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Ronald Kluger

Ronald Kluger

Academic Title: Professor

Phone: 416-978-3582

Office: DB 444


Research Homepage: http://www.chem.utoronto.ca/staff/RHK/kluger_r.html


The study of organic chemistry at the interface of biochemistry provides a view of life processes in terms of the mechanisms of chemistry. Students in our research group can develop knowledge and skills in a broad variety of chemical and biochemical techniques, including organic synthesis, reaction kinetics, spectroscopy, enzymology, and protein chemistry. The objectives of our research are based on utilizing the principles of physical organic chemistry to provide a means of developing biochemical mechanisms and applications. Projects range from physical studies of the reactions of phosphates and organic reaction mechanisms of biochemical models to the design of enzyme inhibitors and reagents for protein modification.

We design and prepare molecules that will react with specific regions of proteins based on the presence of charge and nucleophiles. These site-directed reagents have led to the development of new materials which stabilize proteins and permit them to be used in the development of new materials and drugs. The acyl phosphate monoesters are electrophiles that are anionic, an unusual combination that permits them to react at highly specific sites. We prepare molecules based on examination of the structure of the target protein and then analyze the outcome in the modified protein. We have extended the work to produce proteins covalently linked by defined connections and have examined the effects of the protein-protein interactions.

We have developed methods to produce the intermediates in biochemical reactions of coenzymes. The covalent intermediates correspond in detail to similar enzymic intermediates, which we examine for comparison. The differences in reactivity at every step reveal the contribution of the protein.

We have found that lanthanide ions promote hydroxyl acylation reactions of acyl phosphate monoesters. We are developing the use of this specific combination to modify carbohydrates and nucleotides with site-specificity.

Selected Publications

Ronald Kluger “Red Cell Substitutes from Hemoglobin – Do We Start All Over Again? Curr. Opin. Chem. Biol. 14 538-543 (2010).

Ying Yang and Ronald Kluger “Efficient CuAAC click formation of functional hemoglobin bis-tetramers” Chem. Commun. 7557-7559 46 (2010).

Francine E. Lui and Ronald Kluger “Reviving artificial blood: meeting the challenge of NO scavenging by hemoglobin.” ChemBiochem 11 1816-1824 (2010).

Sohyoung Her and Ronald Kluger “Aminoacylation of nucleosides and nucleotides”, Org. Biomol. Chem. 9, 676 – 678 (2011).

Raj S. Dhiman, Liliana Guevara Opinska, and Ronald Kluger “Biomimetic peptide bond formation in water with aminoacyl phosphate esters” Org. Biomol. Chem., 9, 5645-5647 (2011).

Scott O. C. Mundle, Graeme W. Howe and Ronald Kluger  “Origins of steric effects in general base catalyzed enolization: Solvation and electrostatic attraction”  J. Am. Chem. Soc.134 1066-1070 (2012)

Francine E. Lui, Binglan Yu, David M. Baron, Chong Lei, Warren M. Zapol and Ronald KlugerHemodynamic Responses to a Hemoglobin Bis-Tetramer and its Polyethylene Glycol Conjugate” Transfusion 52 974-982 (2012).

Adelle A. Vandersteen, Scott O.C. Mundle and Ronald Kluger “Protonated Carbonic Acid and Reactive Intermediates in the Acidic Decarboxylation of Indole-Carboxylic AcidsJ. Org. Chem. 77 6505–6509 (2012).

Graeme W. Howe, Michael Bielecki, and Ronald Kluger “Base-Catalyzed Decarboxylation of Mandelylthiamin: Direct Formation of Bicarbonate as an Alternative to Formation of CO2­” J. Am. Chem. Soc.134 20621–20623 (2012).

Ronald Kluger “Analysis of claims of enhanced enzyme catalysis by inorganic colloidosomes” Bioorg. Chem.  49 59-60 (2013).

Ronald Kluger and Francine E. Lui “HBOCs from chemical modification of Hb” in “Hemoglobin-based oxygen carriers as red cell substitutes and oxygen therapeutics”, H. W. Kim, A. G. Greenburg, eds., Springer, Berlin (2013), pp. 159-184. ISBN 978-3-642-40717-8.

Scott O.C. Mundle, Adelle A. Vandersteen, Georges Lacrampe-Couloume, Ronald Kluger, and Barbara Sherwood Lollar “Pressure monitored headspace analysis combined with Compound Specific Isotope Analysis (CSIA) to measure isotope fractionation in gas-producing reactions”  Rapid Commun. Mass Spectrom. 27, 1778–1784 (2013).

Stefan Lüdtke, Piotr Neumann, Karl M. Erixon, Finian Leeper, Ronald Kluger, Ralf Ficner and Kai Tittmann “Sub-Angström resolution crystallography reveals physical distortions that enhance reactivity of a covalent enzymatic intermediate” Nature Chem. 5, 762–767 (2013).

Adelle A. Vandersteen, Scott O. C. Mundle, Georges Lacrampe-Couloume, Barbara Sherwood Lollar, and Ronald Kluger “Carbon kinetic isotope effects reveal variations in reactivity of intermediates in the formation of protonated carbonic acid” J. Org. Chem., 78¸ 12176–12181 (2013).

Ronald Kluger, Graeme W. Howe, and Scott O.C. Mundle “Avoiding CO2 in Catalysis of Decarboxylation” Adv. Phys. Org. Chem. 47 85-128 (2013).

Aizhou Wang and Ronald Kluger “Increasing Efficiency in Protein–Protein Coupling: Subunit-Directed Acetylation and Phase-Directed CuAAC (“Click Coupling”) in the Formation of Hemoglobin Bis-TetramersBiochemistry 53 6793–6799 (2014).

Graeme Howe and Ronald Kluger, “Decarboxylation without CO2: Why Bicarbonate Forms Directly as Trichloroacetate Is Converted to ChloroformJ. Org. Chem. 79 10972–10980 (2014).

Raj S. Dhiman, Aizhou Wang, and Ronald Kluger “Solid phase lanthanum catalysis of monoacylation of diols in water by acyl phosphate monoesters” Can. J. Chem.  93, 445-450 (2015).

Ronald Kluger “Catalyzing Decarboxylation by Taming Carbon Dioxide” Pure Appl. Chem. 87 353-360 (2015).

Serena Singh, Ying Yang, Ina Dubsinsky-Davidchik, and Ronald Kluger “Subunit-Specific Serial Cross-Linking Permits Highly Efficient CuAAC Formation of Functional Hemoglobin bis-Tetrameric Oxygen Carriers” Org. Biomol. Chem. 13 11118-11128 (2015).

Ronald Kluger “Decarboxylation, CO2 and the Reversion Problem” Acc. Chem. Res 48 2843–2849 (2015)

Erika M. J. Siren, Serena Singh, and Ronald Kluger “Bioorthogonal Phase-Directed CuAAC Coupling of Selectively Cross-linked Superoxide Dismutase Dimers” Org. Biomolec. Chem. 13, 10244 – 10249 (2015)

Michael Bielecki, Graeme W. Howe, and Ronald Kluger “Lithium-stabilized nucleophilic addition of thiamin to a ketone provides an efficient route to mandelylthiamin, a critical pre-decarboxylation intermediate” Bioorg. Chem. 64 124-129 (2015)

Graeme W. Howe, Adelle A. Vandersteen, and Ronald Kluger “Formation of Carbonic Acid from a Reactive Intermediate in the Acid-Catalyzed Decarboxylation of a Substituted Benzoic Acid” J. Am. Chem. Soc. 138 7568-7573 (2016)

Serena Singh and Ronald Kluger “Self-Assembly of a Functional Triple Protein: Hemoglobin-Avidin-Hemoglobin via Biotin-Avidin Interactions”, Biochemistry, 55, 2875–2882 (2016).

Aizhou Wang and Ronald Kluger “Enhanced Nitrite Reductase Activity and Its Correlation with Oxygen Affinity in Hemoglobin bis-Tetramers” Biochemistry 55, 6793–6799 (2016). 

Serena Singh, Ina Dubinsky-Davidchik and Ronald Kluger “Strain-Promoted Azide-Alkyne Cycloaddition for Protein-Protein Coupling in the Formation of a bis-Hemoglobin as a Copper-Free Oxygen Carrier. Org. Biomol. Chem., 2016, 14, 10011 – 10017.

Yasaman Heidari, Graeme W. Howe and Ronald Kluger “The reactivity of lactyl-oxythiamin implies the role of the amino-pyrimidine in thiamin catalyzed decarboxylation” Bioorg. Chem. 69, 153–158 (2016).

Scott O. C. Mundle, Barbara Sherwood Lollar, and Ronald Kluger, “Determining carbon kinetic isotope effects using headspace analysis of evolved CO2” Methods in Enzymology, 596, 501-521. (2017)

Michael Bielecki and Ronald Kluger, “The Need for an Alternative to Radicals as the Cause of Fragmentation of a Thiamin-Derived Breslow Intermediate, Angew. Chem. Int. Ed. 56  6321–6323 (2017)

Yuyang Li and Ronald Kluger, “Increased Efficiency in Biomimetic Lewis Acid-Base Pair Catalyzed Monoacylation of Diols by Acyl Phosphate Monoesters” FACETS 2 682-689 (2017).

Adelle A Vandersteen, Graeme A. Howe, Barbara Sherwood Lollar and Ronald Kluger, “Carbon Kinetic Isotope Effects and the Mechanisms of Acid Catalyzed Decarboxylation of 2,4-Mimethoxybenzoic Acid and CO2 Incorporation into 1,2-Dimethoxybenzene.” J. Am Chem. Soc. 139 15049-15053 (2017).

Yuyang Li and Ronald Kluger, “Lead-Catalyzed Aqueous Benzoylation of Carbohydrates with an Acyl Phosphate EsterJ Org Chem (2018) DOI: 10.1021/acs.joc.7b03142 ASAP

Michael Bielecki, Graeme W. Howe, and Ronald Kluger “Charge Dispersion and Its Effects on the Reactivity of Thiamin-Derived Breslow IntermediatesBiochemistry (2018) 57 3867–3872 (2018)