Sir Alan Rushton Battersby (4 March 1925 – 10 February 2018) was an English organic chemist best known for his work to define the chemical intermediates in the biosynthetic pathway to vitamin B12 and the reaction mechanisms of the enzymes involved.
He soon concluded that this decision had been a mistake and so used his spare time to study independently at Salford Technical College for the Higher School Certificate that would be required to enter university.
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, notably Jim Staunton, Ted McDonald and Finian Leeper.
"These tools are the now-familiar mass spectrometry, multi-atom nuclear magnetic resonance spectroscopy and X-ray crystallography: when applied to alkaloids these allowed relationships in structural sub-types to be clarified.
His research group elucidated, in particular, the essential role played by two enzymes, deaminase and cosynthetase, in the steps from aminolevulinic acid via porphobilinogen and hydroxymethylbilane to uroporphyrinogen III.
The work involved the careful study of labelled intermediates, using deuterium, tritium, 13C and 14C placed into potential precursors made by organic or enzyme-assisted synthesis.
The most successful strategy was to incorporate the stable isotope 13C into potential substrates, since the outcome of the biochemical reactions (for example giving uroporphyrinogen III) could readily be followed using high-field 13C NMR.
[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.
It was not until a genetically engineered strain of Pseudomonas denitrificans was used, in which eight of the genes involved in the biosynthesis of cobalamin had been overexpressed, that the complete sequence of methylation and other steps could be determined thus fully establishing all the intermediates in the pathway.
[27] Another challenge requiring pure synthesis was to investigate the function of the enzymes that contained porphyrin-related ligands, or (in the case of haemoglobin) used haem for oxygen-transport, by mimicking these properties without recourse to the protein that in nature surrounds the active site.
Battersby chose to investigate mimics for myoglobin and cytochrome P450, designing artificial targets wherein a single metal-containing coordination complex was synthesised and its behaviour compared with the natural system it was replacing.
He was awarded the Wolf Prize in Chemistry along with Duilio Arigoni of ETH 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".
The Award of the Copley Medal of the Royal 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.