Biological Phosphoryl-Transfer Reactions: Understanding Mechanism and Catalysis

Lassila, Jonathan K.; Zalatan, Jesse G.; Herschlag, Daniel

doi:10.1146/annurev-biochem-060409-092741

Cited by 377 publications

(717 citation statements)

References 161 publications

(189 reference statements)

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“…26 a) as well as the effect of different mutations (Glennon et al 2000 ;Shurki & Warshel, 2004), (see Fig. 26 b), whereas treatments of the type suggested in (Lassila et al 2011) can, at best, tell us the sign of the mutational effect.…”

Section: The Ras/gap System and The Mechanism Of The Corresponding Phmentioning

confidence: 97%

“…It seems to us that the above misunderstanding is compounded by the recent argument (Lassila et al 2011) that (Maegley et al 1996) actually predicted the effect of the Arg finger (Fig. 27) and its relationship to the dissociative mechanism (now suddenly called ' loose ' TS).…”

Section: The Ras/gap System and The Mechanism Of The Corresponding Phmentioning

confidence: 98%

“…The converse, however, is not true, that is, shifting the parabolas for the different mechanisms can give rise to similar LFER (Å qvist et al 1999). The molecular origin for this will be discussed further in Section 3, however, as mentioned above, there exists very strong computational evidence to suggest that the interpretation of observed LFER is, despite assertions otherwise (Lassila et al 2011), actually rather complicated, and that LFER therefore do not need to have a unique mechanistic interpretation. Here we again emphasize (as we will do in other sections) that our arguments about LFER and mechanism cannot be resolved experimentally in any unique way, and the final judgment must involve reliable computations.…”

Section: Qualitative Brønsted-type Linear Free-energy Relationships (mentioning

confidence: 98%

“…In fact, as discussed extensively in this section, we have clearly demonstrated that the substrate-as-base mechanism operates through far more associative or concerted TS. However, it has been argued (most recently in Lassila et al 2011) that there is no impetus for deprotonating the attacking water molecule in the TS (which as we know from the discussion in Section 3.5 is incorrect since the pK a of the attacking water changes drastically). But, if this were true, where would the proton ultimately end up ?…”

Section: Mechanistic Insights Controversies and Misunderstandingsmentioning

confidence: 99%

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Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

340

448

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Phosphoryl transfer plays key roles in signaling, energy transduction, protein synthesis, and maintaining the integrity of the genetic material. On the surface, it would appear to be a simple nucleophile displacement reaction. However, this simplicity is deceptive, as, even in aqueous solution, the low-lying d-orbitals on the phosphorus atom allow for eight distinct mechanistic possibilities, before even introducing the complexities of the enzyme catalyzed reactions. To further complicate matters, while powerful, traditional experimental techniques such as the use of linear free-energy relationships (LFER) or measuring isotope effects cannot make unique distinctions between different potential mechanisms. A quarter of a century has passed since Westheimer wrote his seminal review, ‘Why Nature Chose Phosphate’ (Science 235 (1987), 1173), and a lot has changed in the field since then. The present review revisits this biologically crucial issue, exploring both relevant enzymatic systems as well as the corresponding chemistry in aqueous solution, and demonstrating that the only way key questions in this field are likely to be resolved is through careful theoretical studies (which of course should be able to reproduce all relevant experimental data). Finally, we demonstrate that the reason that naturereallychose phosphate is due to interplay between two counteracting effects: on the one hand, phosphates are negatively charged and the resulting charge-charge repulsion with the attacking nucleophile contributes to the very high barrier for hydrolysis, making phosphate esters among the most inert compounds known. However, biology is not only about reducing the barrier to unfavorable chemical reactions. That is, the same charge-charge repulsion that makes phosphate ester hydrolysis so unfavorable also makes it possible to regulate, by exploiting the electrostatics. This means that phosphate ester hydrolysis can not only be turned on, but also be turned off, by fine tuning the electrostatic environment and the present review demonstrates numerous examples where this is the case. Without this capacity for regulation, it would be impossible to have for instance a signaling or metabolic cascade, where the action of each participant is determined by the fine-tuned activity of the previous piece in the production line. This makes phosphate esters the ideal compounds to facilitate life as we know it.

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Section: The Ras/gap System and The Mechanism Of The Corresponding Phmentioning

confidence: 97%

Section: The Ras/gap System and The Mechanism Of The Corresponding Phmentioning

confidence: 98%

Section: Qualitative Brønsted-type Linear Free-energy Relationships (mentioning

confidence: 98%

Section: Mechanistic Insights Controversies and Misunderstandingsmentioning

confidence: 99%

See 2 more Smart Citations

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

340

448

View full text Add to dashboard Cite

show abstract

“…Other phosphotransfer reactions do, however, take place without the need for a classic general acid/base pair (Cleland and Hengge, 2006). Finally, the metal ion itself may activate the nucleophilic hydroxyl moiety (Lassila et al, 2011) as the phosphoacceptor approaches the active site in order to provide the necessary rate enhancement expected of an enzyme.…”

Section: Implications For the Phosphotransferase Mechanism Catalysed mentioning

confidence: 99%

A widespread family of bacterial cell wall assembly proteins

et al. 2011

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Teichoic acids and acidic capsular polysaccharides are major anionic cell wall polymers (APs) in many bacteria, with various critical cell functions, including maintenance of cell shape and structural integrity, charge and cation homeostasis, and multiple aspects of pathogenesis. We have identified the widespread LytR-Cps2A-Psr (LCP) protein family, of previously unknown function, as novel enzymes required for AP synthesis. Structural and biochemical analysis of several LCP proteins suggest that they carry out the final step of transferring APs from their lipid-linked precursor to cell wall peptidoglycan (PG). In Bacillus subtilis, LCP proteins are found in association with the MreB cytoskeleton, suggesting that MreB proteins coordinate the insertion of the major polymers, PG and AP, into the cell wall.

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Phosphoryl Transfer Reactions

Hengge

2015

Encyclopedia of Life Sciences

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Phosphoryl transfer is the name given to the chemical process of the transfer of the phosphoryl group ( PO 3 ) from a phosphate ester or anhydride to a nucleophile. Nucleophilic attack by water on a phosphate monoester gives the hydrolysis product inorganic phosphate. This net dephosphorylation reaction is the process catalysed by phosphatases. Although the reaction is thermodynamically favourable, it has a very high kinetic barrier, making the uncatalysed hydrolysis of phosphate esters extremely slow. The opposite process, the formation of phosphate esters, is termed phosphorylation and is accomplished in biological systems by kinases. The balance between phosphatase and kinase activities in biology serves to regulate the phosphorylation level of many enzymes and other proteins in the cell, forming an important regulatory mechanism that is found throughout the biological world. Key Concepts The post‐translational phosphorylation levels of proteins are regulated by the complimentary actions of phosphatases and kinases. The uncatalysed hydrolysis of phosphate esters has a very high kinetic barrier, making phosphatases among the most efficient enzymes known. The various families of phosphatases use different catalytic machinery and mechanisms to carry out phosphate ester hydrolysis.

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Biological Phosphoryl-Transfer Reactions: Understanding Mechanism and Catalysis

Cited by 377 publications

References 161 publications

Why nature really chose phosphate

Why nature really chose phosphate

A widespread family of bacterial cell wall assembly proteins

Phosphoryl Transfer Reactions

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