Chemistry of the Gastrointestinal Hormones and Hormone-like Peptides and a Sketch of Their Physiology and Pharmacology

Mutt, Viktor

doi:10.1016/s0083-6729(08)61138-3

Cited by 26 publications

(5 citation statements)

References 939 publications

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“…a Characterized Forms The chemically identified forms of CCK in gut are the peptides of 33 (CCK33) and 39 (CCK39) residues, isolated and sequenced by Mutt and Jorpcs over a decade ago (see review by Mutt, 1980). During the isolation procedure it was found that the biological activity of CCK, i.e., gall-bladder contraction, always moved in parallel with that of pancreozymin, i.e., pancreatic enzyme release.…”

Section: Chemical Relationships Of Cholecystokinins In Brain and Gutmentioning

confidence: 99%

“…The mechanisms of conversion are still largely unknown, although a preparation that specifically converts CCK33 to CCK8 has been obtained from bovine brain (Ryder et al 1980). Recently Mutt (1982) reported that enterokinase cleaves CCK33 to yield CCK8, but the relationships between enterokinase and the endogenous converting enzymes are still uncertain.…”

Section: Chemical Relationships Of Cholecystokinins In Brain and Gutmentioning

confidence: 99%

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The Physiology of Cholecystokinin in Brain and Gut

Dockray

1982

British Medical Bulletin

110

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PHYSIOLOGY OF CHOLECYSTOKININ IN BRAIN AND GUT GJDockray used in biological studies before it became clear that this fragment existed naturally in its own right The identification of CCK8 was made first in extracts of brain of the rat, pig, dog and man, and followed reports of gastrin-like immunoreactivity in brain (Vanderhaeghen et al. 1975; Dockray, 1976; Muller et al. 1977; Rehfeld, 1978). The latter material was reported to occur in high concentrations in cerebral cortex and to have the gel-filtration properties of a molecule smaller than the main forms of gastrin. It is now clear that this material is attributable to CCK8, which cross-reacts with some C-terminal specific gastrin antisera because of the common C-terminal pentapeptide of the two substances (fig. 1). Soon after the identification of CCK8 in brain this material was isolated and shown to possess the full chemical and biological properties of the synthetic peptide (Dockray et al. 1978). A closely related variant of CCK8 that is also biologically active, but on anion-exchange chromatography appears to be slightly less acidic, was isolated as well, but has not yet been fully characterized. All the characterized forms of CCK have a sulphated tyrosine residue at position seven counting from the C terminus. Radioimmunoassay studies using antisera that react equally with sulphated and unsulphated CCK 8 indicate that the desulphated form does not occur naturally in detectable amounts (Dockray, 1980). In contrast, the structurally related hormone gastrin, which also has a tyrosine in the C-terminal region (although in this case at position six from the C terminus), occurs in antral mucosa in about equal proportions of sulphated and unsulphated forms (see Gregory, 1982). The sulphate group is essential for the main gastrointestinal actions of CCK8, but its significance for the neuronal actions of this peptide are less obvious (see section 3).

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Section: Chemical Relationships Of Cholecystokinins In Brain and Gutmentioning

confidence: 99%

Section: Chemical Relationships Of Cholecystokinins In Brain and Gutmentioning

confidence: 99%

The Physiology of Cholecystokinin in Brain and Gut

Dockray

1982

British Medical Bulletin

110

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“…At about the same time, Jorpes and Mutt isolated and sequenced secretin and CCK, and showed CCK and PZ were a single hormone (Jorpes & Mutt, ). Then, after Jorpes’ death, Viktor Mutt discovered many other regulatory peptides in the intestine including vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), and peptide YY (PYY) (Mutt, ). By about the time that Rod Gregory gave his Bayliss and Starling Lecture in 1973 the standard model was that gut hormones were produced in specialised cells (now called enteroendocrine cells, EECs) scattered in the epithelium and responding to luminal nutrient; it was thought likely that some of the EEC products might also have local or paracrine effects, while the targets of hormonal action were recognised to include epithelial cells and smooth muscle.…”

Section: Introductionmentioning

confidence: 97%

Gastrointestinal hormones and the dialogue between gut and brain

Dockray

2014

The Journal of Physiology

156

107

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The landmark discovery by Bayliss and Starling in 1902 of the first hormone, secretin, emerged from earlier observations that a response (pancreatic secretion) following a stimulus (intestinal acidification) occurred after section of the relevant afferent nerve pathway. Nearly 80 years elapsed before it became clear that visceral afferent neurons could themselves also be targets for gut and other hormones. The action of gut hormones on vagal afferent neurons is now recognised to be an early step in controlling nutrient delivery to the intestine by regulating food intake and gastric emptying. Interest in these mechanisms has grown rapidly in view of the alarming global increase in obesity. Several of the gut hormones (cholecystokinin (CCK); peptide YY 3-36 (PYY 3-36 ); glucagon-like peptide-1 (GLP-1)) excite vagal afferent neurons to activate an ascending pathway leading to inhibition of food intake. Conversely others, e.g. ghrelin, that are released in the inter-digestive period, inhibit vagal afferent neurons leading to increased food intake. Nutrient status determines the neurochemical phenotype of vagal afferent neurons by regulating a switch between states that promote orexigenic or anorexigenic signalling through mechanisms mediated, at least partly, by CCK. Gut-brain signalling is also influenced by leptin, by gut inflammation and by shifts in the gut microbiota including those that occur in obesity. Moreover, there is emerging evidence that diet-induced obesity locks the phenotype of vagal afferent neurons in a state similar to that normally occurring during fasting. Vagal afferent neurons are therefore early integrators of peripheral signals underling homeostatic mechanisms controlling nutrient intake. They may also provide new targets in developing treatments for obesity and feeding disorders.

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“…GR is expressed in various human cancers, such as colon adenocarcinoma ( , ). Since the crucial feature for the recognition of gastrointestinal peptides by this receptor is the carboxyl terminal sequence Trp-Met-Asp-Phe amide ( , ), the drugs were designed to contain an acyl linker between the peptide and the triazene which resulted in a carrier-linked conjugate of reasonable stability. One of the resulting triazenes, N -[3-benzyl-3-(carboxypropanoyl)-1-(2-chloroethyl)triazene]-β-Ala-Trp-Met-Asp-Phe amide (CBS-5), effectively competed with gastrin in an assay using either guinea pig stomach fundus or the rat acinar tumor cell line AR42J as the source of the receptor ().…”

Section: Introductionmentioning

confidence: 99%

Specificity of DNA Alkylation by 1-(2-Chloroethyl)-3-alkyl-3-acyltriazenes Depends on the Structure of the Acyl Group: Kinetic and Product Studies

Smith

Schmidt

Czerwiński

et al. 1996

Chem. Res. Toxicol.

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The reactions of calf thymus DNA with ten 1-(2-chloroethyl)-3-alkyl-3-acyltriazenes of varying acyl side chain structure were studied alone, or in the presence of porcine liver esterase in pH 7.0 phosphate buffer. In several of the key triazenes, the acyl substituent contained a free carboxylic acid group. With esterase present in the reaction mixture, the resultant levels of DNA alkylation could be correlated with the kinetic rates of decomposition of the triazenes. Under these conditions, the predominant pathway of decomposition involved deacylation of the parent triazene and eventual production of an alkanediazonium ion. This intermediate subsequently alkylated DNA--guanine to give 7-alkylguanine as the principal reaction product. In the absence of esterase, the order of DNA alkylation for all of the acyltriazenes did not correlate with their respective rates of decomposition, leading to the conclusion that the triazenes did not decompose by the expected mode of uncatalyzed N(2)-N(3) heterolyic cleavage. The major DNA alkylation product from the N(3)-methyltriazenes was 7-methylguanine, instead of the expected 7-(chloroethyl)- and 7-(hydroxyethyl)guanine products, which suggested that the acyl group was being hydrolyzed. However, acyltriazenes with an N(3)-benzyl group rather than a methyl in this position produced very little 7-benzylguanine product, contrary to prediction. An alternative mechanism involving internally assisted hydrolysis of the side chain ester is proposed to explain these results. NMR product analysis and computational studies were carried out to lend support to the postulated mechanism.

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Chemistry of the Gastrointestinal Hormones and Hormone-like Peptides and a Sketch of Their Physiology and Pharmacology

Cited by 26 publications

References 939 publications

The Physiology of Cholecystokinin in Brain and Gut

The Physiology of Cholecystokinin in Brain and Gut

Gastrointestinal hormones and the dialogue between gut and brain

Specificity of DNA Alkylation by 1-(2-Chloroethyl)-3-alkyl-3-acyltriazenes Depends on the Structure of the Acyl Group: Kinetic and Product Studies

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