Academic Title: Professor
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.
Ian James Gray and Ronald Kluger “Chelation-controlled regioselectivity in the lanthanum-promoted monobenzoylation of monosaccharides in water” Carb. Res. 342 1998-2002 (2007).
Svetlana Tzvetkova and Ronald Kluger “Biomimetic Aminoacylation of Ribonucleotides and RNA with Aminoacyl Phosphate Esters and Lanthanum Salts,” J. Am. Chem. Soc. 129 15848 – 15854 (2007).
Dongxin Hu and Ronald Kluger “Efficient Generation of Dendritic Arrays of Cross-Linked Hemoglobin: Symmetry and Redundancy” Org. Biomol. Chem. 6 151 – 156 (2008).
Steven Wrighton, Edwin C.Y. Chow, Lichuan Liu, Noam Ship; Ronald Kluger, and K. Sandy Pang, Role of haptoglobin on the uptake of native and β-chain [trimesyl-(lys82)β(ys82)β] cross-linked human hemoglobins in isolated perfused rat livers Drug Metab. Disp. 36 937-945 (2008).
Ronald Kluger and Kai Tittmann “Thiamin diphosphate catalysis: enzymic and nonenzymic covalent intermediates" Chem. Rev. 108 1797-1833 (2008).
Jolanta Wodzinska and Ronald Kluger “pKa-dependent formation of amides in water from an acyl phosphate monoester and amines” J. Org. Chem. 73 4753-4754 (2008).
Francine E. Lui, Pengcheng Dong, and Ronald Kluger “PEG-conjugation enhances nitrite reductase activity of native and cross-linked hemoglobin” Biochemistry 47 10773-10780 (2008)
Dongxin Hu and Ronald Kluger “Functional cross-linked hemoglobin bis-tetramers: Geometry and cooperativity” Biochemistry 47 12551-12561 (2008)
Ronald Kluger and Steven Rathgeber “Catalyzing separation of carbon dioxide in thiamin diphosphate promoted decarboxylation” FEBS J. 275 6089-6100 (2008).
Scott O. C. Mundle, Steven Rathgeber, Georges Lacrampe-Couloume, Barbara Sherwood Lollar, and Ronald Kluger. “Internal return of carbon dioxide in decarboxylation: catalysis of separation and 12C/13C kinetic isotope effects” J. Am. Chem. Soc. 131, 11638–11639 (2009).
Scott O. C. Mundle and Ronald Kluger, “Decarboxylation via Addition of water to a carboxyl group: acid-catalysis of pyrrole-2-carboxylic acid” J. Am. Chem. Soc. 131 11674-11675 (2009).
Jonathan S. Foot, Francine E. Lui, and Ronald Kluger “Hemoglobin Bis-Tetramers Via Cooperative Azide-Alkyne Coupling” Chem. Commun. 7315-7317 (2009).
Francine E. Lui and Ronald Kluger “Enhancing nitrite reductase activity of modified hemoglobin: bis-tetramers and their PEGylated derivatives” Biochemistry 48 11912–11919 (2009)
Ronald Kluger and Scott O. C. Mundle “The role of pre-association in Brønsted acid-catalyzed decarboxylation and related processes” Adv. Phys. Org. Chem. 44 357-375 (2010).
Ronald Kluger, Jonathan S. Foot, and Adelle A. Vandersteen “Protein-Protein Coupling And Its Application To Functional Red Blood Cell Substitutes” Chem. Commun.(Feature Article), 46, 1194-1202 (2010).
Raj S. Dhiman and Ronald Kluger “Magnesium ion enhances lanthanum-promoted monobenzoylation of a monosaccharide in water”, Org. Biomol. Chem., 8, 2006 – 2008 (2010).
Scott O. C. Mundle, Georges Lacrampe-Couloume, Barbara Sherwood Lollar, and Ronald Kluger “Hydrolytic Decarboxylation of Carboxylic Acids and the Formation of Protonated Carbonic Acid” J. Am. Chem. Soc. 132, 24530-2436 (2010)
Ronald Kluger “Red Cell Substitutes from Hemoglobin – Do We Start All Over Again? Curr. Opin. Chem. Biol. 14 538-543 (2010).
Ronald Kluger, Book Review: Click Chemistry for Biotechnology and Materials Science. (Edited by Joerg Lahann) J. Am. Chem. Soc. 132 6611–6612 (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).
Scott Mundle, Liliana Guevara Opinska, Ronald Kluger and Andrew Dicks, Investigating the mechanism of heteroaromatic decarboxylation using solvent kinetic isotope effects and eyring transition state theory, J. Chem. Educ., 88 1004–1006 (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 Kluger “Hemodynamic 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 Acids” J. 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: principles, approaches and current status”, Hae Won Kim editor (in press, July 2012).
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).