Amyline

Amylin [106602-62-4] (75) (Fig. 4) is a 37-amino acid peptide having approximately 46% sequence similarity to CGRP (33). Amylin is present ia pancreatic P-ceUs along with insulin. It may function as a hormone ia glucoregulation and has been proposed as an etiologic factor ia certain forms of diabetes. Amylin is also present ia dorsal root ganglia (see INSULIN AND OTHER ANTIDIABETIC DRUGS). 

Insulin and Amylin. Insulin is a member of a family of related peptides, the insulin-like growth factors (IGFs), including IGF-I and IGF-II (60) and amylin (75), a 37-amino acid peptide that mimics the secretory pattern of insulin. Amylin is deficient ia type 1 diabetes meUitus but is elevated ia hyperinsulinemic states such as insulin resistance, mild glucose iatolerance, and hypertension (33). Insulin is synthesized ia pancreatic P cells from proinsulin, giving rise to the two peptide chains, 4. and B, of the insulin molecule. IGF-I and IGF-II have stmctures that are homologous to that of proinsulin (see INSULIN AND OTHER ANTIDIABETIC DRUGS). 

Chen, W.-J., Armour, S., Way, J., Chen, G., Watson, C., Irving, P., Cobb, J., Kadwell, S., Beaumont, K., Rimele, T., and Kenakin, T. P. (1997). Expression cloning and receptor pharmacology of human calcitonin receptors from MCF-7 cells and their relationship to amylin receptors. Mol. Pharmacol. 52 1164-1175. 

Human adrenomedullin is a 52-amino acid peptide belonging to the calcitonin/calcitonin gene-related peptide (CGRP)/amylin peptide family. It is synthesized mainly in endothelial cells and elicits vasodilation. 

Amylin analogue Pramlintide Suppress glucagon secretion and slow gastric emptying SC injection6... 

Antidiabetic Drugs other than Insulin. Figure 7 Mechanisms of action of the amylin analogue pramlintide. 

Amylin KCNTA TCATQ RLANF LVHSS NNFGA ILSST NVGSNT... 

Amylin analogue Gastro paresis Hypoglycaemia, nausea b... 

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

V2 VIP/PACAP (VPAC1 3) prostanoid DP, IP CRFU calcitonin/amylin/CGRP Gj/G0 a2-Adrenoceptor M2/4 muscarinic acetylcholine dopamine D2 4 5HT2 opioid 5, p, K, OFQ ... 

Human amylin, or islet amyloid polypeptide (hlAPP), is a 37-residue peptide hormone which forms both intracellular and extracellular (EC) amyloid deposits in the pancreas of most type II diabetic subjects. The core of the structure in the SDS micelle is an ot-helix that runs from about residues 5-28. Although the basic structural unit in the fibrils in... 

Amylin Dendreon Corp. Medinox Siegfried Biologies. 

Kajava, A. V., Aebi, U., and Steven, A. C. (2005). The parallel superpleated beta-structure as a model for amyloid fibrils of human amylin. /. Mol. Biol. 348, 247-252. 

Fig. 1. Structure of amyloid fibrils formed by the human amylin peptide. Negatively stained (A) and metal shadowed (B) fibrils formed by human amylin (adapted from Goldsbury et al., 2000a). (C) A human amylin fibril model formed by three protofibrils having a superpleated /i-structure (adapted from Kajava et al., 2005). Only Ca traces of the polypeptide chains are shown. (D) Atomic model of the cross-/ motif formed by the human amylin peptide (adapted from Kajava et al, 2005). Scale bar, 100 nm (A and B).

The most detailed accounts of amyloid fibril polymorphism have come from EM studies of four different proteins or peptides, namely amyloid-/) (A/ l 4o or A/i v). transthyretin, calcitonin, and human amylin. The fibrils... 

Fig. 2. Electron micrographs highlighting the polymorphism of amyloid fibrils. (A) A single human calcitonin protofibril with a diameter of 4 nm (adapted from Bauer et al., 1995). (B) Different morphologies present in a transthyretin fibril preparation. Black arrowheads show oligomers of different sizes, the black arrow points to a 9- to 10-nm-wide fibril, and the white arrowhead marks an 4-nm-wide fibril (adapted from Cardoso et al., 2002). (C-F) Human amylin fibril ribbons (adapted from Goldsbury et al., 1997). (C) A single 5-nm-wide protofibril. (D-F) Ribbons containing two (D), three (E), or five (F) 5-nm-wide protofibrils. (G) A twisted ribbon made of four 5-nm-wide protofibril subunits of Api-40 (adapted from Goldsbury et al., 2000b). Scale bar, 50 nm (A-G).

For calcitonin, the thinnest single fibril, the protofibril, had a diameter of 4-5 nm and was observed at low (0.1-1 mM) calcitonin concentration (Fig. 2A Bauer et al, 1995). For transthyretin, short and flexible protofibrils 4—5 nm in diameter were observed, but the prominent species was an 8-nm diameter and up to 300-nm-long fibril (Fig. 2B Cardoso et al., 2002). For human amylin, 5-nm-wide protofibrils were rarely depicted by themselves (Fig. 2C), but they could be readily identified as a distinct building block of wider fibrils (Fig. 2D-F Goldsbury et al., 1997). The wider fibrils... 

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