For the Sake of Science

If there’s one phrase that has framed virtually all my education in biology the best, it would be “It’s all about shape.”

Probably the easiest way to think about this is with an analogy of a key and a keyhole. That’s how biological and chemical interactions occur – one thing fits into another. And so that’s the case with what researchers have done with the restoration of the activity of a particular enzyme.

The enzyme, called ALDH2, plays an important role in metabolizing alcohol and other toxins, including those created by a lack of oxygen in the wake of a heart attack. It also is involved in the metabolism of nitroglycerin, which is used to prevent chest pain (angina) caused by restricted blood flow and oxygen to the heart.

The problem is that a lot of people have a mutation in the gene which codes for this enzyme. This presents a couple of options. One is gene therapy where, in effect, a small piece of the genome (just a single gene) is altered, usually using an adeno-associated virus to introduce the correct DNA sequence into a nucleus (as happened with the spider monkeys recently cured of color blindness). This presents some problems because there isn’t a one-to-one correspondence with genes and proteins or enzymes. Alternative splicing means that a single gene can code for several different proteins. Sure, a correction may be just right for making one correct protein, but it may not also be correct for other proteins. This can result in serious side effects (though it didn’t in the spider monkeys). There are other reasons gene therapy can go awry, too, so it isn’t necessarily the best choice, however promising the field is for curing innumerable afflictions.

Then there’s the option these researchers took. Instead of messing around with anything to do with the genome, they looked at the proteome. Specifically, they looked at the enzyme ALDH2. Its mutated form doesn’t perform very well. It still works because it maintains some of its shape, but its active site does not comport to the appropriate substrates of the other molecules its trying to act upon as well as it should. So in effect, researchers took a compound (Alda-1) and injected into test subjects. In turn, this compound altered the shape of ALDH2, putting it back in proper working form.

“Because of the mutation in the gene, parts of the protein structure become loose and floppy. Alda-1 reactivates the enzyme by propping up those parts of the structure so they regain normal function,” said Dr. Hurley, director of the Center for Structural Biology on the Indiana University-Purdue University Indianapolis campus.

It’s an elegantly simple idea with a complex execution.

Incidentally, this all can be related to evolution in that if an enzyme has a given shape which catalyzes something even a little, it can be sculpted by natural selection to better catalyze that reaction, eventually getting to a relative optimum in shape.

Filed under: Science | Tagged: Alda-1, ALDH2, Center for Structural Biology on the Indiana University-Purdue University Indianapolis campus., Daria Mochly-Rosen, Nature Structural Biology, Thomas Hurley |