Paradisi Rese@rch

Discovery Evolution Application

 

Francesca Paradisi

Professor of Sustainable Pharmaceutical Chemistry

About me...

I completed my MSc in Organic Chemistry from the University of Bologna in 1998 under the supervision of Prof. Cainelli. In 2002 I completed my PhD at the same institution with a thesis on the synthesis of non-natural amino acids via diketopiperazine scaffolds. During my PhD I spent a summer in Dublin as a visiting student in Trinity College working with Prof. Thorri Gunnlaugsson and it was a fantastic experience. So after my PhD I had no doubt I wanted to go abroad and I joined the group of Prof. Paul Engel at University College Dublin as Post-Doctoral Fellow where I discovered the wonders of biocatalysis. I remained in Paul’s group until 2005 developing several projects mainly focused on amino acid dehydrogenases and their applications in the synthesis of non-natural amino acids. I owe Paul all I know about enzymes and their reaction mechanisms!

I spent then a few months in Enzolve Technologies in 2005, a spin-off company of UCD where I worked on the use of mutant dehydrogeanse enzymes for neonatal screening of metabolic disorders. In 2006 I won the lotto and was appointed College Lecturer in Chemical Biology at the UCD School of Chemistry. I was promoted in 2014 to Senior Lecturer. I was fortunate to be always surrounded by a team of excellent students that made my research always interesting, certainly challenging, and thankfully rewarding.

I had the great opportunity to spend the summer of 2015 in UC Davis in California as a visiting academic and I joined the group of Dr. Justin Siegel who gave me the possibility of expanding my research to a different class of enzymes (glycosyl hydrolyses) and getting my hands dirty in the lab again was awesome as they say.  While I was in Davis and I thought things couldn’t get any better, I was offered the position of Associate Professor in Biocatalysis and Enzyme Engineering in the School of Chemistry at the Univeristy of Nottingham. I joined Nottingham in February 2016. In 2019 I joined the University of Bern as a Professor in Pharmaceutical and Bioorganic Chemistry. But the more I think of it the more I believe Professor of Sustainable Pharmaceutical Chemistry is much better!

Outside my work life, I have a husband and two children, Oliver and Martina, and a cat. I love skiing and swimming and travelling too.

Francesca Paradisi
Francesca Paradisi
Francesca Paradisi

Professor of Pharmaceutical and Bioorganic Chemistry

About me...

I completed my MSc in Organic Chemistry from the University of Bologna in 1998 under the supervision of Prof. Cainelli. In 2002 I completed my PhD at the same institution with a thesis on the synthesis of non-natural amino acids via diketopiperazine scaffolds. During my PhD I spent a summer in Dublin as a visiting student in Trinity College working with Prof. Thorri Gunnlaugsson and it was a fantastic experience. So after my PhD I had no doubt I wanted to go abroad and I joined the group of Prof. Paul Engel at University College Dublin as Post-Doctoral Fellow where I discovered the wonders of biocatalysis. I remained in Paul’s group until 2005 developing several projects mainly focused on amino acid dehydrogenases and their applications in the synthesis of non-natural amino acids. I owe Paul all I know about enzymes and their reaction mechanisms!

I spent then a few months in Enzolve Technologies in 2005, a spin-off company of UCD where I worked on the use of mutant dehydrogeanse enzymes for neonatal screening of metabolic disorders. In 2006 I won the lotto and was appointed College Lecturer in Chemical Biology at the UCD School of Chemistry. I was promoted in 2014 to Senior Lecturer. I was fortunate to be always surrounded by a team of excellent students that made my research always interesting, certainly challenging, and thankfully rewarding.

A had the great opportunity to spend the summer of 2015 in UC Davis in California as a visiting academic and I joined the group of Dr. Justin Siegel who gave me the possibility of expanding my research to a different class of enzymes (glycosyl hydrolyses) and getting my hands dirty in the lab again was awesome as they say.  While I was in Davis and I thought things couldn’t get any better, I was offered the position of Associate Professor in Biocatalysis and Enzyme Engineering in the School of Chemistry at the Univeristy of Nottingham. I have started this new adventure since February 2016.

Outside my work life, I have a husband and two children, Oliver and Martina, and a cat. I love skiing and swimming and travelling too.

Research Highlights

Latest Post

During the #Covid19 Quarantine

The research during the quarantine, which at the time of this post is still ongoing in...

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Research

Our Projects :
Enzyme Toolbox

We have a special interest in enzymes with inherited stability. We believe they offer a better starting point to advance the implementation of biocatalysis on large scale. While extremophilic microbes which have adapted to life in  peculiar environments offer an excellent source of biocatalysts, we are also looking at mesophilic organisms which, for less clear reasons, also offer particularly stable enzymes. We identify new enzymes by a combination of genomic database scanning and in-silico modelling to handpick possible good hits exploiting our understanding of structural features which induce stability. Mutagenesis is of course also a very powerful tool to increase stability (quaternary structure stabilisation is key) and of course enzyme immobilisation. We have nowadays extensive experience in a range of immobilisation strategies which can be extremely efficient in lengthening the lifespan of a biocatalyst. For a review on this topic click here.

Transaminases are a family of enzymes with high potential in biotechnological applications. They can be very useful for the enantioselective production of a series of compounds with high value such as chiral amines and enantiopure amino alcohols which find use in many chemical fields; above all, for the synthesis of biologically active compounds. The synthesis of enantiopure amines by enzymatically catalyzed reactions presents several advantages as an alternative to traditional approaches such as mild reaction conditions, high stereoselectivity, fewer synthetic steps, potential total substrate conversion and no environmental issues unlike in the case of transition metal catalysts. 

The reaction is reversible and transaminases can also be used for the mild oxidation of amines into aldehydes and ketones.

We have isolated and investigated a number of transaminases, one of our best his has been the one from Halomonas elongata (HEWT) which has shown high enantioselectivity, large substrate spectra and stability in organic solvents, HEWT a highly suitable enzyme for biotechnological applications in the production of chiral amines. This enzyme has been successfully incorporated in many flow-based project and continues to be our go to biocatalyst for amination reactions. However, we have expanded our very own transaminases kit to include an R-selective enzyme from Thermomyces stellatus which is highly stable and can be produced in excellent amounts. 

Acyl-transferases are another very nice class of enzymes which is normally used to make esters. We have developed several projects on an acyl-transferase from Mycobacterium smegmatis which we have used for the scale up of the synthesis of melatonine (an amide) and flavour esters.  

Redox enzymes encompass a number of different biocatalysts of great industrial interest.

We have a collection of enzymes from both salt adapted and mesophilic sources such as alcohol dehydrogenases (ADHs) and ketoreductases (KR) which we have used to synthesise chiral alcohols (in the reductive direction) and in the dynamic kinetic resolution of profenic aldehydes. These enzymes pose an additional challenge as they are cofactor dependent (NAD(P)H). The cofactor cannot be used stoichiometrically as it is prohibitively expensive. We have therefore developed simple recycling strategies which are easily adaptable to flow biocatalysis. NADH oxidases (NOXs) can also be combined for the recycling of the cofactor when the primary reaction is the oxidation of alcohols.

Amino acid dehydrogenases are also redox enzymes which we use often in combination with other biocatalysts (transaminases for example, but also imine reductases, acyl-transferases etc) and have proven very useful in hydrogen-borrowing systems for the production of valuable chemicals.

Hydrolytic enzymes are another large family of very useful biocatalysts.

We have recently expanded our research into reactions which include ester and amide hydrolysis (and eventually also synthesis) as part of an artificial enzymatic cascade. A selection of esterases and amidases are now part of our library. In a separate project ß-glycosyl hydrolyses, all classified as GH1, have been selected to investigate how environmental adaptation affects biocatalytic properties, as well as stability at different temperatures, pHs and in the presence of solvents. We have looked at this enzymes also in the context of food chemistry applicationssuch as wine production and hydrolysis of valuable molecules from their glycol-conjugate form.

Flow Biocatalysis

Enzymes are amazing catalysts which effortlessly, and with extreme precision, regulate reactions of biosynthetic pathways in a biological system. We are taking enzymes from different sources, those that offer the optimal characteristics for our chemistry, and recreate artificial enzymatic cascades, leading to a variety of different molecules, ex-vivo, using a flow reactor. When compared with a microbial machinery, optimised multi-step enzymatic syntheses in flow avoid all unnecessary pathways and energy draining process which are typical of a cell, as well as the physical barrier to substrates and products which is represented by the cellular wall.  

The enzymes we produce, are immobilised onto a variety of solid supports and packed into column reactors. Each enzymatic biotransformation can be individually optimised so that the starting material is fully converted into the product by the time the flow takes it out of the column. Two, three or more columns containing different enzymes can be connected sequencially, and several steps can be performed with high efficiency and fast flow.  Continuous flow biocatalysis is the ultimate evolution of continuous processing and has brought enzymes to a whole new dimension. Flow-chemistry increases the sustainability of a process, specially when the “waste” can be also recycled. 

However, flow biocatalysis can be integrated with other technologies. We are looking at projects where we can generate starting materials from engineered microbial strain (growing on cheap carbon sources) and feed the substrate-rich broth in the flow system for further modifications which are more efficiently carried out extra-cellularly. Exciting times ahead!

 

Semi-synthetic Enzymes and Peptidic Scaffolds

Metals are part of biological molecules and cover different roles. It is fascinating how inorganic elements are pivotal in many cases for biological activity. In collaboration with Prof. Albrecht here in Bern we have started looking at the amino acid residues that hold in place a catalytic metal in the active site of a number of enzymes. Specifically we are investigating the role of histidine as a ligand in copper proteins such as azurin. Azurin is a bacterial blue copper protein that acts as electron shuttle in bacteria denitrification process, where its metal center undergoes oxidation-reduction between Cu(I) and Cu (II) during the electron transfer. We have taken azurin as a model to evaluate the hypothesis that carbon-metal bonding in proteins (other than nitrogen-metal bonding) could play an important role since the interconversion of histidine between the weakly π-acidic imine (N-bound form) and the strongly σ-donating C-bound carbene tautomer is plausible and may have substantial implications on the activity and oxidation-reduction chemistry of the coordinated metal center. We have expanded this research to catalytically active enzyme (NiR) and we are interested in exploring the possible role of carbene incorporation in heme-containing biocatalysts. For recent articles on this topic click here and here.

 

  

Peptidic scaffolds. We have in the past worked on natural peptidic scaffolds to incorporate non-natural amino acids for applications in medicinal chemistry . Angiotensin-(1-7) is a heptapeptide hormone of the renin-angiotensin system (RAS). We are particularly interested in the potential use of Angiotensin-(1-7) in anti-cancer therapy. Its anti-angiogenic and anti-proliferative properties have been investigated Prof. Gallagher at Wake Forest University (NC, USA). A phase II clinical trial recently completed by the Wake Forest School of Medicine successfully showed its therapeutic potential as a second or third line treatment of patients with unresectable or metastatic sarcomas. By stabilising such structure with a structurally rigid amino acid we labelled ACCA, the activity in vitro of the peptide was significantly enhanced 

 

However, peptidic scaffolds can be used also to create artificial ligands in metal based catalysis and our research is now exploring the integration of synthetic ligands with enzymes to broaden the in-situ reactivity we can induce.

 

Integration of Biocatalysis with "Traditional Synthesis"

The overarching goal of our research is SUSTAINABILITY and we want to demonstrate that enzyme based catalysis can be integrated with more traditional synthetic methodologies. Exceptional progress has been madero date, and we are determined to add our contribution. Flow-chemistry, with its ability of compartmentalising reactions in separate reactors, offers an exceptional tool to advance in this filed. We are working on a range of new cascades to combine enzymatic biotransformaitons with synthetic steps. The compatibility of the reaction environments is important but no longer a must.  The versatility of our modular systems allows for each individual reaction step to be optimised and integrated in a cascade.  

Group Members

Dr. Martina L.Contente

From Milan, Italy

University Of Nottingham

University Of Nottingham

Marie Skłodowska-Curie Fellow

Dr. Maria Romero Fernandez

From Huelva, Spain

University Of Nottingham

University Of Nottingham

Post doctoral Fellow

Dr. Nicholas R. Moody

From Ipswich, UK

University Of Nottingham

University Of Nottingham

Post doctoral Fellow

Dr. Eimear Hegarty

From Cork, Ireland

University Of Bern

University Of Bern

Post doctoral Fellow

Dr. David RouraPadrosa

From Girona, Spain

University Of Bern

University Of Bern

Post doctoral Fellow

Dr. Ana I. Benitez-Mateos

From Cadiz, Spain

University Of Bern

University Of Bern

Post doctoral Fellow

LidiaDelgado

From Granada, Spain

University Of Nottingham

University Of Nottingham

PhD. Student

Nourah Almulhim

From Al-Ahsa, Saudi Arabia

University Of Nottingham

University Of Nottingham

PhD. Student

Christian Heckmann

From Rodgau, Germany

University Of Nottingham

University Of Nottingham

PhD. Student

Valentina Marchini

From Venice, Italy

University Of Bern

University Of Bern

PhD. Student

Irene Sacco

From Padua, Italy

University Of Bern

University Of Bern

PhD. Student

Stefania Gianolio

From Bergamo, Italy

University Of Bern

University Of Bern

PhD. Student

Lucia Robustini

From Ferrara, Italy

University Of Bern

University Of Bern

PhD. Student

Calvin Klein

From Greifswald, Germany

University Of Bern

University Of Bern

Master Student

Dr. Martina L.Contente

From Milan, Italy

University Of Nottingham

University Of Nottingham

Marie Skłodowska-Curie Fellow

Dr. Maria Romero Fernandez

From Huelva, Spain

University Of Nottingham

University Of Nottingham

Post doctoral Fellow

Dr. Nicholas R. Moody

From Ipswich, UK

University Of Nottingham

University Of Nottingham

Post doctoral Fellow

Dr. Eimear Hegarty

From Cork, Ireland

University Of Bern

University Of Bern

Post doctoral Fellow

Dr. David RouraPadrosa

From Girona, Spain

University Of Bern

University Of Bern

Post doctoral Fellow

Dr. Ana I. Benitez-Mateos

From Cadiz, Spain

University Of Bern

University Of Bern

Post doctoral Fellow

LidiaDelgado

From Granada, Spain

University Of Nottingham

University Of Nottingham

PhD. Student

Nourah Almulhim

From Al-Ahsa, Saudi Arabia

University Of Nottingham

University Of Nottingham

PhD. Student

Christian Heckmann

From Germany

University Of Nottingham

University Of Nottingham

PhD. Student

Valentina Marchini

From Trieste, Italy

University Of Bern

University Of Bern

PhD. Student

Irene Sacco

From Padua, Italy

University Of Bern

University Of Bern

PhD. Student

Stefania Gianolio

From Bergamo, Italy

University Of Bern

University Of Bern

PhD. Student

Lucia Robustini

From Ferrara, Italy

University Of Bern

University Of Bern

PhD. Student

Calvin Klein

From Greifswald, Germany

University Of Bern

University Of Bern

Master Student

Those that shared the journey

Cillin Mac Donnchadha (MSc, 2009), LEO Pharma, Dublin, IE

Dr. Elaine O’Reilly (PhD, 2010), Assistant Professor, University of Nottingham, UK

Dr. Gabriele Gucciardo (PhD, 2010), Team Leader, Almac Group, Northern Ireland, UK

Dr. Sabrina Devereux (PhD, 2010), Project Manager, Horizon Pharma Ireland, IE

Dr. Leanne Timpson (PhD, 2011), Novozymes,  Nottingham, UK

Dr. Daniela Quaglia (PhD, 2012), Post Doctoral Researcher, Université de Montréal, Canada

Dr. Philip Conway (PhD, 2012), Technical Development Chemist, GSK, Cork, IE

Dr. Lara Pes (PhD, 2013), Post Doctoral Researcher, Weill Cornell Medical College, NY, USA

Dr. Keith Robertson (PhD, 2013), Technical Development Chemist, GSK, Cork, IE

Dr. Diya Alsafadi (PhD, 2013), Researcher, Royal Scientific Society, Jordan

Dr. Jennifer Cassidy (PhD, 2015), Post Doctoral Researcher, University College Dublin, IE

Dr. Anita Wester (PhD, 2016), Post Doctoral Researcher, Københavns Universiter, DK

Dr. Matteo Planchestainer (PhD, 2017), Post Doctoral Researcher, University of Bern, CH

Dr. Larah Bruen (PhD, 2018) Technical Support Scientist at Abbott Diagnostics Division, Longford

Dr. David Roura Padrosa (PhD, 2019), Post Doctoral Researcher, University of Bern, CH

Dr. Eimear Hegarty (PhD, 2019), Post Doctoral Researcher, University of Bern, CH

Dr. Kevin Devine, Senior Lecturer, London Metropolitan University, UK

Dr. Daniele Balducci, Chemistry Teacher, Urbino, Italy

Dr. Jennifer Cassidy, Science Foundation Ireland, IE

Dr. Elena Lestini, Post Doc, Dublin City University, IE

Dr. Ann-Kathrin Liliensiek, Researcher, Federal Institute of Hydrology, Essen, DE

Dr. Maeve O’Neill, Team Leader, Biocatalysts Ltd, Cardiff, UK

2017: Chiara Grazie Marzano (MSc University of Milan, Italy), Benedetta Guidi (PhD University of Milan, Italy), Valerio De Vitis (PhD University of Milan, Italy), Joseph Byrne (Post Doc University of Bern, Switzerland), Nathalie Segaud (Post Doc University of Bern, Switzerland), Anabel Benitez Mateos (PhD CICBiomaGUNE, Spain)

2018: Raphael Alaux (UG Université Paul Sabatier, Toulouse, France), Lorianne Provo (UG Bordeaux Gironde, France)

2019: Stefania Gianolio (Graduate student University of Milan, Italy), Debra Zanconato (MSc University of Bologna)

 

Outputs

Journal Articles

Reviews & Book

Patents

Massive congratulations to Anita who successfully defended her thesis on the 4th of October 2016. Wishing you all the very
To prove that we are a real team, the Paradisi group was trapped inside the ancient Egyptian Crypt. Thanks to
Here we are! After a lot of unpacking and patience too, our lab is ready to run!      
Fran was an invited speaker at the Annual Meeting organised by the (American) Society of Industrial Microbiology and Biotechnology. She
The group will shortly officially move to Nottingham, and we will have a number of new researchers joining us, so we
Here we are! The group is finally complete and ready to kick off this new adventure!!        
We are very happy with the front cover of our article which comes out in the October issue, have a
Emotional moment during Francesca’s leaving lecture in UCD few weeks ago. Many students, colleagues, and friends attended her fascinating summary of ten
Lidia attended an RCS meeting in London back in December (Biotransformations: from science to industrial application) and her poster won
Zoya, our MSc. student (2017-18) was awarded today the Masson Gulland Medal and Prize. This award was founded in 1990 in
Pleasant surprise for Francesca e Matteo during the Novel Enzyme conference in Groningen (The Netherland) last week.   Bernard Lucas

Collaborations

“A knotty puzzle may hold a scientist up for a century, when it may be that a colleague has

the solution already and is not even aware of the puzzle that it might solve.”

(Isaac Asimov, The Robots of Dawn)

Dr. Justin Siegel and Dr. Marc Facciotti, UC Davis, California, USA

Dr. Justin Siegel and Dr. Marc Facciotti, UC Davis, California, USA

Prof. Peg Gallagher and Dr. Ann Tallant

Prof. Peg Gallagher and Dr. Ann Tallant, Wake Forest University, North Carolina, USA

Dr. Cormac Murphy

Dr. Cormac Murphy, University College Dublin, Ireland

Prof. Prem Puri

Prof. Prem Puri, National Children’s Research Centre, Dublin, Ireland

Dr. Thorsten Allers

Dr. Thorsten Allers, University of Nottingham, UK

Dr. Adele Williamson

Dr. Adele Williamson, Tromso University, Norway

Prof. Martin Albrecht

Prof. Martin Albrecht, University of Bern, Switzerland

Prof. Francesco Molinari

Prof. Francesco Molinari, University of Milan, Italy

Dr. Alessandra Tolomelli

Dr. Alessandra Tolomelli, University of Bologna, Italy

Dr. Fernando Lopez-Gallego

Dr. Fernando Lopez-Gallego, University of Zaragoza, Spain

Dr. Diya Alsafadi

Dr. Diya Alsafadi, Royal Scientific Society, Amman, Jordan

Prof. Damien Debecker

Prof. Damien Debecker, University of Louvain, Belgium

Prof. Cinzia Chiappe

Prof. Cinzia Chiappe, University of Pisa,Italy

Synthesis and Solid State Pharmaceutical Centre
Islamic development bank
Islamic development bank
Irish Research Council
United States Environmental Protection Agency
Science Foundation Ireland
Biotechnology and Biological Sciences Research Council (BBSRC)
European cooperation in science and technology
European cooperation in science and technology
European cooperation in science and technology
Image Group research Paradisi

THANKS FOR VISITING US

Francesca Paradisi Research © 2016-2020  

 

Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland

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