Biology Cheat Sheet: Anatomy of an Enzyme

In deciding whether or not Gracie should undergo ERT along with her HSCT (see the previous biology cheat sheet for explanations of those), we were concerned about something Dr. Kurtzberg at Duke mentioned to us as a caution for combination therapy. She said that Gracie's body would mount an immune defense against the injected enzyme (that is, it would recognize it as not being something Gracie had made herself, and attack it as an invader). This immune activity was given as a reason not to have the ERT treatment in conjunction with HSCT unless the patient were already compromised in terms of lung and heart function and needed the enzyme to help her recover and get in shape for transplant. In Gracie's case, her heart and lungs were pretty healthy, and Duke would likely have gone on with HSCT, leaving off the ERT.

We thought that sounded like a pretty good reason, so Mack asked the docs in Minnesota about it. Their answer seemed like a good one--good enough to convince Gracie's parents to go ahead with ERT, even if the immune response was very likely (according to Dr. K, 90% of patients make antibodies to the enzyme--and that's how you know your body is trying to defend itself against something.).

So the answer the Minnesota docs gave was that, yes, Gracie would probably mount an immune defense against the injected enzyme, since almost all patients do, but that there were a couple of reasons to go ahead anyway. First, the response would probably have mild symptoms, and so would not really affect her overall fitness too much--she might have a little rash, they said (some patients do have anaphylaxis--which is an extreme overreaction by the immune system to the drug--and treatment has to be stopped. Gracie has not shown signs of this so far). The second reason was that, while the antibody does attack the enzyme, it doesn't affect the active site, so the enzyme continues to function just fine, even while the body is trying to attack it.

At that, Noodles asked for a review on enzyme active sites, so here's a quick one:


What is an active site?
An enzyme is, generally, a huge molecule that acts as a catalyst for chemical reactions in the cell. Enzymes make cellular reactions happen more efficiently, and aren't used up very fast (that's how catalysts work. They hang around and help out with reactions, but aren't actually "part" of the reaction--that is, the enzyme is not changed by the reaction it catalyzes.) Typically, enzymes are very specific in the reactions they catalyze, although there are a few enzymes out there that catalyze a variety of reactions--those are cutely termed "promiscuous" enzymes.

Tee hee.


So somewhere on this really big molecule is its active site. the active site is the spot on the molecule that actually does the chewing (or "lysing" in the case of enzymes--get it? Lysosome/lysosomal storage? The names do sort of make sense after a while.) During the breakdown reaction. As we said before, the active site is usually pretty specific, in that not very many kinds of things will bind there. Just the molecules the enzyme is supposed to catalyze in reaction.

If Gracie's missing enzyme (alpha-l-iuronidase) were more promiscuous, the antibody might be able to get into its active site and prevent it from doing its job. Luckily for us, alpha-l-iduronidase only has eyes for iduronic acid--a component of Dermatan Sulfate--the GAG Gracie can't break down. The nasty antibodies can't make it stray from its only mate, no matter how they attack it. This means it will still be able to do its job while under attack by antibodies. Or at least, that's how the story goes.

But what about the immune response? Are you worried about that?
Of course, there are other concerns where immune responses are concerned. They do cost the body energy, and don't feel particularly pleasant for the patient, but we are only just beginning with things that are unpleasant for the patient...try chemo, why don't you? I'm sure there are more specific hazards of immune response, but I am not well versed in them. Any MD's or other health care professionals out there who would like to chime in?

So ERT provides Gracie with alpha l-iduronidase, which is the enzyme she needs to prevent further buildup in her tissues of dermatan sulfate/iduronic acid. That buildup would compromise her body systems, particularly her heart and lungs, and reduce her likelihood for a positive transplant outcome. ERT doesn't protect her brain (remember the blood-brain barrier? see other biology cheat sheets for that, too), but nothing else besides transplant would, either, so we want to keep her as healthy as possible while she waits for a donor match. Following transplant, she will continue with ERT until the graft "takes" which means it begins to make cells effectively in Gracie's body. A stronger heart and lungs will make her better able to stand up to GVHD, the subject of the next biology cheat sheet.