Large p<i>K</i><sub>a</sub> Shifts of α‐Carbon Acids Induced by Copper(<scp>II</scp>) Complexes

Zhong, Zhiyuan; Postnikova, Brenda J.; Hanes, Robert E.; Lynch, Vincent M.; Anslyn, Eric V.

doi:10.1002/chem.200400396

Cited by 31 publications

(31 citation statements)

References 35 publications

(40 reference statements)

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“…As mentioned earlier, calculations have indicated that protonated ␣-carboxyl groups of ␣-amino acids show dramatically reduced (factor of Ϸ10 10 ) pK a s for the ␣-proton (13). The observed electrostatic environment of the ␣-carboxylate likely disperses its negative charge far more effectively than protonation, thereby amplifying this effect (22).…”

Section: Resultsmentioning

confidence: 99%

Structural insights into stereochemical inversion by diaminopimelate epimerase: An antibacterial drug target

Pillai

Cherney

Diaper

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

113

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D-amino acids are much less common than their L-isomers but are widely distributed in most organisms. Many D-amino acids, including those necessary for bacterial cell wall formation, are synthesized from the corresponding L-isomers by ␣-amino acid racemases. The important class of pyridoxal phosphate-independent racemases function by an unusual mechanism whose details have been poorly understood. It has been proposed that the stereoinversion involves two active-site cysteine residues acting in concert as a base (thiolate) and an acid (thiol). Although crystallographic structures of several such enzymes are available, with the exception of the recent structures of glutamate racemase from Bacillus subtilis and of proline racemase from Trypanosoma cruzi, the structures either are of inactive forms (e.g., disulfide) or do not allow unambiguous modeling of the substrates in the active sites. Here, we present the crystal structures of diaminopimelate (DAP) epimerase from Haemophilus influenzae with two different isomers of the irreversible inhibitor and substrate mimic aziridino-DAP at 1.35-and 1.70-Å resolution. These structures permit a detailed description of this pyridoxal 5 -phosphate-independent amino acid racemase active site and delineate the electrostatic interactions that control the exquisite substrate selectivity of DAP epimerase. Moreover, the active site shows how deprotonation of the substrates' nonacidic hydrogen at the ␣-carbon (pKa Ϸ 29) by a seemingly weakly basic cysteine residue (pK a Ϸ 8 -10) is facilitated by interactions with two buried ␣-helices. Bacterial racemases, including glutamate racemase and DAP epimerase, are potential targets for the development of new agents effective against organisms resistant to conventional antibiotics.racemase ͉ stereochemical mechanism T he increase in microbial resistance to conventional antibiotics has rekindled intense interest in new methods of inhibiting bacterial cell wall biosynthesis (1), including blocking formation or utilization of D-amino acids such as D-alanine (2), D-glutamate (3), and meso-diaminopimelic acid (4) present in peptidoglycan (5). The inclusion of D-amino acids in the peptidoglycan layer of the cell wall is thought to provide bacteria with protection from the action of host proteases (2). Glutamate racemase (6, 7) and diaminopimelate (DAP) epimerase (EC 5.1.1.7) (8), as well as aspartate racemase (9) and proline racemase (10, 11), are examples of pyridoxal 5Ј-phosphate (PLP)-independent amino acid racemases that invert the configuration at the ␣-carbon of an amino acid without the use of cofactors, metals, or reducible keto or imino functionalities. The proposed ''two-base'' mechanism (11) for these enzymes involves one active-site cysteine thiolate acting as a base to deprotonate the ␣-carbon, while a second cysteine thiol functions as an acid to reprotonate the resulting planar carbanionic intermediate from the opposite face (Scheme 1). This process is not trivial, because the pK a of the ␣-proton is Ϸ21 for the fully protonated fo...

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Section: Resultsmentioning

confidence: 99%

Structural insights into stereochemical inversion by diaminopimelate epimerase: An antibacterial drug target

Pillai

Cherney

Diaper

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

113

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“…In fact the carboxylate of the ligand must be in the anionic form since protonated a-carboxyl groups of a-amino acids show dramatically reduced pK a for the Ha (by a factor of about 10 10 ) thus preventing the reaction to occur [29]. This effect can be ascribed to the electrostatic environment of the acarboxylate which likely disperses its negative charge stabilizing this form and thus amplifying this effect [30]. Hence, the possible state of protonation for L,L-DAP considered in this study are the classical zwitterionic form (prevalent at neutral pH) and the corresponding basic anionic form (prevalent at pH $ 8).…”

Section: Resultsmentioning

confidence: 93%

Catalytic mechanism of l,l-diaminopimelic acid with diaminopimelate epimerase by molecular docking simulations

Brunetti¹,

Galeazzi²,

Orena³

et al. 2008

Journal of Molecular Graphics and Modelling

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“…Physical organic chemistry usually deals with the effects of substituents which are covalently attached to the structure carrying the reactive site. [38] Although many cases of ion-induced pK a shifts are available, [39][40][41][42][43] the concept of photo-ionic triode action is unprecedented. An elegantly tunable fluorescent PET sensor for glucose developed by James and Shinkai [44] does not correspond to photo-ionic triode action.…”

Section: Methodsmentioning

confidence: 99%

Modification of Fluorescent Photoinduced Electron Transfer (PET) Sensors/Switches To Produce Molecular Photo‐Ionic Triode Action

Huxley¹,

Schroeder²,

Gunaratne³

et al. 2014

Angewandte Chemie

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The fluorophore-spacer 1 -receptor 1 -spacer 2 -receptor 2 system (where receptor 2 alone is photoredox-inactive) shows ionically tunable proton-induced fluorescence off-on switching, which is reminiscent of thermionic triode behavior. This also represents a new extension to modular switch systems based on photoinduced electron transfer (PET) towards the emulation of analogue electronic devices.Fluorescent photoinduced electron transfer (PET) sensors/ switches [1][2][3][4] are a well-established application of molecular devices, to the point of real-life deployment worldwide in blood electrolyte diagnostics. [5][6][7][8] Important picosecond laser studies on fluorescent PET sensors/switches have demonstrated the transient existence of radical ion species, [9][10][11] and thus designers can proceed with confidence. As a result of their modular fluorophore-spacer-receptor construction, fluorescent PET systems are very amenable to modification in terms of the format, as well as in terms of the detailed functionalities. The latter approach has yielded many individual examples of sensors and switches based on fluorescence which target important analytes. [12][13][14][15] On the other hand, the former approach has the potential to set up new areas of endeavor and application, which is exploited here.The controllable quenching of molecular fluorescence [1,2] can be exploited to build switchable systems which emulate familiar electronic devices. Some of these molecular systems have unique applications which are inconvenient for their electronic counterparts, such as wireless operation in micrometric spaces. [16] The first molecular logic gate [17][18][19][20][21][22][23] 1 (an advanced molecular switch [24] ) was a fluorophore-spacer 1 -receptor 1 -spacer 2 -receptor 2 system, [25,26] where two photoinduced electron transfer (PET) [4, 27] channels arising from the two receptors were controlled by binding H + and Na + ions, respectively, and thus the fluorescence output corresponded to photo-ionic AND logic. Strong fluorescence emerges only when all PET processes are suppressed (Figure 1 a). [4] Related, but distinct, fluorophore-spacer 1 -receptor 1 -spacer 2 -receptor 2 systems, [28] where both receptors respond to H + ions, for example, 2, give rise to fluorescent off-on-off action, which can correspond to ternary logic behavior. [22] We now demonstrate aspects of molecular photo-ionic triode action for the first time by structurally mutating the fluorophore-spacer 1 -receptor 1 -spacer 2 -receptor 2 system 1 into a novel format exemplified by 3, where the convenient photoredox capability of receptor 2 is removed from 1 (Figure 1 b). Nearly 20 distinct formats of luminescent PET switching systems, each possessing its own defining features and applications, are known. [26] Fluorescence off-on switching is, therefore, controlled within 3 by selective ion binding of receptor 1 . This switching profile is influenced by the orthogonally selective ion binding of receptor 2 , which is forced into a secondary role...

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Large pK_a Shifts of α‐Carbon Acids Induced by Copper(II) Complexes

Cited by 31 publications

References 35 publications

Structural insights into stereochemical inversion by diaminopimelate epimerase: An antibacterial drug target

Structural insights into stereochemical inversion by diaminopimelate epimerase: An antibacterial drug target

Catalytic mechanism of l,l-diaminopimelic acid with diaminopimelate epimerase by molecular docking simulations

Modification of Fluorescent Photoinduced Electron Transfer (PET) Sensors/Switches To Produce Molecular Photo‐Ionic Triode Action

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Large pKa Shifts of α‐Carbon Acids Induced by Copper(II) Complexes

Cited by 31 publications

References 35 publications

Structural insights into stereochemical inversion by diaminopimelate epimerase: An antibacterial drug target

Structural insights into stereochemical inversion by diaminopimelate epimerase: An antibacterial drug target

Catalytic mechanism of l,l-diaminopimelic acid with diaminopimelate epimerase by molecular docking simulations

Modification of Fluorescent Photoinduced Electron Transfer (PET) Sensors/Switches To Produce Molecular Photo‐Ionic Triode Action

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Large pK_a Shifts of α‐Carbon Acids Induced by Copper(II) Complexes