Balancing building blocks: RNR enzyme X-rayed

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Ezine

  • Published: Jan 15, 2016
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Balancing building blocks: RNR enzyme X-rayed

Enzymic balancing act

Molecular basis for allosteric specificity regulation in class Ia ribonucleotide reductase from Escherichia coli Credit:Drennan et al/eLife

Cells need the ribonucleosides, adenosine, guanosine, cytidine, and thymidine, for their DNA, or strictly speaking they need the deoxyribonucleosides. However, there can be too much of a good thing and if the relative abundances of A, G, C and T goes awry, the cell can die. Now, chemists at Massachusetts Institute of Technology, MIT, have used X-ray studies to help them fathom how the enzyme ribonucleotide reductase (RNR) can generate all four of the DNA building blocks and maintain the requisite balance between them.

Most enzymes act on their substrate and convert it into another molecule. RNR is different it essentially has an active site that can accommodate with specificity four different substrates and convert them into the deoxyribonucleosides deoxyadenosine, deoxyguanosine, deoxycytidine, and thymidine. According to Catherine Drennan, "Ribonucleotide reductase is very unusual. I've been fascinated with this question of how it actually works and how this enzyme's active site can be moulded into four different shapes." Writing in the journal eLife, Drennan and her colleagues Christina Zimanyi, Percival Yang-Ting Chen, Gyunghoon Kang, Michael Funk, describe how the interactions of RNR with its downstream products function through an "effector site" that induces the enzyme to change the shape of its active site in order to determine which of the four DNA building blocks it will produce.

Effectors are involved in the activity of other enzymes, of course, but commonly it is a regulatory system that simply raises or lowers activity depending on demand. "I can't think of any other examples of effector binding changing what the substrate is. This is just very unusual," Drennan muses. RNR is an ancient enzyme in terms of evolution, its function having been important for the transition from the earliest ribonucleic acid (RNA) organisms to the myriad DNA organisms we see today. Drennan add that there is no other enzyme that can do the chemistry RNR does; it is unique and very different from most other enzymes showing many rather unusual features.

Four snapshots

With X-ray snapshots of RNR binding to each of its four substrates, the MIT team have shown how shape changes depending on the specific effector molecule bound to a relatively distant site on the enzyme. The effectors are deoxynucleoside triphosphates such as deoxyadenosine triphosphate (dATP) or thymidine triphosphate (TTP) and depending on which is attached determines the substrate that will be recognised by the enzyme's active site and processed. Specifically, effector binding promotes closing of part of the protein over the active site like a latch to lock in the substrate. If the wrong base is in the active site, the latch cannot be shut and the substrate will diffuse out and allow any of the others to enter. Closing only on the correct substrate associated with the specific effector.

It is "exquisite", Drennan says. The system has evolved so that if you have the wrong substrate in there, you cannot close the active site. "It's a really elegant set of movements that allows for this kind of molecular screening process." The RNR enzyme can also be shut down completely by effectors if the total pool of building blocks has grown too large for health and safety of the cell.

Anticancer and antibiotic target

The research may seem of an entirely fundamental nature, but where cell health and DNA replication are involved cancer studies are never far away. Of course, cancer cells, which are uncontrollably replicating need a large pool of DNA building blocks. Drugs that interfere with RNR are thus a target of research because they could be key to halting all kinds of cancers. The new work might now make it possible to design rationally drug molecules to target and block the activity of RNR, Drennan suggests. RNR is also essential to bacterial replication and so the bacterial form might be a target for novel antibiotics. Indeed, the current work studied RNR from the well-known bacterium Escherichia coli rather than human RNR. "My lab is interested in studying both human and bacterial RNRs, because I feel like we really need to understand whether they all work the same way, or whether there are going to be differences," Drennan adds.

Related Links

eLife 2016, online: "Molecular basis for allosteric specificity regulation in class Ia ribonucleotide reductase from Escherichia coli"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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