Examining The Effects Of Vitamin B12 Conjugation On The Biological Activity Of Insulin: A Molecular Dynamic And In Vivo Oral Uptake Investigation

Published in MedChemComm (direct link: xlink.rsc.org/?doi=C2MD20040F). And Happy Belated New Year. After the methodological work that went into the Molecular Biosystems paper, this was a remarkably simple molecular dynamics study of the changes to vitamin B12 binding in transcobalamin II (TCII) with the B12 conjugated to the first amino acid side chain in the B-Chain of insulin. The structure of the B12-insulin conjugate is shown below in a molecular dynamics snapshot, which reveals that the binding of B12 to its TCII transport protein is negligibly affected.

And apparently the experiments went well, too. Cover hopefully to follow.

Susan Clardy-James, Damian G. Allis, Timothy J. Fairchild and Robert P. Doyle

Abstract: The practical use of the vitamin B12 uptake pathway to orally deliver peptides and proteins is much debated. To understand the full potential of the pathway however, a deeper understanding of the impact B12 conjugation has on peptides and proteins is needed. We previously reported an orally active B12 based insulin conjugate attached at LysB29 with hypoglycaemic properties in STZ diabetic rats. We are exploring an alternative attachment for B12 on insulin in an attempt to determine the effect B12 has on the protein biological activity. We describe herein the synthesis, characterization, and purification of a new B12-insulin conjugate, which is attached between the B12 ribose hydroxyl group and insulin PheB1. The hypoglycemic properties resulting from oral administration (gavage) of such a conjugate in STZ diabetic rats was similar to that noted in a conjugate covalently linked at insulin LysB2911, demonstrating the availability of both position on insulin for B12 attachment. A possible rationale for this result is put forward from MD simulations. We also conclude that there is a dose dependent response that can be observed for B12-insulin conjugates, with doses of conjugate greater than 10-9 M necessary to observe even low levels of glucose drop.

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 scientificamerican.com 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