Derek George Smyth

Background

Derek Smyth was Head of the Laboratory of Peptide Chemistry at the National Institute for Medical Research (NIMR) from 1972-1992. He had worked previously with Professor Joseph Fruton at Yale University where he gained experience in protein and peptide chemistry (1-3) and in 1960 transferred to Rockefeller University in New York City where in the laboratory of Stanford Moore and William Stein he reinvestigated and established the definitive amino acid sequence of pancreatic ribonuclease (4-9), the first enzyme to have its primary structure determined. On moving to NIMR in 1963, Derek Smyth prepared two novel derivatives of oxytocin, N-carbamylcystine-1-oxytocin and N-carbamyl cystine-1-O-carbamyltyrosine-2-oxytocin, and in a collaborative study with Gordon Bisset it was shown that while the monocarbamyl hormone retained weak biological activity (10), the dicarbamyl derivative proved to be a specific inhibitor of oxytocin devoid of intrinsic activity (11,12), demonstrating that the action of the hormone takes place in consecutive stages that could be studied independently (13). Maintaining his interest in protein structure (14-16), Derek Smyth together with Sayaki Utsumi unravelled the structure of the ‘hinge region’ of rabbit 7S gamma globulin, juxtaposing the FAB and (FAB)2 fragments of the 4-chain IgG molecule, locating the bridge that links the two half molecules and revealing a new oligosaccharide chain (17-21). He followed this by sequencing the connecting peptide (C-peptide) of proinsulin (22-25), modelling its contribution to the 3 dimensional structure of the prohormone (25) and building on the crystallographic studies of insulin by Tom Blundell and his colleagues. The enzymatic processing of prohormones to release their biologically active constituents was a dominant lifetime interest. His major contribution came from studies of β-lipotropin (61), now recognised as a component of the pro-opiomelanocortin locus. In a classic series of papers from 1975-1982, he and his collaborators* (26-34) showed that the C-terminal fragment of lipotropin, first isolated in his laboratory from pituitary (35-37), was an endogenously expressed opiate (38). They showed that this 31 amino acid peptide, now known to all as β-endorphin, is a neurohormone with potent analgesic activity (39-43) and producing profound behavioural effects in the brain (40, 44, 45). Later, with Alan Bradbury, he elucidated the mechanism of peptide amidation, a post-translational modification essential for the activity of many peptide hormones (46-49) and more recently he and his colleagues have isolated a series of pyroglutamyl peptide amides that may play an important role in the regulation of hormone activity (50-54). After retiring from NIMR, he continued his research at the Institute for Molecular Biology in Salzburg (55, 56) and then in the Pharmacology Department of the University of Murcia, Spain (57-59). For several years (1977-1982) he assisted the Nobel Committee in their nomination of candidates for the Nobel Prize in Physiology or Medicine and in 1997 he was elected as an honorary member (Excmo) of the Royal Academy of Medicine and Surgery in Murcia (60).