Derek George Smyth

Derek Smyth (born 24 April 1927) is a British biochemist who specialises in peptide structure and function. In 2002, he was admitted as a Fellow of the Royal Society of Chemistry.
Background.
Derek Smyth was Head of the Laboratory of Peptide Chemistry at the National Institute for Medical Research (NIMR) in Mill Hill, London from 1972 to 1992. He had worked previously with Professor Joseph Fruton, Head of the Biochemistry Department 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 Howard Stein (Nobel Prize winners) he reinvestigated and established the definitive amino acid sequence of pancreatic ribonuclease (4-8), the first enzyme (some say the first protein) to have its primary structure determined (9).
On moving to NIMR in 1963, 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), Smyth and Sayaki Utsumi unravelled the structure at the ‘hinge region’ of rabbit 7S gamma globulin, juxtaposing the FAB and (FAB)2 fragments in the 4-chain IgG molecule, locating the bridge that links the half molecules, and revealing a new oligosaccharide chain adjacent to the disulphide bridge (17-21). Present on one H-chain and not the other, the carbohydrate renders the IgG molecule asymmetric but the biological function of the carbohydrate is not known. It could serve to anchor the antibody molecule at sites where toxic glycoproteins (viruses) act.
He followed this by sequencing the connecting peptide (C-peptide) of proinsulin in a range of species, indicating a conservation of secondary structure (22-25). The contribution made by the C-peptide to a 3-dimensional structure of proinsulin was proposed by Snell and Smyth (25) who constructed a model of the prohormone by aligning the secondary structure of the C-Peptide with the structure of insulin (established in the crystallographic studies of Tom Blundell and his colleagues). In the model, the C-peptide masked the ‘active site’ of the insulin moiety, accounting for the inactivity of the prohormone, and the paired basic residues sites were located externally, accessible to enzymic activation.
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 to 1982, he and his team (26-34) showed that the C-terminal fragment of lipotropin, discovered by Smyth in the pituitary (35-37), was an endogenously expressed opiate (38). Feldberg and Smyth demonstrated that this 31 amino acid peptide, now known as β-endorphin, is a neurohormone with potent analgesic activity (39-43) and profoundly significant in brain function (40, 44, 45).
Among the peptides he isolated from pituitary was a 39 residue glycopeptide with a strongly conserved sequence of amino acids (46), subsequently shown to represent the entire C-terminal region of the vasopressin prohormone. Immunohistochemical mapping with antibody to the glycopeptide has made possible complete differentiation to be made between the distribution of vasopressin and oxytocin in the brain.
Subsequently, Bradbury and Smyth elucidated the mechanism of peptide amidation (46-49), a post-translational modification essential for the activity of many peptide hormones and hormone releasing peptides and more recently Smyth and his colleagues isolated and identified a series of tripeptide amides with structure related to thyrotropin-releasing hormone (50-54). These peptides possess inhibitory properties and appear to fulfil a physiological role in hormone regulation. Thus pGlu Phe Pro amide which occurs in testis has been shown to inhibit the release of testosterone (51) while pGlu His Pro amide which is present in thyroid inhibits release of thyroglobulin.
The continuing line of his research culminated in the proposal of a new concept for the regulation of peptide hormone activity (54). In the mechanism involved, although increase in activity is initiated by synthesis of hormone releasing peptide in the hypothalamus, the action of the releasing peptide is counteracted by inhibition at its target site in the periphery. That hormone activity should be sensitive to processes involving both activation and inhibition makes possible 'minute-by-minute' fine control, a key feature not present in the conventional switch on-switch off mechanism.
It may be noted that the dual mechanism proposed for hormone regulation is analogous to the mechanism involved in synaptic transmission in the central nervous system, in line with a common evolutionary origin for the central and peripheral processes.
His wide-ranging studies of structure and function in biologically active peptides indicated that the regulation of their activity involves a dual mechanism. It embodies a fundamental principle, that 'activation' and 'inhibition' act diametrically to determine the levels of hormones in the circulation and transmitters in the CNS. Overall his research demonstrated that at the molecular level, biological activity is 'structure and change of structure'.
After retiring from NIMR, Smyth continued his research at the Institute for Molecular Biology in Salzburg (56, 57), in the Pharmacology Department of the University of Murcia (58-61) and in the William Harvey Research Institute, University of London (62). For a number of years (1977-1982) he was invited formally to assist 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).