Phosphoryl functionalities

Synaptobrevins (VAMPs) Synaptogyrin Synaptophysins PKA but diverge C-terminally. Synapsins Ia/b contain C-terminal phosphorylation sites for CaMKII and CDK 5. Interact with microfilaments, neurofilaments, microtubules, SH3 domains, calmodulin and annexin VI in vitro. Small-membrane proteins that are cleaved by tetanus toxin and by botulinum toxins B, D, F and G. Polytopic membrane protein that is tyrosine-phosphorylated. Function unknown. Polytopic membrane proteins, including synaptoporin, that are tyrosine-phosphorylated and bind to synaptobrevins. May regulate SNARE function... 

Centromere protein A (CENP-A), one of several variants of histone H3, is phosphorylated on Ser 7 by Aurora B kinase which is equivalent to Ser 10 of histone H3 (Zeitlin et al, 2001). Recent studies demonstrate that Aurora A kinase also phosphorylates CENP-A (S7) (Kunitoku et al, 2003) (Table 1). The presence of CENP-A in centromeric nucleosomes is required for kinetochore organization and function (Choo 2001). Loss of CENP-A phosphorylation function at Ser 7 caused a mislocalisation of Aurora B, a putative partner phosphatase (PPl-yl) and inner centromere protein (INCENP). H3.3, another variant of histone H3 is phosphorylated on Ser 31 in vivo (Table 1). H3.3 (S31) is a mitosis-specific modification that is present only in late prometaphase and metaphase. Furthermore, H3.3 (S31) is excluded from centromeres. However it is enriched in distinct chromosomal areas immediately adjacent to centromeres (Hake et al, 2005). 

Ergiiden, J.-K. Schaumann, E. Phosphoryl functionalized bishomoallyl alcohols by ring opening of epoxides with lithiated allyldiphe-nylphosphane oxide. Synthesis 1996, 707—710. 

The phosphonomethylation of dialkyl [(alkylamino)alkyl]phosphonates (238) in the customary way yields products with mixed phosphoryl functions, e.g. the acids 239 or their esters 240 and 241 are obtained by the phosphonomethylation of alkyl[(alkylamino)-methyljphosphinic acids ... 

In general, Lawesson s reagent (and, in principle, other dithioxophosphorane dimers) is a powerful agent for simple thiations at both carbonyl and phosphoryl functions, for the preparation of sulphur- and of phosphorus-sulphur-containing heterocyclic compounds (these last being fundamentally derivatives of 4-methoxyphenylphosphono(di, tri)thioic acids and for the coupling of acids and amides, particularly in peptide synthesis. 

The field of acylphosphonates (a-ketophosphonates) has been reviewed previously This chapter will deal mostly with the advances made since the publication of the previous review however, results from the older literature will be included for completeness. This chapter includes functional derivatives of both the phosphoryl and the carbonyl groups. With regard to the phosphoryl group, this refers to acylphosphonic acids esterified to various degrees, and also to acylphosphonoamidates and to acylphosphonic mono-and dihalides. With respect to the carbonyl group, this refers mainly to enolates, enamines, oximes and hydrazones in which the closeness of the phosphoryl function has yielded a wealth of recent results. These are discussed separately in Sections II and IV. 

Dissimilatory nitrite reductase of denitrifying bacteria is usually a soluble enzyme and it has been difficult to ascribe a phosphorylative function associated with the conversion of nitrite to nitric oxide. However, the demonstration by Wood (1978) that the terminal reductase in nitrite respiration is located in the periplasm implies that electrons generated in the cytoplasm must traverse the cytoplasmic membrane to the periplasmic nitrite reduction site. This location would require proton pumping, thus facilitating phosphorylation by the chemiosmotic mechanism. 

With a dicopper complex bearing bis-imidazole ligands (Figure 25d), a strong cooperativity was observed for the 1,3 distal complex. The suggested mechanism involved double activation of the bridging phosphoryl function, followed by nucleophilic attack assisted by the coordinated hydroxide. ... 

However, the phosphoryl function does not consist of a 7c-bond between two p orbitals as does the carbonyl function. The phosphoryl 7c-bond involves an overlap between the p orbital of the oxygen atom and the d orbital... 

The phosphoryl function has significant double bond character, but the ylid is also important. 

In the case of acid phosphatase, the nucleophile is an imidazole (the intermediate phosphoramidate is susceptible to acid pH) and in the case of alkaline phosphatase, the nucleophile is a serine. Alkaline phosphatase is known to contain a zinc atom which probably functions as a binding site and a Lewis acid for the phosphoryl function. This is understandable when it is remembered how difficult the hydrolysis of phosphomonoesters is at alkaline pH. 

In keeping with its biogenetic origin m three molecules of acetic acid mevalonic acid has six carbon atoms The conversion of mevalonate to isopentenyl pyrophosphate involves loss of the extra carbon as carbon dioxide First the alcohol hydroxyl groups of mevalonate are converted to phosphate ester functions—they are enzymatically phosphorylated with introduction of a simple phosphate at the tertiary site and a pyrophosphate at the primary site Decarboxylation m concert with loss of the terti ary phosphate introduces a carbon-carbon double bond and gives isopentenyl pyrophos phate the fundamental building block for formation of isoprenoid natural products... 

In the example shown the 5 OH group is phosphorylated Nucleotides are also possible in which some other OH group bears the phosphate ester function Cyclic phosphates are common and important as biochemical messengers... 

The biochemical basis for the toxicity of mercury and mercury compounds results from its ability to form covalent bonds readily with sulfur. Prior to reaction with sulfur, however, the mercury must be metabolized to the divalent cation. When the sulfur is in the form of a sulfhydryl (— SH) group, divalent mercury replaces the hydrogen atom to form mercaptides, X—Hg— SR and Hg(SR)2, where X is an electronegative radical and R is protein (36). Sulfhydryl compounds are called mercaptans because of their ability to capture mercury. Even in low concentrations divalent mercury is capable of inactivating sulfhydryl enzymes and thus causes interference with cellular metaboHsm and function (31—34). Mercury also combines with other ligands of physiological importance such as phosphoryl, carboxyl, amide, and amine groups. It is unclear whether these latter interactions contribute to its toxicity (31,36). 

Phosphorus. Eighty-five percent of the phosphoms, the second most abundant element in the human body, is located in bones and teeth (24,35). Whereas there is constant exchange of calcium and phosphoms between bones and blood, there is very Httle turnover in teeth (25). The Ca P ratio in bones is constant at about 2 1. Every tissue and cell contains phosphoms, generally as a salt or ester of mono-, di-, or tribasic phosphoric acid, as phosphoHpids, or as phosphorylated sugars (24). Phosphoms is involved in a large number and wide variety of metaboHc functions. Examples are carbohydrate metaboHsm (36,37), adenosine triphosphate (ATP) from fatty acid metaboHsm (38), and oxidative phosphorylation (36,39). Common food sources rich in phosphoms are Hsted in Table 5 (see also Phosphorus compounds). 

Aminophenol is a selective nephrotoxic agent and intermpts proximal tubular function (121,122). Disagreement exists concerning the nephrotoxity of the other isomers although they are not as potent as 4-aminophenol (123,124). Respiration, oxidative phosphorylation, and ATPase activity are inhibited in rat kidney mitochondria (125). The aminophenols and their derivatives are inhibitors of 5-Hpoxygenase (126) and prostaglandin synthetase... 

The use of QM-MD as opposed to QM-MM minimization techniques is computationally intensive and thus precluded the use of an ab initio or density functional method for the quantum region. This study was performed with an AMi Hamiltonian, and the first step of the dephosphorylation reaction was studied (see Fig. 4). Because of the important role that phosphorus has in biological systems [62], phosphatase reactions have been studied extensively [63]. From experimental data it is believed that Cys-i2 and Asp-i29 residues are involved in the first step of the dephosphorylation reaction of BPTP [64,65]. Alaliambra et al. [30] included the side chains of the phosphorylated tyrosine, Cys-i2, and Asp-i 29 in the quantum region, with link atoms used at the quantum/classical boundaries. In this study the protein was not truncated and was surrounded with a 24 A radius sphere of water molecules. Stochastic boundary methods were applied [66]. 

Figure 6.24 The function of the enzyme phosphofructokinase. (a) Phosphofructokinase is a key enzyme in the gycolytic pathway, the breakdown of glucose to pyruvate. One of the end products in this pathway, phosphoenolpyruvate, is an allosteric feedback inhibitor to this enzyme and ADP is an activator, (b) Phosphofructokinase catalyzes the phosphorylation by ATP of fructose-6-phosphate to give fructose-1,6-bisphosphate. (c) Phosphoglycolate, which has a structure similar to phosphoenolpyruvate, is also an inhibitor of the enzyme.

The polypeptide chain of Src tyrosine kinase, and related family members, comprises an N-terminal "unique" region, which directs membrane association and other as yet unknown functions, followed by a SH3 domain, a SH2 domain, and the two lobes of the protein kinase. Members of this family can be phosphorylated at two important tyrosine residues—one in the "activation loop" of the kinase domain (Tyr 419 in c-Src), the other in a short... 

In the example shown, the 5 -OH group is phosphorylated. Nucleotides ae also possible in which sorme other OH group beas the phosphate ester-function. Cyclic phosphates ae cormrmon and irmportant as biochermical rmessengers. 

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