Alan Fersht

Fersht was born on 21 April 1943{{Who's Who | title=Fersht, Sir Alan (Roy) |author=Anon | doi=10.1093/ww/9780199540884.013.U15668|id = U15668 | year = 2020 | edition = online Oxford University Press}} in Hackney, London.{{cite web | title=Sir Alan Roy FERSHT FRS FMedSci - Curriculum Vitae | website=MRC Laboratory of Molecular Biology | date=21 April 1943 | url=https://www2.mrc-lmb.cam.ac.uk/groups/fersht/cv.html | access-date=10 January 2025}} His father, Philip, was a ladies' tailor and his mother, Betty, a dressmaker. His grandparents were Jewish immigrants from Poland, Lithuania and Belarus.{{citation needed|date=May 2022}} He was educated at Sir George Monoux Grammar School, an all-boys grammar school in Walthamstow, London. He was a keen chess player and was the Essex County Junior champion in 1961.{{Cite book|title=The selected papers of Sir Alan Fersht : development of protein engineering|first1= Alan|last1=Fersht|first2=Qinghua|last2=Wang|date=2010|publisher=Imperial College Press|isbn=978-1-84816-554-0|location=London|oclc=646400491}} He was awarded a State Scholarship to read Natural Sciences at Gonville and Caius College, Cambridge, where he obtained First Class in Pt I of the Natural Sciences Tripos in 1964, First Class in Pt II (Chemistry) in 1965 and was awarded his PhD degree in 1968.{{cite thesis |degree=PhD |first=Alan Roy|last=Fersht |title=Intramolecular Catalysis of Ester Hydrolysis |publisher=University of Cambridge |year=1968 |url=http://www.theses.com|author-link=Alan Fersht}} {{subscription required}} He was President of the University of Cambridge Chess Club in 1964–65 and awarded a half blue in 1965.{{Cite newspaper The Times

|title=Sweeping Chess Win by Oxford

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He spent a post-doctoral year (1968–1969) at Brandeis University working under William Jencks. He returned to Cambridge in 1969 as a group leader at the MRC Laboratory of Molecular Biology until 1977 and a junior research fellow at Jesus College, Cambridge until 1972. Fersht was Wolfson Research Professor of the Royal Society and Professor of Biological Chemistry at Imperial College London from 1978 to 1988. He spent a sabbatical year at Stanford University on an Eleanor Roosevelt Fellowship of the American Cancer Society with Arthur Kornberg (1978–79). Fersht was Herchel Smith Professor of Organic Chemistry at Cambridge from 1988 to 2010. He was the Director of the Cambridge Centre for Protein Engineering from 1990 to 2010 when, on reaching the retirement age, he became an Emeritus Group Leader at the MRC Laboratory of Molecular Biology. He is a Life Fellow of Gonville and Caius College.

Fersht studied for his PhD intramolecular catalysis in the hydrolysis of aspirin as a model for catalysis by enzymes. He was recruited by David Mervyn Blow and Max Perutz at the MRC Laboratory of Molecular Biology to work on the mechanism of the enzymes that were being solved there. He became a self-taught enzymologist. According to Athel Cornish-Bowden, the last major advance in understanding steady-state kinetics was made by Fersht, who introduced for the first time a meaningful definition of specificity. Fersht pointed out that $k\_\backslash text\{cat\}/K\_\backslash mathrm\{m\}$ of Michaelis-Menten kinetics is the parameter that measures the capacity of an enzyme to discriminate between substrates that are available simultaneously, and so it provides the only meaningful physiological definition of specificity.{{Cite journal

| pmid = 4155501

| year = 1974

| last1 = Fersht

| first1 = A. R.

| author-link1 = Alan Fersht

| title = Catalysis, binding and enzyme–substrate complementarity

| journal = Proceedings of the Royal Society of London. Series B. Biological Sciences

| volume = 187

| issue = 1089

| pages = 397–407

| doi = 10.1098/rspb.1974.0084

| bibcode = 1974RSPSB.187..397F

}} For that reason, the International Union of Biochemistry and Molecular Biology has recommended the name specificity constant for this ratio.{{Cite journal

| year = 2024

| last1 = Cornish-Bowden

| first1 = A

| author-link1 = Athel Cornish-Bowden

| title = One Hundred years of Michaelis-Menten kinetics

| journal = Perspectives in Science

| volume = 4

| pages = 3–9

| doi= 10.1016/j.pisc.2014.12.002

| doi-access = free

}}

Fersht used measurements of $k\_\backslash text\{cat\}/K\_\backslash mathrm\{m\}$ to quantify the role of binding energies in catalysis and specificity, particularly in the fidelity of selection of amino acids during protein biosynthesis by the aminoacyl-tRNA synthetases, where he formulated the double-sieve editing mechanism.{{Cite journal

| pmid = 375976 | year = 1979 | last1 = Fersht | first1 = A. R. | author-link1 = Alan Fersht

| title = Evidence for the double-sieve editing mechanism in protein synthesis. Steric exclusion of isoleucine by valyl-tRNA synthetases | journal = Biochemistry | volume = 18 | issue = 12 | pages = 2627–31| last2 = Dingwall | first2 = C. | doi=10.1021/bi00579a030}} Fersht was one of the first classical enzymologists to use Recombinant DNA technology, which he learned in the laboratory of Arthur Kornberg, while measuring the fidelity of DNA replication from kinetics of mutagenesis in vivo.

In 1982, he began a collaboration with Sir Gregory Winter in which they were the first to engineer a mutation in a protein of known structure, the tyrosyl-tRNA synthetase.{{Cite journal | pmid = 6811955 | year = 1982 | last1 = Winter | first1 = G. | author-link1 = Gregory Winter | title = Redesigning enzyme structure by site-directed mutagenesis: tyrosyl tRNA synthetase and ATP binding | journal = Nature | volume = 299 | issue = 5885 | pages = 756–8 | last2 = Fersht | first2 = A. R. | last3 = Wilkinson | first3 = A. J.| last4 = Zoller | first4 = M. | last5 = Smith | first5= M. | author-link5 = Michael Smith (chemist) | doi= 10.1038/299756a0| bibcode = 1982Natur.299..756W }} Fersht went on to pioneer protein engineering as a tool for analysing protein structure and mechanism while Winter as a tool for antibody engineering. From 1990-2010, they were respectively the Director and Deputy Director of the Centre for Protein Engineering.

Fersht showed that Free-energy relationships can be applied to analyse non-covalent interactions in transition states of enzyme-catalysed reactions and infer their structures in an analogous procedure to physical chemical methods for transition states in covalent reactions by measuring changes in the kinetics and thermodynamics on small changes in the structure of reagents. This procedure of studying protein engineered mutants, named Phi value analysis, was then applied to inferring the structure of transition states of protein folding and elucidating mechanisms of protein folding.{{Cite journal | pmid = 2739734 | year = 1989 | last1 = Matouschek | first1 = A.| author-link1 = Andreas Matouschek | title = Mapping the transition state and pathway of protein folding by protein engineering | journal = Nature | volume = 340 | issue = 6229 | pages = 122–6 | last2 = Kellis | first2 = J. T. | last3 = Serrano | first3 = L. | last4 = Fersht | first4 = A.R. | author-link4 = Alan Fersht | doi= 10.1038/340122a0| bibcode = 1989Natur.340..122M }}{{Cite journal | pmid = 1569556 | year = 1992

| last1 = Fersht

| first1 = A. R.

| title = The folding of an enzyme I. Theory of protein engineering analysis of stability and pathway of protein folding

| journal = Journal of Molecular Biology

| volume = 224

| issue = 3

| pages = 771–782

| last2 = Matouschek

| first2 = A.

| last3 = Serrano

| first3 = L.

| doi= 10.1016/0022-2836(92)90561-w

}}{{Cite journal

| pmid = 38597675

| year = 2024

| last1 = Fersht

| first1 = A. R.

| author-link1 = Alan Fersht

| title = From covalent transition states in chemistry to noncovalent in biology: from β- to Φ-value analysis of protein folding

| journal = Quarterly Reviews of Biophysics

| volume = 57 e4

| pages = e4

| doi = 10.1017/S0033583523000045

| doi-access = free

}} Phi value analysis of the folding of the single-domain protein chymotrypsin inhibitor 2 uncovered a fundamental folding mechanism, “nucleation-condensation” whereby the folding chain collapses in an extended transition state around a concomitantly formed nucleus.{{Cite journal | pmid = 7490748 | year = 1995 | last1 = Itzhaki | first1 = L. S.| title = The structure of the transition state for folding of chymotrypsin inhibitor 2 analysed by protein engineering methods: evidence for a nucleation-condensation mechanism for protein folding | journal = Journal of Molecular Biology | volume = 254 | issue = 2 | pages = 260–88 | last2 = Otzen | first2 = D.E. | last3 = Fersht | first3 = A. R. | doi =10.1006/jmbi.1995.0616}}

His interests also include protein misfolding, disease and cancer.

• Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding{{Cite book|title=Structure and mechanism in protein science : a guide to enzyme catalysis and protein folding|first=Alan|last=Fersht|isbn=978-981-322-519-0|location=New Jersey|oclc=986523773|year = 2017}}
• The Selected Papers of Sir Alan Fersht: Development of Protein Engineering

File:L1Caius1994.jpg, Samuel Frederick Edwards, David Tabor, David Shoenberg, Rodney Hill, and Alan Fersht)]]

Fersht was elected a Fellow of the Royal Society (FRS) in 1983.{{cite web |url=https://collections.royalsociety.org/DServe.exe?dsqIni=Dserve.ini&dsqApp=Archive&dsqDb=Catalog&dsqCmd=show.tcl&dsqSearch=(RefNo==%27EC%2F1983%2F09%27) |title=EC/1983/09: Fersht, Alan Roy |publisher=The Royal Society |archive-date=9 January 2016 |archive-url=https://web.archive.org/web/20160109075921/https://collections.royalsociety.org/DServe.exe?dsqIni=Dserve.ini&dsqApp=Archive&dsqDb=Catalog&dsqCmd=show.tcl&dsqSearch=(RefNo==%27EC%2F1983%2F09%27) |location=London |url-status = dead|df=dmy-all }} The Royal Society awarded him the Gabor Medal in 1991 for molecular biology, in 1998 the Davy Medal for chemistry, in 2008 the Royal Medal and in 2020 the Copley Medal for his development and application of methods of protein engineering to provide descriptions of protein folding pathways at atomic resolution.{{cite web|website=The Royal Society|title=Royal Society announces 2020 winners of prestigious medals and awards|url=https://royalsociety.org/news/2020/08/Medals-and-awards-winners-2020/|access-date=9 August 2020}} He is a Foreign Associate of the United States National Academy of Sciences,{{cite web|url=http://www.nasonline.org/member-directory/members/64214.html|archive-url=https://web.archive.org/web/20150417135757/http://www.nasonline.org/member-directory/members/64214.html|archive-date=17 April 2015|title=Alan Fersht, University of Cambridge, Election Year: 1993|publisher=National Academy of Sciences}} a Foreign Member of the American Philosophical Society, a Foreign Member of the Accademia dei Lincei, Member of Academia Europaea, an Honorary Foreign Member of the American Academy of Arts and Sciences and a Fellow of the Academy of Medical Sciences (FMedSci).{{cite web|archive-url=https://web.archive.org/web/20150417140157/http://www.acmedsci.ac.uk/fellows/fellows-directory/ordinary-fellows/professor-sir-alan-fersht/|title=Professor Sir Alan Fersht FRS FMedSci|url=http://www.acmedsci.ac.uk/fellows/fellows-directory/ordinary-fellows/professor-sir-alan-fersht/|archive-date=17 April 2015|publisher=Academy of Medical Sciences}} His nomination for the Royal Society reads: {{blockquote|Distinguished for work on mechanisms of enzyme catalysis, especially by stopped and quenched flow methods. He showed that a slow relaxation of chymotrypsin was not a chemical step on the reaction pathway, but a pH-dependent isomerisation between active and inactive forms, and investigated the energetics and equilibria of the transition. He elucidated the leaving-group specificity, leading to a detailed structural interpretation which showed the energetics of "strain" at the binding site. Another experiment dispelled final doubts about the role of a tetrahedral intermediate. More recently Fersht has studied a more complex group of enzymes, the aminoacyl tRNA synthetases. He demonstrated that their precise specificity depends on consecutive independent recognition steps, and under appropriate conditions he trapped a transiently discharged aminoacyl tRNA. Fersht has shown how binding energy can be used to enhance either specificity or rate in an enzymatic reaction, leading to a demonstration of thermodynamic limitations on mechanisms of the "induced fit" type.}}

Fersht holds honorary doctorates from Uppsala University (1999),{{Cite web | url=http://www.uu.se/en/about-uu/traditions/prizes/honorary-doctorates/ |title = Honorary doctorates – Uppsala University, Sweden| date=9 June 2023 }} Vrije Universiteit Brussel (1999), Weizmann Institute of Science (2004), Hebrew University of Jerusalem (2006), and Aarhus University (2008). He is an Honorary Fellow of Darwin College, Cambridge (2014) and Jesus College, Cambridge (2017).

Fersht has received many prizes and medals including: the FEBS Anniversary Prize; Novo Biotechnology Award; Charmian Medal of the Royal Society of Chemistry; Max Tishler Lecture and Prize Harvard University; The Datta Lectureship and Medal of the Federation of European Biochemical Societies; Jubilee Lecture and the Harden Medal of the Biochemical Society; Feldberg Foundation Prize, Distinguished Service Award, Miami Nature Biotechnology Winter Symposium; Christian B. Anfinsen Award of the Protein Society; Natural Products Award of the Royal Society of Chemistry, Stein and Moore Award of the Protein Society;{{Cite journal

| pmid = 15484254

| year = 2004

| title = Alan R. Fersht receives Bader Award / Corey Award to David W. C. Mac Millan / Breslow Award to Peter B. Dervan

| journal = Angewandte Chemie International Edition

| volume = 43

| issue = 41

| pages = 5430

| doi = 10.1002/anie.200462026

}}{{Cite journal

| pmid = 11345067

| year = 2001

| title = Alan Fersht. 2001 Stein and Moore Award

| journal = Protein Science

| volume = 10

| issue = 4

| pages = 905

}} Bader Award of the American Chemical Society; Kaj Ulrik Linderstrøm-Lang Prize and Medal; Bijvoet Medal of the Bijvoet Center for Biomolecular Research of Utrecht University in 2008 and the Gilbert N. Lewis Medal University of California, Berkeley, and the Wilhelm Exner Medal in 2009.editor, ÖGV. (2015). Wilhelm Exner Medal. Austrian Trade Association. ÖGV. Austria.

In 2003 he was knighted for his pioneering work on protein science. His citation on election to the Academy of Medical Sciences reads: {{blockquote|Herchel Smith Professor of Organic Chemistry at the MRC Centre for Protein Engineering, Cambridge, Sir Alan is one of the world's leading protein scientists. He was elected to the Royal Society in his late 30s in 1983 for his work illuminating enzymic catalysis and how enzymes attain high fidelity in the translation of the genetic code. Subsequently he was one of the pioneering founders of protein engineering, developing it as an analytical procedure for understanding interactions in proteins and enzyme catalysis. This radical new approach unravelled the relationships between the structure, activity and function of proteins. The full power of his methods became apparent in his seminal and far reaching contributions to the field of protein folding and stability. These studies opened the way to development of novel therapies in cancer and other diseases. He currently works on mutations that affect the stability and activity of the tumour suppressor p53 and how mutants may be "rescued" by small molecule drugs. His contributions have been widely recognised nationally and internationally by prizes for both chemistry and molecular biology, and by memberships of foreign academies.}}

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Fersht married Marilyn Persell in 1966 and has one son and one daughter. His recreations include chess,{{cite book |author =Fersht, Alan |title=Jaques Staunton Chess Sets 1849–1939 |publisher=Kaissa Publications |year=2007 |isbn=978-0-9557325-0-8 }}He has written an account of the history of Staunton and other chess sets. {{cite book| isbn=979-8-8002-0852-8|title = Jaques and British Chess Company Chess Sets|author = Alan Fersht | date = 2010|publisher = Kaissa Publications}} horology and wildlife photography.

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{{s-ttl|title=Gabor Medal|years=1991}}

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Category:1943 births

Category:Living people

Category:British chemists

Category:Alumni of Gonville and Caius College, Cambridge

Category:Fellows of Gonville and Caius College, Cambridge

Category:Members of the University of Cambridge Department of Chemistry

Category:Academics of Imperial College London

Category:Fellows of the Royal Society

Category:Knights Bachelor

Category:Foreign associates of the National Academy of Sciences

Category:Members of the European Molecular Biology Organization

Category:Fellows of the Academy of Medical Sciences (United Kingdom)

Category:Royal Medal winners

Category:English biophysicists

Category:Masters of Gonville and Caius College, Cambridge

Category:People educated at Sir George Monoux College

Category:People from Walthamstow

Category:Jewish chemists

Category:Bijvoet Medal recipients

Category:Recipients of the Copley Medal

Category:Jewish British scientists

Category:International members of the American Philosophical Society