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So, what are the biological roles or functions of glycans? And, if I were to use one slide
to hit home something that we needed the whole organism genetics to get us to, and appreciate,
if you had a mutation or if you knocked in genes that were responsible for carbohydrate
assembly or carbohydrate synthesis, this picture is worth a thousand words. It's essentially
the most dramatic picture of a similar locus, where alternations in the carbohydrate structure,
on the protein that displays these polysaccharides, if you will, on cell surfaces, give you
very dramatically different phenotype. Obviously, the question is, how do we get to the
molecular basis of this, try to really understand what are the fundamental roles in these
processes, and to be able to understand the structure function relationship.
So, it gets us to sort of the central molecular picture. And, what I'd like to do is frame
these central roles of polysaccharides, using the molecular dogma, if you will, of how DNA
makes RNA makes protein. And, we thought that we understood much of life, and genomics was
the answer to a lot of the basic questions, which is true in some sense, in terms of
understanding pathways. But, if you truly look at it, one of the things that you see with
regard to proteins is the fact that the most extensive form of post-translation modification
of proteins is glycosilation or the process of attaching carbohydrates to proteins.
Because, you're able to get a huge amount of functional diversity. What do I mean by that?
Using erythropointin, which is a biologic, it's a protein that essentially plays a central
role in how red blood cells are replenished, you begin to see that one EPO molecule,
one protein molecule, has greater than 150 unique, different carbohydrate
structures attached to it. And, that begs the question, how do these molecules impinge on
the functionality of erythropointin, and what are the functional consequences of this, these
kinds of attachments? So, it is fair to say that, as a consequence of our understanding of
these carbohydrates attached to proteins, the fact that you are one gene, one protein,
and many glycol proteins, the central dogma is truly be revisited in a sense that you're now
able to get a huge amount of functional diversity by using a combination of these different
carbohydrates that are attached to proteins, so that you can get a diversity on the function.
And, as I walk through some of these examples, you'll begin to see why the roles of these
kinds of modification eventually play a role in biological function.
Very simply put, there are two broad families of carbohydrates. One, which are branched,
and I'm going to very quickly summarize. The other, which are linear, which I summarize in
the next slide. And, building on the previous slide, one of the things you begin to see is
the fact that glycosilation is the most extensive form of post translation modification that
I just mentioned. And, these are determinants of recognition function, protein folding,
targeting half life, and stability and specificity. So, the question is, how do you assemble these?
How do you know where they are modified? And, hence, how are they going to affect the functional
attributes of a protein? But, in reality, the sites and structures and the abundances of glycans
on a given protein have only been established for a handful of glycol proteins. So, you can begin
to appreciate that, we're at the early stages of these field, truly trying to understand what the
functional consequences of these modifications are, given the fact that we're just beginning to
access what the various glycans are on different proteins, such as erythropointin.
If you actually look at the following point, which is you take the top nine of the ten protein-based
bio therapeutic products that are used in the clinic, they're glycosilated. They have sugars
attached to them, and they have functional consequences in the way these sugar molecules function.
So, part of trying to understand protein function, you truly need to get to access the carbohydrates,
and how these carbohydrates are attached to proteins.