The Ubiquity of the Insulin Superfamily Across the Eukaryotes Detected Using a Bioinformatics Approach

Piñero, Janet; González-Pérez, Abel

doi:10.1089/omi.2010.0141

Cited by 11 publications

(6 citation statements)

References 30 publications

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“…Insulin and related peptides (insulin-like peptides, insulin-like growth factors and relaxins) form a large superfamily of peptide hormones (Shabanpoor et al, 2009) that is found throughout the animal kingdom (Piñero-González and González-Pérez, 2011). In vertebrates, insulin is synthesized in pancreatic β-cells and is the key regulator of carbohydrate and fat metabolism (Blumenthal, 2010).…”

Section: Discussionmentioning

confidence: 99%

Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor

Ahorukomeye

Disotuar

Gajewiak

et al. 2019

eLife

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The fish-hunting marine cone snail Conus geographus uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this venom insulin, Con-Ins G1, has unique characteristics relevant to the design of new insulin therapeutics. Here, we show that fish-hunting cone snails provide a rich source of minimized ligands of the vertebrate insulin receptor. Insulins from C. geographus, Conus tulipa and Conus kinoshitai exhibit diverse sequences, yet all bind to and activate the human insulin receptor. Molecular dynamics reveal unique modes of action that are distinct from any other insulins known in nature. When tested in zebrafish and mice, venom insulins significantly lower blood glucose in the streptozotocin-induced model of diabetes. Our findings suggest that cone snails have evolved diverse strategies to activate the vertebrate insulin receptor and provide unique insight into the design of novel drugs for the treatment of diabetes.

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Section: Discussionmentioning

confidence: 99%

Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor

Ahorukomeye

Disotuar

Gajewiak

et al. 2019

eLife

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“…3−5 In Homo sapiens, the insulin superfamily consists of ten members: insulin, insulin-like growth factors (IGF) I and II, and a relaxin subfamily that comprises relaxin-1, -2, and -3 and four other insulin-like peptides (INSL 3, 4, 5, and 6). 3,5,6 IGFs I and II are unique in that they both possess a single peptide chain structure that is cross-linked by three disulfide bonds in the same disposition as for insulin. Whereas insulin and IGFs I and II interact with tyrosine kinase receptors, the members of the relaxin subfamily interact with G-protein-coupled receptors known as relaxin family peptide receptors.…”

Section: ■ Introductionmentioning

confidence: 99%

Novel Methods for the Chemical Synthesis of Insulin Superfamily Peptides and of Analogues Containing Disulfide Isosteres

Hossain

Wade

2017

Acc. Chem. Res.

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The insulin superfamily of peptides is ubiquitous within vertebrates and invertebrates and is characterized by the presence of a set of three disulfide bonds in a unique disposition. With the exception of insulin-like growth factors I and II, which are single chain peptides, the remaining 8 members of the human insulin superfamily are two-chain peptides containing one intramolecular and two intermolecular disulfide bridges. These structural features have long made the chemical synthesis of the peptides a considerable challenge, in particular, including their correct disulfide bond pairing and formation. However, they have also afforded the opportunity to develop modern solid phase synthesis methods for the preparation of such peptides that incorporate novel or improved chemical methods for the controlled introduction of both disulfide bonds and their surrogates, both during and after peptide chain assembly. In turn, this has enabled a detailed probing of the structure and function relationship of this small but complex superfamily of peptides. After initially using and subsequently identifying significant limitations of the approach of simultaneous random chain combination and oxidative folding, our laboratory undertook to develop robust chemical synthesis strategies in concert with orthogonal cysteine S-protecting groups and corresponding regioselective disulfide bond formation. These have included the separate synthesis of each of the two chains or of the two chains linked by an artificial C-peptide that is removed following postoxidative folding. These, in turn, have enabled an increased ease of acquisition in a good yield of not only members of human insulin superfamily but other insulin-like peptides. Importantly, these successful methods have enabled, for the first time, a detailed analysis of the role that the disulfide bonds play in the structure and function of such peptides. This was achieved by selective removal of the disulfide bonds or by the judicious insertion of disulfide isosteres that possess structurally subtle variations in bond length, hydrophobicity, and angle. These include lactam, dicarba, and cystathionine, each of which has required modifications to the peptide synthesis protocols for their successful placement within the peptides. Together, these synthesis improvements and the novel chemical developments of cysteine/cystine analogues have greatly aided in the development of novel insulin-like peptide (INSL) analogues, principally with intra-A-chain disulfide isosteres, possessing not only improved functional properties such as increased receptor selectivity but also, with one important and unexpected exception, greater in vivo half-lives due to stability against disulfide reductases. Such analogues greatly will aid further biochemical and pharmacological analyses to delineate the structure-function relationships of INSLs and also future potential drug development.

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“…The insulin superfamily is a large, ubiquitous group of peptides with diverse physiological activities found throughout the animal kingdom . A recent analysis using a sequence similarity algorithm identified insulin‐like peptides in 46 vertebrate and invertebrate genomes . The family name derives from its oldest and most prominent member, insulin, a hormone of immense historical and medicinal importance.…”

Section: Introductionmentioning

confidence: 99%

Chemical synthesis of peptides within the insulin superfamily

Liu

Zaykov

Levy

et al. 2016

Journal of Peptide Science

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The synthesis of insulin has inspired fundamental advances in the art of peptide science while simultaneously revealing the structure-function relationship of this centrally important metabolic hormone. This review highlights milestones in the chemical synthesis of insulin that can be divided into two separate approaches: (i) disulfide bond formation driven by protein folding and (ii) chemical reactivity-directed sequential disulfide bond formation. Common to the two approaches are the persistent challenges presented by the hydrophobic nature of the individual A-chain and B-chain and the need for selective disulfide formation under mildly oxidative conditions. The extension and elaboration of these synthetic approaches have been ongoing within the broader insulin superfamily. These structurally similar peptides include the insulin-like growth factors and also the related peptides such as relaxin that signal through G-protein-coupled receptors. After a half-century of advances in insulin chemistry, we have reached a point where synthesis is no longer limiting structural and biological investigation within this family of peptide hormones. The future will increasingly focus on the refinement of structure to meet medicinal purposes that have long been pursued, such as the development of a glucose-sensitive insulin. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

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The Ubiquity of the Insulin Superfamily Across the Eukaryotes Detected Using a Bioinformatics Approach

Cited by 11 publications

References 30 publications

Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor

Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor

Novel Methods for the Chemical Synthesis of Insulin Superfamily Peptides and of Analogues Containing Disulfide Isosteres

Chemical synthesis of peptides within the insulin superfamily

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