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Studies on Phosphohistidine Phosphatase 1: What? Where? Why?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Phosphohistidine phosphatase 1 (PHPT1) is a small protein, consisting of 125 amino acids, that catalyzes the dephosphorylation of histidine but does not have any activity towards other phosphorylated amino acids. PHPT1 was identified in 2002, and is so far the only mammalian histidine phosphatase known, but still little is known about its physiological role. No mammalian histidine kinases have hitherto been identified.

Phosphorylation is one of the most important ways in which the structure and activity of a protein may be changed after translation. Proteins are phosphorylated on the side chain of amino acid residues. When a hydroxyl is phosphorylated the result is a phosphoester and when a nitrogen is phosphorylated the result is a phosphoamidate. Histidine may be phosphorylated on either of the two nitrogens of the imidazole ring of the side chain. The resulting phosphoamidate bond is labile and rich in energy, which makes histidine phosphorylation highly reversible and flexible. However, histidine phosphorylation is less studied than that of the phosphoesters due to the acid lability of the phosphoamidate bond.

The work described in this thesis was focused on further elucidating the physiological role of PHPT1. Amino acid residues of importance for the activity of PHPT1 were identified, and mutants with decreased phosphatase activity were produced. These mutants have been used in studies on the function of PHPT1. By using immunohistochemical methodology the localization of PHPT1 in both mouse and human tissues was determined, with mainly similar results. A general finding was that expression of PHPT1 was high in epithelial cells with short turnover time, indicating that PHPT1 may have an important role in proliferating cells. We have also developed a comparatively fast and simple screening method for determination of PHPT1 activity. Since research in this field has been hampered by the lack of efficient and practical methodology, hopefully this new method will be an asset in search of inhibitors for PHPT1, which in turn may be used for detection of the elusive mammalian histidine kinases, the finding of which may give major breakthroughs in the field.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 44 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 760
Keyword [en]
PHPT1, Phosphohistidine phosphatase, PHP, Assay
National Category
Other Basic Medicine
Research subject
Medical Biochemistry
URN: urn:nbn:se:uu:diva-171881ISBN: 978-91-554-8329-6OAI: diva2:512904
Public defence
2012-05-16, C10:301, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Available from: 2012-04-25 Created: 2012-03-28 Last updated: 2012-08-01Bibliographically approved
List of papers
1. Mutational study of human phosphohistidine phosphatase: effect on enzymatic activity.
Open this publication in new window or tab >>Mutational study of human phosphohistidine phosphatase: effect on enzymatic activity.
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2005 (English)In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 337, no 3, 887-91 p.Article in journal (Refereed) Published
Amino Acid Sequence, Amino Acid Substitution, Binding Sites, Enzyme Activation, Evolution; Molecular, Humans, Molecular Sequence Data, Mutagenesis; Site-Directed, Mutation, Phosphoprotein Phosphatase/analysis/*chemistry/genetics/*metabolism, Protein Binding, Recombinant Proteins/analysis/chemistry/metabolism, Research Support; Non-U.S. Gov't, Sequence Homology; Amino Acid, Structure-Activity Relationship, Substrate Specificity
urn:nbn:se:uu:diva-80308 (URN)16219293 (PubMedID)
Available from: 2006-05-05 Created: 2006-05-05 Last updated: 2012-05-30
2. Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues
Open this publication in new window or tab >>Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues
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2009 (English)In: Uppsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, no 2, 65-72 p.Article in journal (Refereed) Published
Abstract [en]

Protein histidine phosphorylation accounts for about 6% of the total protein phosphorylation in eukaryotic cells; still details concerning histidine phosphorylation and dephosphorylation are limited. A mammalian 14-kDa phosphohistidine phosphatase, also denominated PHPT1, was found 6 years ago that provided a new tool in the study of phosphohistidine phosphorylation. The localization of PHPT1 mRNA by Northern blot analysis revealed high expression in heart and skeletal muscle. The main object of the present study was to determine the PHPT1 expression on protein level in mouse tissues in order to get further information on the physiological role of the enzyme. Tissue samples from adult mice and 14.5-day-old mouse embryos were processed for immunostaining using a PHPT1-specific polyclonal antibody. The same antibody was also provided to the Swedish human protein atlas project (HPR) ( The results from both studies were essentially consistent with the previously reported expression of mRNA of a few human tissues. In addition, several other tissues, including testis, displayed a high protein expression. A salient result of the present investigation was the ubiquitous expression of the PHPT1 protein and its high expression in continuously dividing epithelial cells.

Phosphohistidine phosphatase, PHPT1, PHP, phosphohistidine, dephosphorylation, HPR-project
National Category
Medical and Health Sciences
urn:nbn:se:uu:diva-119851 (URN)10.1080/03009730802642337 (DOI)000265454800001 ()19396692 (PubMedID)
Available from: 2010-03-02 Created: 2010-03-02 Last updated: 2012-05-30Bibliographically approved
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