Sir Alan Battersby | |
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 Battersby in his office | |
| Born | Alan Rushton Battersby (1925-03-04)4 March 1925 Leigh, Lancashire, England |
| Died | 10 February 2018(2018-02-10) (aged 92) |
| Education | University of Manchester University of St Andrews |
| Spouse | Margaret Ruth née Hart |
| Parents |
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| Awards | Davy Medal(1977) Paul Karrer Gold Medal(1977) Royal Medal(1984) Wolf Prize in Chemistry(1989) Tetrahedron Prize(1995) Copley Medal(2000) |
| Scientific career | |
| Fields | Organic Chemistry Natural Products |
| Institutions | University of St Andrews Rockefeller University University of Illinois University of Bristol University of Liverpool Cambridge University |
| Thesis | Researches into the structure of Emetine (1949) |
| Doctoral advisor | Dr Hal T Openshaw |
| Doctoral students | Andrew D. Hamilton Craig Hawker |
Sir Alan Rushton Battersby (4 March 1925 – 10 February 2018) was an Englishorganic chemist best known for his work to define the chemical intermediates in the biosynthetic pathway tovitamin B12 and thereaction mechanisms of theenzymes involved. His research group was also notable for itssynthesis ofradiolabelled precursors to studyalkaloid biosynthesis and thestereochemistry ofenzymic reactions. He won numerous awards including theRoyal Medal in 1984 and theCopley Medal in 2000. He was knighted in the1992 New Year Honours. Battersby died in February 2018 at the age of 92.[1]
Alan Battersby was born inLeigh, Lancashire, on 4 March 1925, one of three children of William Battersby, a master plumber, and his wife Hilda née Rushton.[2] At the age of 11 he entered Leigh Grammar School, where his chemistry teacher, Mr Evans, nurtured and encouraged him. He would have continued his schooling into the sixth form but for the fact that by age sixteen theSecond World War was underway and he decided that he should join the war effort by working forBICC in their local factory. He soon concluded that this decision had been a mistake and so used his spare time to study independently at Salford Technical College for theHigher School Certificate that would be required to enter university.[2][3][4] In October 1943, Battersby took up his place at theUniversity of Manchester's Chemistry Department, having won a scholarship to support his undergraduate studies. He graduated with first class honours in 1946 and that year obtained a Mercer Chemistry Research Scholarship (named in honour ofJohn Mercer) and aDSIR grant. These awards allowed him to complete an MSc (Manchester) in 1947 under the supervision of Dr Hal T Openshaw. When Openshaw was appointed as aReader at theUniversity of St Andrews, they both moved there and Battersby completed his PhD, which was awarded in 1949.[5] He was immediately appointed an assistant lecturer at St Andrews.[3] This first appointment extended from 1949 to 1953 but was interrupted by two years owing to aCommonwealth Fund Fellowship he obtained for post-doctoral study in the United States. The first year was spent withLyman C. Craig at theRockefeller Institute for Medical Research,New York, working on thepeptideantibioticstyrocidine andgramicidin S. The second year involved a move to thebiochemistry department of theUniversity of Illinois, working withHerbert Carter onpyruvate oxidation factor.[6][7][a]
In 1954, Battersby was appointed a lecturer at the University of Bristol, where he stayed until 1962. This was the period when his own research group of doctoral and post-doctoral students became established. In 1962 he was appointed as a professor of chemistry atLiverpool University until, in 1969, he moved to a professorship at theUniversity of Cambridge and became aFellow ofSt Catharine's College. At the time, this was the second Chair of Organic Chemistry at the university, created especially for him;Lord Todd then held the first. In 1988, Professor Battersby was elected to the prestigious1702 Chair of Chemistry in hisdepartment and held that post until his retirement in 1992 when he was grantedemeritus status within his college and department, reflecting his distinguished service.[6][7][8]
The full output of Battersby's work has been published in over 350, mainlypeer-reviewed, articles.[9] His research, particularly at Cambridge, took a very collaborative approach which was necessary given the extended time period of the ambitious projects undertaken. Aside from his postgraduate and post-doctoral students, who participated typically for one to three years, the Battersby group included other members of the academic staff of the department, notablyJim Staunton, Ted McDonald andFinian Leeper.[10] The group was funded by external grants, including those from theSERC, theEPSRC, theLeverhulme Trust,Hoffman-La Roche, theWolfson Foundation andZeneca.[10]
Alkaloids are a group of naturally occurring chemical compounds that mostly containbasicnitrogen atoms. They have a wide range ofpharmacological activities which has made them of considerable interest to researchers. Prior to the 1950s, experimentation, often involvingchemical degradation and partial or complete synthesis of possible structures, was necessary to determine theirchemical identity which, owing to theirstereochemistry, was often difficult to fully describe.[11] This, for example, was the case foremetine, used for the treatment ofamoebic infections and the subject of Battersby's PhD thesis.[5] As he later commented[7]
"Roughly 100 g of emetine had been consumed in this work; modern tools would allow the structure of emetine to be determined in three days at most using about 10 mg of recoverable material (365 times faster using 10,000 times less material)."
These tools are the now-familiarmass spectrometry, multi-atomnuclear magnetic resonance spectroscopy andX-ray crystallography: when applied to alkaloids these allowed relationships in structural sub-types to be clarified. This meant that attention could switch to an understanding of the biosynthetic pathways by which these materials are produced in thebacteria,fungi,plants andanimals in which they are found. In 1937, Sonderhoff and Thomas showed howdeuterium-labelled acetate could be used to investigate the biosynthesis of fats and steroids;[12] by 195013C and14C labelled acetate had been incorporated intocholesterol.[13] Battersby realised that these techniques could be used to study alkaloid biosynthesis and that it was timely to do so because simple one-carbon precursors had become commercially available. By usingradiolabelled starting materials incorporatingtritium or, especially,14C to follow intermediates on the pathway, he determined the sequence in which the multiple alkaloids found together in a given organism were formed. For example, the biosynthesis ofmorphine was shown to proceed from L-tyrosine viareticuline,salutaridine,thebaine,codeinone andcodeine.[14][15] The Battersby group worked on many other alkaloids, for examplecolchicine, (from the autumn crocusColchicum autumnale) which is used to treatgout. This was shown to be derived from the amino acidsphenylalanine andtyrosine via (S)-autumnaline.[16] Similarly, the biosynthesis of theindole alkaloidsajmalicine,corynantheal,catharanthine andvindoline was shown to involve the precursorstryptamine andloganin.[17] To Alan Battersby's surprise,quinine, theanti-malarial drug was shown to derive from corynantheal, although it does not share itsindole substructure.[7]
Battersby is, above all, known for his research on the biosynthesis of the "pigments of life" that are built on closely relatedtetrapyrrolic structural frameworks. His research group elucidated, in particular, the essential role played by two enzymes,deaminase andcosynthetase, in the steps fromaminolevulinic acid viaporphobilinogen andhydroxymethylbilane touroporphyrinogen III. The latter is the firstmacrocyclic intermediate in thebiosynthesis ofhaem,chlorophyll,vitamin B12 (cobalamin),sirohaem andcofactor F430. The work involved the careful study of labelled intermediates, usingdeuterium,tritium,13C and14C placed into potential precursors made byorganic orenzyme-assisted synthesis. The most successful strategy was to incorporate the stable isotope13C into potential substrates, since the outcome of the biochemical reactions (for example givinguroporphyrinogen III) could readily be followed using high-field13C NMR. The Battersby group's use of doubly-13C-labelledporphobilinogen was especially revealing of the rearrangement step which had puzzled those who wished to understand the details of the biosynthesis of uroporphyrinogen III.[18][19] Based on these results, Battersby suggested that a spiro-pyrrolenine intermediate was generated at the active site of cosynthetase and to prove this mechanism his group designed and synthesised a spiro-lactam analogue which was indeed shown to inhibit the enzyme.[20]
Later steps towards vitamin B12, especially the incorporation of the additional methyl groups of its structure, were investigated using methyl-labelledS-adenosyl methionine. It was not until agenetically engineered strain ofPseudomonas denitrificans was used, in which eight of the genes involved in thebiosynthesis of cobalamin had beenoverexpressed, that the complete sequence of methylation and other steps could be determined thus fully establishing all the intermediates in the pathway.[7][21][22][23]As Battersby wrote in his review article inAccounts of Chemical Research[24]
"One can get some appreciation of the massive effort that was involved by the groups ofArigoni, Battersby, Francis Blanche, Vladimir Bykhovski, Joel Crouzet, Gerhard Muller and A. Ian Scott; K. Bernhauer and David Shemin also made some early contributions."
The Battersby group's work on the biosynthesis of haem-relatednatural products involved considerableorganic synthesis. For example, they produced fully synthetichaem a,[25]haem d1[26] andsirohydrochlorin.[27] Another challenge requiring pure synthesis was to investigate the function of theenzymes that contained porphyrin-related ligands, or (in the case ofhaemoglobin) used haem foroxygen-transport, bymimicking these properties without recourse to theprotein that in nature surrounds theactive site. Battersby chose to investigate mimics formyoglobin andcytochrome P450, designing artificial targets wherein a single metal-containingcoordination complex was synthesised and its behaviour compared with the natural system it was replacing. The small-molecule targets were porphyrins carrying substituents in positions where they would be unlikely to interfere with the electronic properties of the metal complex. By the time that he retired in 1992, this area of chemistry had become very active.[28][29]
The work described above is a subset of a broader field which attempts to understand thestereochemistry andmechanism ofenzyme catalysis. The Battersby group used their expertise in the use oftritium-labelled substrates to probe a number of enzyme systems, for examplehistidine decarboxylase andtyrosine decarboxylase.[15]
Battersby married Margaret Ruth née Hart in 1949. She was abotanist by profession who died of cancer in 1997. They had two sons, Martin and Stephen, four grandchildren and, after Margaret died, Alan acquired three great-grandchildren. In retirement, he enjoyedhiking andfly-fishing but he also kept in touch with his many colleagues and former students.[3][4][30]
Battersby receivedHonorary Doctorates from hisalma mater theUniversity of St Andrews, in 1977,[31]Rockefeller University, theUniversity of Sheffield in 1986,[32]Heriot-Watt University in 1987,[33]Bristol University in 1994[34] andLiverpool University in 1994.[35]In 1988, he was elected a Foreign Honorary Member of theAmerican Academy of Arts and Sciences,[36] and a Foreign Fellow of the National Academy of Sciences of India in 1990. He was awarded theWolf Prize in Chemistry along withDuilio Arigoni ofETH Zurich in 1989 for "their fundamental contributions to the elucidation of the mechanism of enzymic reactions and of the biosynthesis of natural products, in particular the pigments of life".[37]
The Award of theCopley Medal of theRoyal Society was made:
In recognition of his pioneering work in elucidating the detailed biosynthetic pathways to all the major families of plant alkaloids. His approach, which stands as a paradigm for future biosynthetic studies on complex molecules, combines isolation work, structure determination, synthesis, isotopic labelling and spectroscopy, especially advanced NMR, as well as genetics and molecular biology. This spectacular research revealed the entire pathway to vitamin B12.[43]
Notes
References
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