FROM THE LAB-March 2007

by Dr. Malcolm Leissring

To regular readers of From The Lab, please accept my apologies for not updating until now. I have been busy submitting 3 grants proposals that consumed all my time. Funding levels are at historic lows, so please consider donating.

This is the latest in a series of posts that strive to use ordinary language to describe the Alzheimer's research going on in laboratories at Scripps Florida, as generously supported by donations to The Unforgettable Fund. Readers who are new to this series are encouraged to read prior From The Lab posts for relevant background.

In the last several posts, we described a very exciting advance in the Alzheimer's field. As reported in the journal Nature last October, a team led by Dr. Wei-Jen Tang at the University of Chicago solved the 3-dimensional structure of insulin-degrading enzyme (IDE), an enzyme that can rapidly destroy beta-amyloid, a toxic protein fragment that accumulates in the plaques that litter the brains of Alzheimer's disease patients. This information is useful for a number of reasons, but is especially exciting from the point of view of designing new drugs that alter the activity of IDE. Amazingly, Dr. Tang's team showed how IDE can be activated by small changes that could be mimicked by drugs.

This time, I want to focus in on a special part of IDE, known as the “active site.” This is the business end of the molecule, the bit that is responsible for cutting beta-amyloid into pieces. You might think of it as the "teeth” of the enzyme.

Recall that IDE is a member of a special class of enzymes known as “proteases”, that cut proteins into smaller pieces. Proteins are made up of multiple amino acids linked together in a chain. For this reason, proteins or shorter fragments of proteins like beta-amyloid, are sometimes called “polypeptides.” The chemical bond that joins adjacent amino acids, naturally enough, is called a peptide bond. For simplicity, the figures below show just two amino acids linked together, but beta-amyloid has from 37 to 43 amino acids, and some proteins can have thousands of amino acids.

So how does IDE cut beta-amyloid or other polypeptides into pieces? It does this by catalyzing a special type of chemical reaction known as “hydrolysis.” The term “hydro” means water, and the term “lysis” means cutting. And that is literally what occurs in the active site of a protease-a water molecule is used to separate a protein into two smaller fragments. The reaction is illustrated in the following animation. (Please click the image to view animation.)

It turns out that there are a couple of different classes of proteases, which feature different kinds of active sites. IDE is an example of a “metalloprotease,” because there is a metal atom inside the active site that helps achieve the hydrolysis reaction. For most metalloproteases, the metal is zinc.

I'm going to conclude this blog entry by showing you a little movie of IDE's active site that AJ Brockman and I put together. The brown sphere is the zinc atom, and you can see some dotted lines that show where it interacts with different amino acids inside IDE. To give you some perspective, the movie shows about 2% of all the amino acids in IDE, and is magnified about one billion times. (Please click the image to view animation.)