Phosphoryl group, transfer acid phosphatase

A/B Phosphatases Phosphoryl group transfer from a phosphoric monoester to water as an acceptor molecule. (Phosphoric monoesters are cleaved hydrolytically). 3.1.3. 3.6.1. Phosphoric ester hydrolases Hydrolases acting on acid anhydrides in phosphorous-containing anhydrides... 

Historically, the protein phosphatases were classified into two groups according to their substrate specificity tyrosine phosphatases and serine/threonine protein phosphatases. The latter are metalloenzymes we will refer to these as metallophospha-tases, a superfamily of enzymes that includes the serine/threonine protein phosphatases, purple acid phosphatases, and other enzymes capable of phosphoryl group transfer reactions such as bacteriophage A protein phosphatase [17, 18]. 

Phosphates of pharmaceutical interest are often monoesters (Sect. 9.3), and the enzymes that are able to hydrolyze them include alkaline and acid phosphatases. Alkaline phosphatase (alkaline phosphomonoesterase, EC 3.1.3.1) is a nonspecific esterase of phosphoric monoesters with an optimal pH for catalysis of ca. 8 [140], In the presence of a phosphate acceptor such as 2-aminoethanol, the enzyme also catalyzes a transphosphorylation reaction involving transfer of the phosphoryl group to the alcohol. Alkaline phosphatase is bound extracellularly to membranes and is widely distributed, in particular in the pancreas, liver, bile, placenta, and osteoplasts. Its specific functions in mammals remain poorly understood, but it seems to play an important role in modulation by osteoplasts of bone mineralization. 

Stereochemistry is another powerful tool for determining the net reaction pathway of phosphatases and sulfatases. These enzymes catalyze the net transfer of a phosphoryl or sulfuryl group to water from a monoester, producing inorganic phosphate or sulfate. Inversion results when the reaction occurs in a single step (Scheme 2, pathway a). Phosphatases that transfer the phosphoryl group directly to water with inversion typically possess a binuclear metal center and the nucleophile is a metal-coordinated hydroxide. Examples of phosphatases that follow this mechanism are the purple acid phosphatases (PAPs) and the serine/threonine phosphatases (described in Sections 8.09.4.3 and 8.09.4.4.1). Net retention of stereochemistry occurs when a phosphorylated or sulfiirylated enzyme intermediate is on the catalytic pathway, which is hydrolyzed by the nucleophilic addition of water in a subsequent step (Scheme 2, pathway b). 

Figure 17-1 Universal regulation by protein phosphorylation. Protein phosphorylation requires the coordinated actions of protein kinases, which transfer a phosphoryl group to a target protein, and protein phosphatases, which remove it via hydrolysis. Phosphorylation of a target protein can change its biological activity in many ways including enzymatic activity, intracellular localization, and its ability to interact with other macromolecules such as DNA, RNA, and proteins. The most common amino acids which are phosphorylated in eukaryotic organisms are serine, threonine, and tyrosine. Phosphorylation on histidine with subsequent phosphoryl transfer to aspartic acid represents a coitunon modification in prokaryotic two-component signal transduction s)rstems (see Figure 17-15A).

Earlier, we have reviewed the most fundamental properties about zincdD s nucleophilicity and the basicity of L— Zn —OH (L = model ligands such as macrocyclic polyamines or tris(pyrazolyl)borate) (6). More recent model studies by us and other groups have been trying to answer further questions (i) Why (or how) is serine needed in alkaline phosphatase More indirectly, what are the points of the serine OH group intervening as acyl- or phosphoryl-transfer agents (ii) Why is a bimetallic system favorable for phosphate hydrolysis (iii) Why does nature adopt zinc(II) as a Lewis acid in zinc enzymes or imidazole as a Lewis base (in the serine-imidazole-carboxylate triad) in serine enzymes (iv) Why are four zinc(II)-bound cysteines used for demethyl-ation (repair) of methyl-DNA phosphotriester, damaged DNA In this review, we want to present the latest results related to these puzzles. 

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