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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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April 23, 2013

Pseudoenzymes: Back From the Dead as Targets?

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Posted by Derek

There's a possible new area for drug discovery that's coming from a very unexpected source: enzymes that don't do anything. About ten years ago, when the human genome was getting its first good combing-through, one of the first enzyme categories to get the full treatment were the kinases. But about ten per cent of them, on closer inspection, seemed to lack one or more key catalytic residues, leaving them with no known way to be active. They were dubbed (with much puzzlement) "pseudokinases", with their functions, if any, unknown.

As time went on and sequences piled up, the same situation was found for a number of other enzyme categories. One family in particular, the sulfotransferases, seems to have at least half of it putative members inactivated, which doesn't make a lot of sense, because these things also seem to be under selection pressure. So they're doing something, but what?

Answer are starting to be filled in. Here's a paper from last year, on some of the possibilities, and this article from Science is an excellent survey of the field. It turns out that many of these seem to have a regulatory function, often on their enzymatically active relations. Some of these pseudoenzymes retain the ability to bind their original substrates, and those events may also have a regulatory function in their downstream protein interactions. So these things may be a whole class of drug targets that we haven't screened for - and in fact may be a set of proteins that we're already hitting with some of our ligands, but with no idea that we're doing so. I doubt if anyone in drug discovery has ever bothered counterscreening against any of them, but it looks like that should change. Update: I stand corrected. See the comment thread for more.

This illustrates a few principles worth keeping in mind: first, that if something is under selection pressure, it surely has a function, even if you can't figure out how or why. (A corollary is that if some sequence doesn't seem to be under such constraints, it probably doesn't have much of a function at all, but as those links show, this is a contentious topic). Next, we should always keep in mind that we don't really know as much about cell biology as we think we do; there are lots of surprises and overlooked things waiting for us. And finally, any of those that appear to have (or retain) small-molecule binding sites are very much worth the attention of medicinal chemists, because so many other possible targets have nothing of the kind, and are a lot harder to deal with.

Comments (8) + TrackBacks (0) | Category: Biological News


1. emjeff on April 23, 2013 7:59 AM writes...

We should not be so arrogant. As you point out, Derek, we don't know even 10% of what we need to know to be so dismissive of something we don't understand.

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2. Andy on April 23, 2013 8:01 AM writes...

The EGFR-family HER3 "kinase" has a "kinase-dead" domain that originally made the molecule seem uninteresting, however, it was later found to contribute to signaling through trans-phosphorylation by heterodimerizing with other EGFR family member kinases and then subsequently transducing a growth signal to AKT by way of PI3K. HER3 is one of the current hot oncology drug targets even though it has no detectable enzymatic activity. The lesson seems to be that "inactive" enzymes that can heterodimerize with active enzymes can retain selection-driven function without catalytic activity.

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3. lt on April 23, 2013 8:21 AM writes...

There is some analogy with GPCRs, where for example a non ligand binding receptor that couples to G-proteins (ie GABA(B2)) heterodimerizes with a ligand binding receptor (GABA(B1)) that does not couple to any G-proteins - forming a fully functional signaling complex...

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4. patentgeek on April 23, 2013 8:47 AM writes...

The peptidyl-prolyl isomerases (PPIs; immunophilins)are examples of enzymes that haven't lost their enzymatic activity, but engage in considerable cellular function that is independent of enzymatic activity per se. FKBP12 (which recognizes Leu-Pro preferentially for rotamase activity) binds to the subunits of the IP3 receptor at Leu-Pro motifs and thereby modulates calcium flux; but mutants FKBPs that are devoid of rotamase activity (but retain FK506 binding) are functionally equivalent in this system. There are other examples of FKBPs, and cyclophilins, acting as docking units a la SH2 and SH3 domains, in a manner not requiring rotamase activity but retaining the recognition component that was selected for in evolving as an enzyme.

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5. pkinase on April 23, 2013 9:13 AM writes...

"I doubt if anyone in drug discovery has ever bothered counterscreening against any of them"

Not all of us ever believed that pseudokinases had no function, and Ambit have had 1 of the supposedly inactive JAK domains as part of their profiling panel for 5-10 years.

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6. ptm on April 23, 2013 10:58 AM writes...

Oh, come on, it was obvious from the start that many such pseudoenzymes had to have a regulatory function. Sure it still had to be proven but that's not the same as not having any idea what they were doing.

Doubling the gene and letting the copies drift apart is a perfect way to build more sophisticated regulatory networks over already existing ones.

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7. Derek Lowe on April 23, 2013 11:04 AM writes...

#5 - I didn't know that. I'll put up a note in the main post.

#6 - In my experience, "some sort of regulatory function" is an often-invoked synonym for "we don't really know what it does". It was clear from the evolutionary perspective that a function was there, but if you're not going to have actual enzymatic activity, "regulatory" is a big enough category to fit in most everything else. You're right, though, that duplicate-and-diverge is something that we see a lot of.

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8. barry on April 23, 2013 11:06 AM writes...

what is implicit is that even a perfect small-molecule inhibitor of an enzyme doesn't fully mimic the knock-out mutant because the non-enzymatic functions (scaffolding, reguatory...) of the target aren't blocked when one blocks the active site.

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