Guanidinium Groups Act as General-Acid Catalysts in Phosphoryl Transfer Reactions:  A Two-Proton Inventory on a Model System

Piątek, Anna; Gray, Mark; Anslyn, Eric V.

doi:10.1021/ja046894v

Cited by 59 publications

(44 citation statements)

References 18 publications

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“…The rate enhancement attributed to assistance by the guanidinium group is 42 [56]: impressive for this flexible system in solvent water, and comparable with the best systems designed to show general acid catalysis of intramolecular nucleophilic catalysis discussed in the following section. 13) of the very weakly acidic guanidinium group, and the proton inventory (in water, pH 10.4 at 50 C; B ¼ N-methyl piperidine) is consistent with two protons in flight in the rate determining step shown.…”

Section: Scheme 227supporting

confidence: 65%

General Acid–Base Catalysis in Model Systems

Kirby

2006

Hydrogen‐Transfer Reactions

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IntroductionProton transfer is the most common reaction in living systems, in which reactions have to be strictly controlled, and most are catalyzed by enzymes. The great majority of enzyme catalyzed reactions are ionic, involving heterolytic bond making and breaking, and thus the creation or neutralization of charge. Under conditions of constant pH this requires the transfer of protons (Eq. (2.1)). ð2:1ÞGeneral acid and general base catalysis are terms commonly used to describe two different characteristics of reactions, the (observable) form of the rate law or a (hypothetical) reaction mechanism proposed to account for it. It is important to be aware of (and for authors to make clear) which is meant in a particular case.General acid-base catalysis provides mechanisms for bringing about the necessary proton transfers without involving hydrogen or hydroxide ions, which are present in water at concentrations of only about 10 À7 M under physiological conditions. At pHs near neutrality relatively weak acids and bases can compete with lyonium or lyate species because they can be present in much higher concentrations. 2.1.1 KineticsThe basics of general acid and general base catalysis are described clearly and in detail in Chapter 8 of Maskill [1]. Acid-base catalysis is termed specific if the rate of the reaction concerned depends only on the acidity (pH, etc.) of the medium. This is the case if the reaction involves the conjugate acid or base of the reactant preformed in a rapid equilibrium process -normal behavior if the reactant is weakly basic or acidic. The conjugate acid or base is then, by definition, a strong 975 acid or base, and the reverse proton transfer to solvent is thus rapid, probably diffusion-controlled -and certainly faster than a competing forward reaction involving the making or breaking of covalent bonds. This forward reaction of the conjugate acid or base of the reactant is therefore rate determining, and the rate expression -for example for the hydrolysis of an unreactive ester (Scheme 2.1)contains only a single term in (lyonium) acid concentration:General acid-base catalysis is defined experimentally by the appearance in the rate law of acids and/or bases other than lyonium or lyate ions. For example, the hydrolysis of enol ethers 1.2 (Scheme 2.2) is general acid-catalyzed. In strong acid the rate expression will be the same as in Scheme 2.1, but near neutral pH the rate is found to depend also on the concentration of the buffer ðHA þ A À Þ used to maintain the pH. Measurements at different buffer ratios show that the catalytic species is the acid HA. (If more than one acid is present there will be an additional term k HAi ½HA i ½1:2 for each.)If in these experiments the measurements at different buffer ratios showed that the catalytic species was the conjugate base A À the reaction would be kinetically general base catalyzed. In which case HA and A À would probably subsequently be referred to as BH þ and B. Thus the enolisation of ketones is general base catalysed (Scheme 2.3). Àd½1:3=dt ¼ k...

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Section: Scheme 227supporting

confidence: 65%

General Acid–Base Catalysis in Model Systems

Kirby

2006

Hydrogen‐Transfer Reactions

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“…In the ESI mass spectrum (Figure S6, Supporting Information), the signals at m/z 267.94 and 348. 16 show the presence of ApA cleavage products adenosine (calcd 268.10) and adenine monophosphate (AMP, calcd 348.06). The generation of the adenosine and AMP indicates that the phosphodiester bond of ApA was cleaved by Cu 2 + -4 through the hydrolysis pathway.…”

Section: Wwwchemeurjorgmentioning

confidence: 99%

“…[33] In the present work, copper(II) can be coordinated to one of the pendant guanidines of 4 to form a (Scheme 2) in neutral aqueous solution. Anslyn [16] and Krämer [8] have demonstrated independently that the metal-bound water is easily deprotonated to form the metal-bound OH, when the guanidine (or amino) arms are in close proximity to the metal-bound water. As a result, there is a possible equilibrium (Scheme 2) between the copper(II)-bound water (a) and the copper(II)-bound OH (b).…”

Section: Wwwchemeurjorgmentioning

confidence: 99%

“…In particular, the transitionmetal complexes of macrocyclic polyamine derivatives such as 1,4,7,10-tetraazacyclododecane (cyclen) and 1,4,7-triazacyclononane (TACN) exhibit excellent ability to cleave nucleic acids, phosphodiesters, dipeptides, and proteins [3] and also show anti-tumor or anti-HIV virus activities. [4] In nature, the cleavage rate of the phosphodiesters of DNA and RNA by a hydrolytic pathway is accelerated 10 15 -10 16 -fold by metalloenzymes such as staphylococcal nuclease (SNase) from Staphylococcus aureus [5] and nuclease S1 from Aspergillus oryzae. [6] At the active site of SNase, a calcium(II) ion and two of the guanidinium groups of arginine residues cooperate to activate the substrate and stabilize phosphorate-like transition states by electrostatic interaction, hydrogen bonding, and/or proton transfer.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, DNA‐Binding, Cleavage, and Cytotoxic Activity of New 1,7‐Dioxa‐4,10‐diazacyclododecane Artificial Receptors Containing Bisguanidinoethyl or Diaminoethyl Double Side Arms

Sheng¹,

Lü²,

Chen³

et al. 2007

Chemistry A European J

105

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Novel 1,7-dioxa-4,10-diazacyclododecane artificial receptors with two pendant aminoethyl (3) or guanidinoethyl (4) side arms have been synthesized. Spectroscopy, including fluorescence and CD spectroscopy, of the interactions of 3, 4, and their copper(II) complexes with calf thymus DNA indicated that the DNA binding affinity of these compounds follows the order Cu(2+)-4>Cu(2+)-3>4>3, and the binding constants of Cu(2+)-3 are Cu(2+)-4 are 7.2x10(4) and 8.7x10(4) M(-1), respectively. Assessment by agarose gel electrophoresis of the plasmid pUC 19 DNA cleavage activity in the presence of the receptors showed that the complexes Cu(2+)-3 and Cu(2+)-4 exhibit powerful supercoiled DNA cleavage efficiency. Kinetic data of DNA cleavage promoted by Cu(2+)-3 and Cu(2+)-4 under physiological conditions fit to a saturation kinetic profile with kmax values of 0.865 and 0.596 h(-1), respectively, which give about 10(8)-fold rate acceleration over uncatalyzed supercoiled DNA. This acceleration is due to efficient cooperative catalysis of the copper(II) center and the functional (diamino or bisguanidinium) groups. In-vitro cytotoxic activities toward murine melanoma B16 cells and human leukemia HL-60 cells were also examined: Cu(2+)-4 shows the highest activity with IC(50) values of 1.62x10(-4) and 1.19x10(-5) M, respectively.

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“…16, 19, 25, 26 Functional groups attached to the ligand can enhance the strength of substrate binding and offer further stabilisation of the transition state by additional interactions. Functional groups that are capable of hydrogen bonding, such as amino,34, 35 imidazole36 or guanidinium,34, 37 might facilitate the reaction by additional phosphate group polarisation, by lowering the p K a of the metal‐aqua ion and/or by protonation of the leaving group 34. 38 We have previously reported on the cleavage of UpU in the presence of bimetallic Zn 2+ complex 3 , in which the amino‐substituted pyridine groups can form hydrogen bonds to the phosphoryl oxygen atoms 39.…”

Section: Introductionmentioning

confidence: 99%

Overcoming challenges in WAVE bioreactors without feedback controls for pH and dissolved oxygen

Yuk¹,

Baskar²,

Duffy

et al. 2011

Biotechnology Progress

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The biopharmaceutical industry is increasing its use of the WAVE Bioreactor for culturing cells. Although this disposable bioreactor can be equipped to provide real-time pH and dissolved oxygen (DO) monitoring and control, our goal was to develop a process for culturing CHO cells in this system without relying on pH and DO feedback controls. After identifying challenges in culturing cells without controlling for pH and DO in the WAVE Bioreactor, we characterized O(2) and CO(2) transfer in the system. From these cell-free studies, we identified rock rate and rock angle as key parameters affecting O(2) transfer. We also identified the concentration of CO(2) in the incoming gas and the rate of gas flow into the headspace as key parameters affecting CO(2) transfer--and therefore pH--in the disposable culture chamber. Using a full-factorial design to evaluate the rock rate, rock angle, and gas flow rate defined for this WAVE Bioreactor process, we found comparable cell growth and pH profiles in the ranges tested for these three parameters in two CHO cell lines. This process supported cell growth, and maintained pH and DO within our desired range--pH 6.8-7.2 and DO exceeding 20% of air saturation--for six CHO cell lines, and it also demonstrated comparable cell growth and viability with the stirred-tank bioreactor process with online pH and DO control. By eliminating the use of pH and DO probes, this process provides a simple and more cost-effective method for culturing cells in the WAVE Bioreactor.

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Guanidinium Groups Act as General-Acid Catalysts in Phosphoryl Transfer Reactions: A Two-Proton Inventory on a Model System

Cited by 59 publications

References 18 publications

General Acid–Base Catalysis in Model Systems

General Acid–Base Catalysis in Model Systems

Synthesis, DNA‐Binding, Cleavage, and Cytotoxic Activity of New 1,7‐Dioxa‐4,10‐diazacyclododecane Artificial Receptors Containing Bisguanidinoethyl or Diaminoethyl Double Side Arms

Overcoming challenges in WAVE bioreactors without feedback controls for pH and dissolved oxygen

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