Derek George Smyth

Derek Smyth
Born	(1927-04-24) 24 April 1927 Kingston Upon Thames
Nationality	British
Fields	Biochemistry
Institutions	Medical College of St Bartholomews Hospital, Yale School of Medicine, Rockefeller University, National Institute for Medical Research

Derek Smyth is a British born scientist who specialises in peptide chemistry.

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, 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).

• Other members of the Laboratory of Peptide Chemistry: Alan Bradbury, Sheena Cockle, David Parish, Chris Snell, Siraik Zakarian, Derek Massey. Some other NIMR collaborators: Nigel Birdsall, Edward Hulme, Wilhelm Feldberg, William Deakin, Mike Geisow; in addition essential collaboration with Margaret Ghilchik of St Bartholomews Hospital, London.

Selected References

1. Smyth, D.G., Nagamatsu, A. and Fruton, J.S. (1960) Some reactions of N-ethyl maleimide. J. Amer. Chem. Soc. 82, 4600-4604.

2. Smyth, D.G. Battaglia., F.C. and Meschia, G. (1961) Studies on the Bohr effect of sheep haemoglobin. J. Gen. Physiol. 44, 889-898.

3. Smyth, D.G. and Tuppy, H. (1968) Acylation reactions with cyclic imides. Biochim. Biophys. Acta, 168, 173-180.

4. Smyth, D.G., Stein, W.H. and Moore, S. (1962) On the sequence of residues 11-18 in Bovine Pancreatic Ribonuclease. J. Biol. Chem., 237, 1845-1850.

5. Smyth, D.G., Stein, W.H. and Moore, S. (1963) The Sequence of Amino Acid Residues in Bovine Pancreatic Ribonuclease: revisions and confirmations. J. Biol. Chem., 238, 227-234.

6. Smyth, D.G. (1963) Proteins and Peptides. Annual Reports of the Chemical Society, 468-485.

7. Smyth, D.G. and Elliott, D.F. (1964) Some analytical problems in determining the structure of proteins and peptides. J. Soc. Analyt. Chem., 89, 81-94.

8. Smyth, D.G., (1967) Techniques in enzymic hydrolysis and sequence determination. In: Methods in Enzymology, C.H.W. Hirs (Ed) Academic Press, 11, 214-231.

9. Smyth, D.G. (1967) Use of pepsin, papain and subtilisin in sequence determination. In: Methods in Enzymology, C.H.W. Hirs (Ed) Academic Press, 11, 421-426.

10. Bisset, G.W., Poisner, A.M. and Smyth, D.G. (1963) Carbamylation of oxytocin and arginine vasopressin. Nature, 199, 69-70.

11. Smyth, D.G. (1964) Reactions of cyanate with amino and hydroxyl groups: application to oxytocin. Hung. Chim. Acta, 44, 197-204.

12. Smyth, D.G. (1967) Carbamylation of amino and tyrosine hydroxyl groups: preparation of an inhibitor of oxytocin with no intrinsic activity on the isolated uterus. J. Biol.Chem., 242, 1579-1591.

13. Smyth, D.G. (1970) On the molecular mechanism of oxytocin action. Biochim. Biophys. Acta, 200, 395-403; Library of Congress Publication data, Current Research in oxytocin, 11-19.

14. Smyth, D.G. (1964) Proteins and Peptides. Annual Reports of the Chemical Society, 507-525.

15. Smyth, D.G. (1965) Proteins and Peptides. Annual Reports of the Chemical Society, 488-509. .

16. Smyth, D.G. (1967) Proteins and Peptides. Annual Reports of the Chemical Society, 249-261.

17. Smyth, D.G. and Utsumi, S. (1967) Structure at the “hinge” region of rabbit immunoglobulin-G. Nature, 216, 232-235.

18. Fanger, M.W. and Smyth, D.G. (1972) The oligosaccharide units of rabbit immunoglobulin-G: multiple carbohydrate attachment sites. Biochem. J., 127, 757-765.

19. Fanger, M.W. and Smyth, D.G. (1972) The oligosaccharide units of rabbit immunoglobulin-G: asymmetric attachment of the C2 oligosaccharide. Biochem. J., 127, 767-774.

20. Hinrichs, W.A. and Smyth, D.G. (1970) Studies on the asymmetrically attached oligosaccharide of rabbit immunoglobulin-G; on the biological function of the C2 oligosaccharide. Immunology, 18, 768-774.

21. Hinrichs, W.A. and Smyth, D.G. (1970) Studies on the asymmetrically attached oligosaccharide of rabbit immunoglobulin-G; biosynthesis and stability of the C2 oligosaccharide. Immunology, 18, 759-770.

22. Ko, A.S.C., Smyth, D.G., Markussen, J. and Sundby, F. (1971) The amino acid sequence of the C-peptide of Human Proinsulin. Eur.J. Biochem., 20, 190-199.

23. Massey, D.E. and Smyth, D.G. (1975) Guinea Pig Proinsulin: primary structure of the C-peptide isolated from pancreas. J. Biol. Chem., 250, 6288-6290.

24. Salokangas, A., Smyth, D.G., Markussen,J. and Sundby, F. (1971) Bovine Proinsulin: amino acid sequence of the C-peptide isolated from pancreas. Eur.J. Biochem., 20, 183-189.

25. Snell, C.R. and Smyth, D.G. (1975) Proinsulin: a proposed three dimensional structure. J. Biol. Chem., 250, 6291-6295.

26. Smyth, D.G. (1981) Chemistry of the opiate peptides: enkephalins and endorphins. In: Proceedings of the 6th European Peptide Symposium, K. Brunfeld (ed). Scriptor, Copenhagen, pp 56–69.

27. Zakarian, S. and Smyth, D.G. (1981) Distribution of β-endorphin related peptides in rat pituitary and brain. Biochem. J., 202, 561-571; Proc.Natl.Acad. USA, (76) 5972-5976.

28. Smyth, D.G., (1984) Chromatography of peptides related to β-endorphin. Analyt. Biochem., 136, 127-135.

29. Smyth, D.G., Massey, D.E., Zakarian, S. and Finnie, M.D. (1979) Endorphins are stored in biologically active and inactive forms; isolation of alpha-N-acetyl peptides. Nature, 272, 252-254.

30. Zakarian, S. and Smyth, D.G. (1982) β-endorphin is processed differently in specific regions of rat pituitary and brain. Nature, 296, 250-253.

31. Smyth, D.G., Smith, C.C.F. and Zakarian, S. (1981) Isolation and identification of two new peptides related to β-endorphin. In: advances in endogenous and exogenous opioids. H. Takagi (Ed) Kodanski-Elsevier, Tokyo-Amsterdam., 145-148.

32. Geisow, M.J., Dostrovsky, J.F.W. and Smyth, D.G. (1977) Analgesic activity of lipotropin C-Fragment depends on carboxyl terminal tetrapeptide. Nature, 269, 167-168.

33. Parish, D.C. and Smyth D.G. (1982) Isolation of glycylglutamine, the C-terminal dipeptide of the β-endorphin corticotropin prohormone, Biochem Soc Trans. 10,221.

34. Parish, D.C. and Smyth D.G., Normanton J.R. and Wolstencroft, J.H. (1983) Glycylglutamine, an inhibitory neuropeptide derived from β-endorphin, Nature (London), 306,267-270.

35. Bradbury, A.F., Smyth, D.G. and Snell, C.R. (1975) Biosynthesis of β-MSH and ACTH. In: Peptides, Chemistry, Structure and Biology. R. Walters and J. Meienhofer (Eds). Ann Arbor Science Publishers Inc., Michigan, 609-615.

36. Bradbury, A,F., Smyth, D.G. and Snell, C.R. (1976) Prohormones of β-melanotropin (β-melanocyte stimulating hormone, β-MSH) and corticotrophin (ACTH): structure and activation. In: Polypeptide Hormones, molecular and cellular aspects. R. Porter and D.W. FitzSimons (Eds) Elsevier/ Excerpta Medica, North Holland, 61-75.

37. Smyth, D.G., Snell, C.R. and Massey, D.E. (1978) Isolation of the C-fragment and C/-fragment of lipotropin from pig pituitary and the C-fragment from brain. Biochem. J., 175, 261-270.

38. Bradbury, A.F., Smyth, D.G., Snell, C.R. Birdsall, N.J.M. and Hulme, E.C. (1976) C-Fragment of lipotropin has a high affinity for brain opiate receptors. Nature, 260, 793-796.

39. Feldberg, W.S. and Smyth, D.G. (1976) The C-Fragment of lipotropin, a potent analgesic. J. Physiol. (London), 260, 30P.

40. Feldberg, W.S. and Smyth, D.G. (1977) C-Fragment of lipotropin, an endogenous potent analgesic peptide. Brit. J. Pharm., 60, 445-454.

41. Bradbury, A.F., Smyth, D.G., Snell, C.R., Deakin, J.F.W. and Wendlandt, S. (1977) Comparison of the analgesic properties of lipotropin C-Fragment and stabilised enkephalins in the rat. Biochem. Biophys. Res. Commun. 64, 748-753.

42. Smyth, D.G. (1983) Opioid Peptides and Pain. In: Clinics in Anaesthesiology, 1, 201-217.

43. Smyth, D.G. (1976) Searching for the endogenous analgesic. Lancet Editorial, 665-666.

44. Gispen, W.H., de Wied, D., Bradbury, A.F., Hulme, E.C., Smyth, D.G. and Snell, C.R. (1976) Induction of excessive grooming in the rat by fragments of lipotropin. Nature, 264, 792-794.

45. Van Ree, J.M., Smyth, D.G. and Colpaert, F.C. (1979) Dependence creating properties of lipotropin C-Fragment (β-endorphin): evidence for its internal control of behaviour. Life Sci., 24, 495-502.

46. Bradbury, A. F., Finnie, M.D.F. and Smyth, D.G. (1982) Mechanism of C-terminal amide formation by pituitary enzymes. Nature, 298, 686-689.

47. Bradbury, A.F. and Smyth, D.G. (1991) Peptide amidation. TIBS., 16, 112-115.

48. Bradbury, A.F. and Smyth, D.G. (1987) Enzyme catalysed peptide amidation: isolation of a stable intermediate formed by reaction of the amidating enzyme with an imino acid. Eur. J. Biochem. 169, 579-584.

49. Bradbury, A.F., Mistry, J., Roos, B.A. and Smyth, D.G. (1990) 4-Phenyl-3-butenoic acid, an in vivo inhibitor of peptidylglycine hydroxylase (peptide amidating enzyme). Eur.J.Biochem., 189, 363-368.

50. Cockle, S,M., Aitken, A., Beg, F. and Smyth, D.G. (1989) A novel peptide, pyroglutamylglutamylproline amide,in the rabbit prostate complex, structurally related to thyrotropin releasing hormone. J. Biol. Chem., 264, 7788-7791

51. Khan, Z., Aitken,A., del Rio-Garcia, J. and Smyth, D.G. (1992) Isolation and identification of two neutral thyrotropin hormone-like peptides, pyroglutamylphenylalanine proline amide and pyroglutamylglutamine proline amide from human seminal fluid. J. Biol. Chem., 267, 7464-7469.

52. Cockle, S.M., Aitken, A., Beg, F. and Smyth, D.G. (1989) The TRH-related peptide pyroglutamylglutamylproline amide is present in human seminal fluid. FEBS Letts., 252, 113-117.

53. del Rio-Garcia, J. and Smyth, D.G. (1990) Distribution of pyroglutamylpeptide amides in the central nervous system and periphery of the rat. J. Endocrinol., 127, 445-450.

54. Bilek, R., Gkonos, P.J., Tavianini, M., Smyth, D.G. and Roos, B.A. (1992) The thyrotropin releasing hormone (TRH)-like peptides in rat prostate are not formed by expression of the TRH gene but are suppressed by thyroid hormone. J. Endocrinol., 132, 177-184.

55. Linden, H., del Rio-Garcia, J., Huber, A., Kreil, G. and Smyth, D.G. (1996) The TRH-like peptides in rabbit testis are different from the TRH-like peptide in the prostate. FEBS Letts., 379, 11-14.

56. Huber, A.E., Fraser, H., del Rio-Garcia, J., Kreil, G. and Smyth, D.G. (1998) Molecular cloning in the marmoset shows that the TRH-like peptide pGlu-Glu-Pro amide is not formed from semenogelin. Biochem. Biophys. Acta, 1387, 143-152.

57. Rausell, V., Fraser, H.M., Tobaruela, M., del Rio-Garcia, J. and Smyth, D.G. (1998) Identification of the TRH-like peptides pGlu-Glu-Pro amide and pGlu-Phe-Pro amide in rat thyroid: regulation by thyroid status. Regulatory peptides, 31, 55-60.

58. Ghilchik, M.W., Tobaruela, M., del Rio-Garcia,J. and Smyth, D.G. (2000) The TRH-like peptide pGlu-Phe-Pro amide is present in rat and human mammary gland and is secreted in the milk. Biochem. Biophys. Acta, 1475, 55-60.

59. Smyth, D.G., del Rio-Garcia, J., Wallnofer, H., Gogl, H., Simma, W., Huber, A., Embacher, R., Fraser, H. and Kreil, G. (1999) Protirelin (thyrotropin-releasing hormone) in the thyroid gland: possible involvement in regulation of thyroid status. Acta Pharmacol. Sin., 20, 289-291.

60. Smyth, D.G. (1997) Discovering biologically active peptides; from structure to function, Anales de la Real Academia de Medicina y Cirugia de Murcia. 49-70.