Agnes Rinaldo-Matthis Group

Agnes Rinaldo-Matthis profile page.

Professional interest

Enzymes are biological catalysts that perform essential cellular metabolic and biochemical reactions in living beings. Enzymes basically reduce the energy barrier (activation energy), which has to be crossed by reactants to form products. During this process, the enzyme forms intermediate structures, or transition state structures, through which the initial arrangement atoms have to pass in order to form products. The transition state is very short-lived and dynamic and the only method available today to directly get evidence and map the transition state structure is Kinetic Isotope Effect (KIE) measurements. Data obtained from KIE combined with crystallographic data can be used to design potent transition state analog inhibitors. This type of compounds have shown to be very tight binding inhibitors.

Our group studies the catalytic mechanism of different enzymes and we aim for the understanding of the enzymatic transition state structure to allow for the development of transition state analog inhibitors. We work with several enzymes systems that are important targets in inflammatory disorders.

Examples of enzyme systems that we focus on are those catalyzing formation and degradation of eicosanoids such as human 5 lipoxygenase, LTC4 synthase, LTA4 hydrolase and prostaglandin dehydrogenase. We also work with enzymes catalyzing formation of sphingolipids such as glucosylceramid synthases.

Human 5-lipoxygenase (5-LO) is important in biosynthesis of lipid mediators such as leukotrienes and its action is associated with inflammatory diseases like atherosclerosis and asthma. 5-LO catalyses the oxidation reaction of arachidonic acid to produce 5-HPETE and LTA4. LTA4 is further metabolized to leukotrienes by LTA4 hydrolase and LTC4 synthase. The enzyme glucosylceramid synthase is involved in the biosynthesis of glycosylceramid, the committed step in the spingolipid biosynthesis. Sphingolipid and ceramid has recently been seen to be involved in several inflammatory disorders.

A student in our lab can receive training in basic biochemical and molecular techniques, protein expression, protein purification techniques, biochemical assays, isotope effect studies, X-ray crystallography, inhibitor design, organic chemistry and isothermal titration calorimetry. Projects can be designed using several of these methods according to candidates interest.

Research group

Agnes Rinaldo-MatthisAssociated

Published articles

Pre-steady-state kinetic characterization of thiolate anion formation in human leukotriene C₄ synthase.
Rinaldo-Matthis A, Ahmad S, Wetterholm A, Lachmann P, Morgenstern R, Haeggström J
Biochemistry 2012 Jan;51(4):848-56

A high-affinity adenosine kinase from Anopheles gambiae.
Cassera M, Ho M, Merino E, Burgos E, Rinaldo-Matthis A, Almo S, et al
Biochemistry 2011 Mar;50(11):1885-93

Arginine 104 is a key catalytic residue in leukotriene C4 synthase.
Rinaldo-Matthis A, Wetterholm A, Martinez Molina D, Holm J, Niegowski D, Ohlson E, et al
J. Biol. Chem. 2010 Dec;285(52):40771-6

Advances in eicosanoid research, novel therapeutic implications.
Haeggström J, Rinaldo-Matthis A, Wheelock C, Wetterholm A
Biochem. Biophys. Res. Commun. 2010 May;396(1):135-9

Four generations of transition-state analogues for human purine nucleoside phosphorylase.
Ho M, Shi W, Rinaldo-Matthis A, Tyler P, Evans G, Clinch K, et al
Proc. Natl. Acad. Sci. U.S.A. 2010 Mar;107(11):4805-12

Structures and mechanisms of enzymes in the leukotriene cascade.
Rinaldo-Matthis A, Haeggström J
Biochimie 2010 Jun;92(6):676-81

Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing.
Gutierrez J, Crowder T, Rinaldo-Matthis A, Ho M, Almo S, Schramm V
Nat. Chem. Biol. 2009 Apr;5(4):251-7

L-Enantiomers of transition state analogue inhibitors bound to human purine nucleoside phosphorylase.
Rinaldo-Matthis A, Murkin A, Ramagopal U, Clinch K, Mee S, Evans G, et al
J. Am. Chem. Soc. 2008 Jan;130(3):842-4

Crystal structures of human and murine deoxyribonucleotidases: insights into recognition of substrates and nucleotide analogues.
Walldén K, Rinaldo-Matthis A, Ruzzenente B, Rampazzo C, Bianchi V, Nordlund P
Biochemistry 2007 Dec;46(48):13809-18

Anopheles gambiae purine nucleoside phosphorylase: catalysis, structure, and inhibition.
Taylor E, Rinaldo-Matthis A, Li L, Ghanem M, Hazleton K, Cassera M, et al
Biochemistry 2007 Oct;46(43):12405-15

Neighboring group participation in the transition state of human purine nucleoside phosphorylase.
Murkin A, Birck M, Rinaldo-Matthis A, Shi W, Taylor E, Almo S, et al
Biochemistry 2007 May;46(17):5038-49

Inhibition and structure of Trichomonas vaginalis purine nucleoside phosphorylase with picomolar transition state analogues.
Rinaldo-Matthis A, Wing C, Ghanem M, Deng H, Wu P, Gupta A, et al
Biochemistry 2007 Jan;46(3):659-68

Reaction mechanism of deoxyribonucleotidase: a theoretical study.
Himo F, Guo J, Rinaldo-Matthis A, Nordlund P
J Phys Chem B 2005 Oct;109(42):20004-8

Structural basis for substrate specificity of the human mitochondrial deoxyribonucleotidase.
Walldén K, Ruzzenente B, Rinaldo-Matthis A, Bianchi V, Nordlund P
Structure 2005 Jul;13(7):1081-8

Structural and mutational studies of the carboxylate cluster in iron-free ribonucleotide reductase R2.
Andersson M, Högbom M, Rinaldo-Matthis A, Blodig W, Liang Y, Persson B, et al
Biochemistry 2004 Jun;43(24):7966-72

Crystal structures of the mitochondrial deoxyribonucleotidase in complex with two specific inhibitors.
Rinaldo-Matthis A, Rampazzo C, Balzarini J, Reichard P, Bianchi V, Nordlund P
Mol. Pharmacol. 2004 Apr;65(4):860-7

Crystal structure of a human mitochondrial deoxyribonucleotidase.
Rinaldo-Matthis A, Rampazzo C, Reichard P, Bianchi V, Nordlund P
Nat. Struct. Biol. 2002 Oct;9(10):779-87