Gumming Up Appetite to Treat Obesity – Vitamin B12 Bioconjugate Project (& Graphic) Mention In Scientific American

From the “free press” division of the blog, a recent post by Ferris Jabr on the site highlights yet another evolutionarily fascinating application of cyanocobalamin (herein referred to as B12) out of the Rob Doyle Lab for the non-invasive delivery of small molecules into the human-person. Here, a mechanism for the delivery of human peptide YY (hPYY) into the bloodstream via a food-free mechanism (unless you count the gum flavorings as a fruit). From the thorough and accessible article (with a decent balance of sciam and non-sciam redirecting)…

CHEMICAL COUPLE: The appetite-suppressing hormone hPYY hitches a ride with vitamin B-12 from the stomach to the bloodstream (caption credit: sciam).

Losing weight is not always about anticipating swimsuit season or squeezing into skinny jeans—for the clinically obese, losing weight is about fighting serious illness and reclaiming health. But the primal part of the brain that regulates appetite will not place a moratorium on hunger just because someone and their doctor acknowledge the need to lose weight. Researchers at Syracuse University are working toward a unique solution: a stick of chewing gum that suppresses appetite.

A slightly-larger version of the image on the site is reproduced above (with the image credit most welcome on the site). For a bit more information about the general properties of B12 and its potential applications for other diet-related issues, a few articles described here @swv link to more complete discussions…

* Vitamin B12 In Drug Delivery: Breaking Through The Barriers To A B12 Bioconjugate Pharmaceutical

* The Binding Of Vitamin B12 To Transcobalamin(II); Structural Considerations For Bioconjugate Design – A Molecular Dynamics Study

* B12-Insulin Bioconjugate/Transcobalamin(II)/Insulin Receptor Cover Image For The April Issue Of Clinical Chemistry

* New B12-Insulin-TCII-Insulin Receptor Cover Image For This Month’s ChemMedChem (March 2009)

* Exploring the Implications of Vitamin B12 Conjugation to Insulin on Insulin Receptor Binding and Cellular Uptake

B12-Insulin Bioconjugate/Transcobalamin(II)/Insulin Receptor Cover Image For The April Issue Of Clinical Chemistry

A brief post about some free research press (and the new addition to the Cover Gallery). Having already been featured on the cover of the ChemMedChem March 2009 issue (see the New B12-Insulin-TCII-Insulin Receptor Cover Image For This Month’s ChemMedChem (March 2009) post) , the side-on view of the B12-Insulin/TCII/Insulin Receptor structure was chosen for this month’s cover of Clinical Chemistry. While the originating article itself is not included in the issue (I should have recommended citing the ChemMedChem article in the image caption), several diabetes-related articles are featured in this month’s issue.

ON THE COVER: Scientists are investigating ways to develop effective oral insulin therapies. One such model is a vitamin B12–insulin conjugate bound to transcobalamin II and is shown here docked in the insulin receptor. The discovery of easier ways to deliver insulin into the blood stream would improve the lives of the millions of individuals living with diabetes. This month’s issue of Clinical Chemistry contains 4 articles related to diabetes. The first 2 articles provide readers with a point/counterpoint discussion of the value of reporting estimated glucose along with Hb A1c. Next is an article on the association of apolipoprotein B with incident type 2 diabetes. Lastly, the development of the first radioimmunoassay for insulin led to a Nobel Prize and is chronicled in this month’s Citation Classic feature. (See pages 545, 547, 666, and 671.) Image reproduced with permission from Damian G. Allis and Robert P. Doyle, Department of Chemistry, Syracuse University.

As a brief explanation of the image, this “scene” is meant to show (without proper molecular dynamics simulations to show how well it would work) that the Transcobalamin(II) transport/protection protein for cobalamin/cyanocobalamin (vitamin B12) and the B12-insulin bioconjugate discussed in the ChemMedChem article is small enough to fit within the Insulin Receptor protein such that insulin may still be able to bind to its receptor. This is the final piece of the puzzle in the proposed mechanism (and experimentally demonstrated event) by which the B12-insulin bioconjugate retains all of the benefits of free B12 (transport from the digestive system to the bloodstream) and insulin (proper receptor binding and the subsequent induction of cellular glucose uptake).

The figure caption and April 2010 Table of Contents can be found in PDF format at the Clinical Chemistry website (with a local copy of the PDF also available HERE.

New B12-Insulin-TCII-Insulin Receptor Cover Image For This Month’s ChemMedChem (March 2009)

As was the case for the first ChemMedChem December, 2007 cover issue (posted previously), the cover story in this month’s issue is a communication by myself and members and collaborators of the Robert Doyle Group here at Syracuse University.  In this case, the work for the cover image actually went into computational research published in the associated article (instead of just a pretty cover image to complement the associated article, which was the intent of the previous cover).

The image below shows the Transcobalamin II (TCII) protein (in teal ribbons, with a bound cyanocobalamin (B12) shown in red.  The PDB code for this complex is 2BB5) sitting within the surface-accessible fragment of the gigantic insulin receptor (PDB code 2DTG.  The cell membrane would be at the bottom of this image, with the remainder of the complete protein sitting both within the cell membrane and then into the cytoplasm).  Saving the lead-up to this structure generation for the associated published article, this image was created to show one of the most important steps in the Oral Insulin project being worked on in the Doyle Group, with the fact that we know it works making the validity of the image content all the more relevant.  In brief, this figure shows that the TCII/B12-Insulin complex can fit within the insulin receptor such that the insulin molecule can bind to its receptor position on the appropriately described insulin receptor (IR), thereby instigating the cascade of events that leads to cellular glucose uptake.

For a larger view, click on the image.

Like many of the protein structures I render, this image would not have been possible without VMD and MegaPOV, my favorite OSX POV-Ray variant (there’s quite a bit of Photoshop layering as well).  The final layout for the cover is below, which I think would have benefited from the aerial view on the upper left side being shifted slightly to the left to fill out the black square.

According to the ChemMedChem website:

The cover picture shows three views of a vitamin B12-insulin conjugate bound to transcobalamin II, docked in the insulin receptor (IR). This study reveals how the structure of an orally deliverable insulin changes in solution after vitamin B12 conjugation and its effect on IR binding capacity. The results demonstrate that chemical modification of insulin by linking relatively large pendant groups does not interfere with IR recognition. For more details, see the Full Paper by T. J. Fairchild, R. P. Doyle, et al. on p. 421 ff.

To date, the associated work has received some additional linkage, both in the form of inclusion in the Spotlight list in Angew. Chem. Int. Ed. 2009, 48, 2072 – 2073 and, for those looking for a more pop-sci discussion of the applications of the research, New Scientist (Insulin Chewing Gum, 14 January 2009).  PDFs of the associated content are provided here for Angewandte Chemie and New Scientist.

There is a considerable amount of additional computational work being done on this system and the complete B12 pathway for potential use in various other applications.  Stay tuned for next year’s cover.