View source for Phosphatase Superfamily PHP

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[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PHP|PHP Fold]]: [[Phosphatase_Superfamily_PHP|PHP Superfamily]]

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

=== Evolution ===
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 (memo: carry out positive selection analysis to infer whether they evolved different functions). They 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
Note: His-53 and Lys-21 are critical to its catalytic activity (see below).

=== Domain ===
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 <cite>Gong</cite>): (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.

=== Functions ===
Several substrates have been reported, including ''beta'' subunit of heterotrimeric G proteins <cite>Maurer04</cite>, the metabolic enzyme adenosine 5’-triphosphate-citrate lyase (ACL) <cite>Klumpp03</cite>, and the Ca2+-activated K+ channel KCa3.1 <cite>Skolnik08</cite>. These are known or suspected substrates of the nucleoside diphosphate kinases ([http://kinase.com/wiki/index.php/Kinase_Group_NDK 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 [http://www.gtexportal.org/home/gene/PHPT1 GTEx]. In ''C. elegans'', PHP is expressed exclusively in neurons <cite>Klumpp02</cite>. In human cells, the overexpression of PHPT1 decreases the activity of adenosine 5’-triphosphate-citrate lyase (ACL) and reduces the viability of neuronal cells <cite>Klumpp09</cite>.

=== References ===
<biblio>
#Gong pmid=18991813
#Maurer04 pmid=16039992
#Klumpp03 pmid=12788074
#Skolnik08 pmid=18796614
#Klumpp02 pmid=12468887
#Klumpp09 pmid=19138678
</biblio>