Li Y, Cui G, Hu J, Fang H, Jin C, and Xia B. Solution structure and catalytic mechanism of human protein histidine phosphatase 1. Biochem J. 2009 Mar 1;418(2):337-44. DOI:10.1042/BJ20081571 | PubMed ID:18991813 | HubMed [Gong]
  2. Mäurer A, Wieland T, Meissl F, Niroomand F, Mehringer R, Krieglstein J, and Klumpp S. The beta-subunit of G proteins is a substrate of protein histidine phosphatase. Biochem Biophys Res Commun. 2005 Sep 9;334(4):1115-20. DOI:10.1016/j.bbrc.2005.06.200 | PubMed ID:16039992 | HubMed [Maurer04]
  3. Klumpp S, Bechmann G, Mäurer A, Selke D, and Krieglstein J. ATP-citrate lyase as a substrate of protein histidine phosphatase in vertebrates. Biochem Biophys Res Commun. 2003 Jun 20;306(1):110-5. DOI:10.1016/s0006-291x(03)00920-3 | PubMed ID:12788074 | HubMed [Klumpp03]
  4. Srivastava S, Zhdanova O, Di L, Li Z, Albaqumi M, Wulff H, and Skolnik EY. Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14442-6. DOI:10.1073/pnas.0803678105 | PubMed ID:18796614 | HubMed [Skolnik08]
  5. Klumpp S, Hermesmeier J, Selke D, Baumeister R, Kellner R, and Krieglstein J. Protein histidine phosphatase: a novel enzyme with potency for neuronal signaling. J Cereb Blood Flow Metab. 2002 Dec;22(12):1420-4. DOI:10.1097/01.wcb.0000045041.03034.99 | PubMed ID:12468887 | HubMed [Klumpp02]
  6. Klumpp S, Faber D, Fischer D, Litterscheid S, and Krieglstein J. Role of protein histidine phosphatase for viability of neuronal cells. Brain Res. 2009 Apr 6;1264:7-12. DOI:10.1016/j.brainres.2008.12.052 | PubMed ID:19138678 | HubMed [Klumpp09]
All Medline abstracts: PubMed | HubMed