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Functional Analysis of Promiscuous Enzymes

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Functional Analysis of Promiscuous Enzymes
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Interview with Karen N. Allen, Boston University, USA Karen Allen is talking with Martin Hicks about the functional analysis and impact of the ‘promiscuity’ of enzymes. Enzymologists use this term to describe the ambivalency of enzyme activity. Either these enzymes carry out different but related chemical reactions or they catalyse a different set of substrates. Karen describes the significance of promiscuous enzymes for the evolutionary development of enzymes when selectivity and efficiency is optimized and underlines that promiscuity is still of importance for the adaptation of organisms to changing environments. She also points out that promiscuity are a considerable challenge for drug discovery since either these enzymes circumvent drug effects or even metabolize drugs as alternative substrates. However, the more enzymologists study the dynamics of enzymes the more promiscuity is found among a wide variety of enzyme families.
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Funktionelle GruppeEnzymTransformation <Genetik>EnzymComputeranimation
Besprechung/Interview
Chemische ReaktionMetabolomRauschgiftAktivität <Konzentration>GesundheitsstörungSubstrat <Chemie>EnzymBaseSetzen <Verfahrenstechnik>MultiproteinkomplexStereoselektivitätPhosphatasenQuerprofilRöntgendiffraktometrieMolekülMeeresspiegelChemische SyntheseGezeitenstromOrganische ChemieNebenproduktProteineQuarz <alpha->ChemotherapieArzneimittelforschungChemischer ProzessFunktionelle GruppeChemische ForschungKristallographiePhosphoreszenzGletscherzungeEukaryontische ZelleStoffwechselElektronische ZigaretteKristallviolettBukett <Wein>Besprechung/Interview
Besprechung/Interview
Transkript: Englisch(automatisch erzeugt)
So we're here at the Barshtine Enzymology Symposium 2017. I'm talking to Professor Karen Allen of Boston University. So Karen, let's start off with a question about structure analysis. So we've heard a lot about cryo-EM recently. When's it going to replace x-ray crystallography?
Ah, whenever a new technique comes out, everyone always asks, okay, this is going to replace, you know, everything else. But I think that x-ray crystallography and cryo-EM are going to wind up complementing one another. So cryo-EM is going to higher and higher resolution. So it's really natural for people to say it can replace the atomic resolution that x-ray crystallography provides.
Basically, I think that, you know, cryo-EM is going to be a great thing because it's going to be able to bridge the cellular data that we have down to the molecular level of finding large complexes and getting atomic resolution of large complexes.
So I think the two will wind up complementing each other beautifully and that it will be an incredible advance going forward. Yeah. And of course with cryo-EM we don't actually need crystals. No, and that's a huge advantage. Anyone who's grown crystals can tell you that. Absolutely.
Yeah. So moving on to enzymes now. In your talk here, you were talking about enzyme promiscuity. And as an organic chemist, that term is not terribly usually used in terms of molecules. So perhaps you could explain what it actually means and how you define it in terms of enzymes.
So basically what enzyme promiscuity means in the context of the way enzymologists talk about it, as opposed to organic chemists, is that the idea that the enzyme could either do different but related chemical reactions or could take a number of different substrates. So having a broad selection of substrates that it can take. And so in the kind of promiscuity that you often see is
that is observed is the kind of promiscuity where enzymes will either do two related reactions, like a phosphatase and a sulfatase reaction, or they will take a broad range of substrates that are different in their size or their
electrostatics, like they're charged basically. Okay. Do you think then that enzyme promiscuity is something which has turned out to be, in terms of evolution, advantageous? Or is it more of a byproduct of very complex networks, sort of
coming together and merging? Yeah, that's a really good question. So, you know, people are, I think that since the beginning, people have, with the work of Jensen, people have started to think about evolution of enzymes as being
promoted by promiscuity. So in other words, the ability to take on a second reaction gives the ability through evolution to hone that reaction to perfection. And so it should be an evolutionary advantage to have that in the first place. In the second place, it does give the ability to take on a side reaction, which could wind up being advantageous to the organism.
Okay, so now sort of looking further forward in terms of drug discovery, would then in areas where you're trying to treat some disease or something, where
there are enzymes which are promiscuous and have multiple functions, would that actually be an advantage or a disadvantage in terms of bringing out and developing new drugs? Right, in terms of developing new drugs, it could wind up being an advantage to the organic chemists, such as yourself. And so the idea there is that you could use
enzymes and evolve enzymes, taking advantage of those nascent promiscuous activities, to do new types of chemical syntheses chemo-enzymatically. And then the other, the disadvantage would be, of course, that if it turns out that that some underlying low promiscuous activity
in the metabolome of a bacteria, if that protein can then metabolize a drug and you don't know that that activity is even there, that's going to be more of a problem. So it's not something you would primarily screen against. It's just something that will come up as
you get to the cellular and organismal level. Okay. Yeah. How widespread is it then in terms of enzyme families? So in enzyme families, we see more and more of it. So the more people have looked for it, the more people have found it. So we found it in our research in two of the large families of phosphatases.
We know that also in thiowest races it occurs. So it is rather prevalent, and so it is something that we should be on the lookout for. Well, thank you very much Karen. It's been a very interesting interview. You're welcome, Martin.