The histidine phosphatase superfamily is so named because catalysiscentres on a conserved His residue that is transiently phosphorylatedduring the catalytic cycle. Other conserved residues contribute to a'phosphate pocket' and interact with the phospho group of substratebefore, during and after its transfer to the His residue. Structure andsequence analyses show that different families contribute differentadditional residues to the 'phosphate pocket' and, more surprisingly,differ in the position, in sequence and in three dimensions, of acatalytically essential acidic residue. The superfamily may be dividedinto two main branches. The relationship between the two branches isnot evident by (PSI-)BLAST but is clear from more sensitive sequencesearches and structural comparisons [1].

The larger branch 1 contains a wide variety of catalytic functions, thebest known being fructose 2,6-bisphosphatase (found in a bifunctionalprotein with 2-phosphofructokinase) and cofactor-dependentphosphoglycerate mutase. The latter is an unusual example of a mutaseactivity in the superfamily: the vast majority of members appear to bephosphatases. The bacterial regulatory protein phosphatase SixA is alsoin branch 1 and has a minimal, and possible ancestral-like structure,lacking the large domain insertions that contribute to binding of smallmolecules in branch 1 members.

Phosphoglycerate mutase (5.4.2.1) (PGAM) and bisphosphoglycerate mutase (5.4.2.4) (BPGM) are structurally related enzymes that catalyse reactions involving the transfer of phospho groups between the three carbon atoms of phosphoglycerate [2, 3, 4]. Both enzymes can catalyse three different reactions with different specificities, the isomerization of 2-phosphoglycerate (2-PGA) to 3-phosphoglycerate (3-PGA) with 2,3-diphosphoglycerate (2,3-DPG) as the primer of the reaction, the synthesis of 2,3-DPG from 1,3-DPG with 3-PGA as a primer and the degradation of 2,3-DPG to 3-PGA (phosphatase 3.1.3.13 activity).

In mammals, PGAM is a dimeric protein with two isoforms, the M (muscle) and B (brain) forms. In yeast, PGAM is a tetrameric protein.

BPGM is a dimeric protein and is found mainly in erythrocytes where it plays a major role in regulating haemoglobin oxygen affinity as a consequence of controlling 2,3-DPG concentration. The catalytic mechanism of both PGAM and BPGM involves the formation of a phosphohistidine intermediate [5].

A number of other proteins including, the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase [6] that catalyses both the synthesis and the degradation of fructose-2,6-bisphosphate and bacterial alpha-ribazole-5'-phosphate phosphatase, which is involved in cobalamin biosynthesis, contain this domain [7].

1. The histidine phosphatase superfamily: structure and function. Biochem. J. 409, 333-48
2. Molecular cloning and nucleotide sequence of murine 2,3-bisphosphoglycerate mutase cDNA. Biochem. Biophys. Res. Commun. 156, 874-81
3. Sequence of the gene encoding phosphoglycerate mutase from Saccharomyces cerevisiae. FEBS Lett. 229, 383-7
4. Structure, function, and evolution of phosphoglycerate mutases: comparison with fructose-2,6-bisphosphatase, acid phosphatase, and alkaline phosphatase. Prog. Biophys. Mol. Biol. 73, 263-87
5. Intermediates in the phosphoglycerate mutase and bisphosphoglycerate synthase reactions. Meth. Enzymol. 87, 42-51
6. Evolution of a bifunctional enzyme: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Proc. Natl. Acad. Sci. U.S.A. 86, 9642-6
7. The cobC gene of Salmonella typhimurium codes for a novel phosphatase involved in the assembly of the nucleotide loop of cobalamin. J. Biol. Chem. 269, 26503-11

The histidine phosphatase superfamily is so named because catalysiscentres on a conserved His res
Show more...

Download genes (select columns to include)