Phosphatase Subfamily LHPP

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Phosphatase Classification: Fold HAD: Superfamily HAD: Family NagD: Subfamily LHPP

LHPP is a protein histidine phosphatase, similar to Subfamily PHP


Two clear subsets of this subfamily are seen across eumetazoa: LHPP (lysine histidine pyrophosphate phosphatase) and HDHD2 (Haloacid Dehalogenase-like Hydrolase Domain containing 2). Distinct HDHD2 and LHPP genes are found as single copies in most animals, though Drosophila lacks LHPP and sea urchin has an additional HDHD2 pseudogene [1]. A HDHD2 homolog is seen in other holozoa, and very similar genes are seen fungi (but lost in ascomycetes), in a few algae and in both bacteria and archaea.


LHPP proteins consist of a twin HAD domains, from different subfamilies (Hydrolase_6 and Hydolase_like in Pfam), part of the IIA subfamily of HAD superfamily hydrolases. A number of structure are available from the structural genomics consortium, but have not been analyzed for publication.


LHPP from cow was shown to dephosphorylate succinic thiokinase and nucleoside diphosphate kinase autophosphorylated at His residues. LHPP also has activity against free phospho-lysine and phospho-histidine amino acids [2].

HDHD2 has not been experimentally studied in any species.


  1. Chen MJ, Dixon JE, and Manning G. Genomics and evolution of protein phosphatases. Sci Signal. 2017 Apr 11;10(474). DOI:10.1126/scisignal.aag1796 | PubMed ID:28400531 | HubMed [Chen]
  2. Hiraishi H, Yokoi F, and Kumon A. Bovine liver phosphoamidase as a protein histidine/lysine phosphatase. J Biochem. 1999 Aug;126(2):368-74. DOI:10.1093/oxfordjournals.jbchem.a022459 | PubMed ID:10423531 | HubMed [Hiraishi]
All Medline abstracts: PubMed | HubMed