Histidine residues, phosphorylation

FIGURE 19.24 A mechanism for the phosphoglycerate mutase reaction in rabbit muscle and in yeast. Zelda Rose of the Institute for Cancer Research in Philadelphia showed that the enzyme requires a small amount of 2,3-BPG to phosphorylate the histidine residue before the mechanism can proceed. Prior to her work, the role of the phosphohistidine in this mechanism was not understood. 

Interestingly, however, the mechanisms of the two phosphate hydrolysis reactions in steps 9 and 11 are not the same. In step 9, water is the nucleophile, but in the glucose 6-phosphate reaction of step 11, a histidine residue on the enzyme attacks phosphorus, giving a phosphoryl enzyme intermediate that subsequently reacts with water. 

Histidine phosphatases and aspartate phosphatases are well established in lower organisms, mainly in bacteria and in context with two-component-systems . Reversible phosphorylation of histidine residues in vertebrates is in its infancy. The first protein histidine phosphatase (PHP) from mammalian origin was identified just recently. The soluble 14 kD protein does not resemble any of the other phosphatases. ATP-citrate lyase and the (3-subunit of heterotrimeric GTP-binding proteins are substrates of PHP thus touching both, metabolic pathways and signal transduction [4]. 

Klumpp S, Krieglstein J (2005) Reversible phosphorylation of histidine residues in vertebrate proteins. Minireview Biochim Biophys Acta 1754 291—295... 

Phenylphosphate synthase consists of three subunits with molecular masses of 70, 40, and 24kDa. Subunit 1 resembles the central part of classical phospho-enolpyruvate synthase which contains a conserved histidine residue. It catalyzes the exchange of free [ C] phenol and the phenol moiety of phenylphosphate but not the phosphorylation of phenol. Phosphorylation of phenol requires subunit 1, MgATP, and another protein, subunit 2 (40kDa), which resembles the N-terminal part of phosphoenolpyruvate synthase. Subunit 1 and 2 catalyze the following reaction ... 

The reaction of X with S must be fast and reversible, close to if not at equilibrium with concentration of S. It can be that there is an intermediate step in which X binds to a protein kinase (a protein which phosphorylates other proteins mostly at histidine residues in bacteria) using phosphate transferred from ATP. It then gives XP which is the transcription factor, where concentration of S still decides the extent of phosphorylation. No change occurs in DNA itself. Here equilibrium is avoided as dephosphorylation involves a phosphatase, though changes must be relatively quick since, for example, cell cycling and division depend on these steps, which must be completed in minutes. We have noted that such mechanical trigger-proteins as transcription factors are usually based on a-helical backbones common to all manner of such adaptive conformational responses (Section 4.11). 

N-phosphorylation has been reported for HI and H4, modifying HI at lysine residues (N -phosphoryl lysine) and H4 at a histidine residue (1- or 3-phosphoryl histidine) [109]. The modification is acid-labile and alkali-stable, and is destroyed by acid-extraction procedures used in isolating histones. 

P ADP -I- phosphohistone H4 <1> (a histidine residue is phosphorylated at r-position, yielding 3-phosphohistidine) [1]... 

Ribonuclease A hydrolyzes RNA adjacent to pyrimidine bases. The reaction proceeds through a 2, 3 -phosphate cyclic diester intermediate. Formation and breakdown of the cyclic diester appear to be promoted by concerted general-base and general-acid catalysis by two histidine residues, and by electrostatic interactions with two lysines. These reactions proceed through pentavalent phosphoryl intermediates. The geometry of these intermediates resembles the geometry of vanadate compounds that act as inhibitors of the enzyme. 

In a series of elegant studies, Miller and colleagues demonstrated that small peptides containing modified histidine residues (re-methyl-histidine) were effective catalysts for enantioselective acylation and phosphorylation reactions [12, 13]. As peptides in this family are able to transfer stereochemical information, these catalysts were also tested to carry out site- and regio-selective reactions, which take place against kinetic expectations. The screening of a small library (36 members)... 

Accordingly, Hammett constants or combinations of the argnments a and b can be used to estimate both complex stabilities of substituted aromatics with donor site atoms other than C in biology/biochemistry. Therefore the connection between the rest of the protein and tyrosine phenolate, tryptophan indole or histidine imidazole moieties is taken to be one huge substituent (e.g. in the frequent cases where three histidine residues coordinate to one copper or zinc ion or with tyrosine residues in water photooxidation), possibly introducing charge effects by pH, phosphorylation ( P switch ) or by complexation of other metals like Ca on the outer periphery of the molecule. 

In V. harveyi, in the absence of the AI-2 pheromone, the membrane-bound kinase LuxQ undergoes autophosphorylation on a conserved histidine residue (20, 21). The phosphoryl group is then transferred from the histidine of LuxQ to an aspartate of the response regulator LuxU. Phospho-LuxU in turn phosphorylates LuxO. Phospho-LuxO together with the sigma factor 0 then activates transcription of a set of small... 

Figure 17.14. Structure of Succinyl CoA Synthetase. The enzyme is composed of two subunits. The a subunit contains a Rossmann fold that binds the ADP component of CoA, and the (3 subunit contains a nucleotideactivating region called the ATP-grasp domain. The ATP-grasp domain is shown here binding a molecule of ADP. The histidine residue picks up the phosphoryl group from near the CoA and swings over to transfer it to the nucleotide bound in the ATP-grasp domain.

This system is employed by prokaryotic organisms, and homologous pathways have recently been identified in eukaryotes. The prototypical two-component pathway consists of two proteins A protein histidine kinase (sensor kinase) and a response regulator. Histidine kinases are very distinct from the superfamily of conventional protein serine/threonine and tyrosine kinases. The histidine kinases auto-phosphorylate on histidine residues and are involved in the phosphorylation of aspartate amino acids and their targets. 

The fructose released during this process (Fig. 15.9b-ii) binds to a glycan phosphotransferase system (PTS) of enzymes on the cell surface. This binding activates an enzyme on the cytosolic side of the PTS to attach a phosphate residue from phosphoenolpyruvate in the cytosol to a histidine residue of a PTS protein on the cytosoic side of the inner membrane. This activates the PTS enzyme system to transfer fructose 6-phosphate to the cytosol where it is phosphorylated and metabolized to lactate by glycolysis (Fig. 1.7). The PTS returns to its original conformation and another fructose molecule attaches and is transferred. The lactic acid is excreted, but trapped at the tooth surface by the glucan capsule. 

---