Wednesday, October 30, 2013

Time to Re-Write the Textbooks! Nature Publishes a New Version of the Citric Acid Cycle

I was looking through my copy of Nature the other day trying to take seriously all the special reviews on "Transcription and Epigenetics." One article caught my eye ...

Gut, P. and Verdin, E. (2013) The nexus of chromatin regulation and intermediary metabolism. Nature 502:489-498. [doi: 10.1038/nature12752]
Living organisms and individual cells continuously adapt to changes in their environment. Those changes are particularly sensitive to fluctuations in the availability of energy substrates. The cellular transcriptional machinery and its chromatin-associated proteins integrate environmental inputs to mediate homeostatic responses through gene regulation. Numerous connections between products of intermediary metabolism and chromatin proteins have recently been identified. Chromatin modifications that occur in response to metabolic signals are dynamic or stable and might even be inherited transgenerationally. These emerging concepts have biological relevance to tissue homeostasis, disease and ageing.
The authors argue that, among other things, methylation of histones is regulated by changes in the concentrations of some citric acid cycle metabolites. I find it difficult to imagine that the concentrations of the citric acid cycle intermediates could change significantly enough to act as allosteric effectors but that's not what grabbed my attention.

It's the figure showing the citric acid cycle (TCA cycle) that shocked me.


Textbooks show that the products of the citric acid cycle are ...
That's three NADH, one QH2, and one GTP (or ATP) for a total of ten ATP equivalents. The new version, published last week in the most prestigious science journal in the world, shows that there are six NADH produced per cycle for a total of 15 ATP equivalents. It must be correct because this is a paper about intermediary metabolism and it was reviewed by experts in the field. Unfortunately, the authors don't give a reference to this new information. I assume that it's common knowledge among the top metabolism researchers so they didn't bother citing the papers.

Can anyone out there direct me to the revolutionary papers that I missed?

P.S. I'm not even going to mention that FADH2 is NOT a product of enzyme-catalyzed β-oxidation.


13 comments :

  1. I'm not a biologist... is this something that could be fixed by attaching a multiplicity to the different occurrences of NADH in their diagram? i.e. saying that one step involved 1 NADH, but that another involves 2 NADHs, etc.?

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  2. Mitchell, I am no biologist either, but even with my limited knowlegde I can see what's wrong. They have three superfluous occurrences of NAD+ → NADH in the diagram, in places where they have no business to be (while things like GDP → GTP or Q → QH2 are missing). I suppose the artist hired to draw the diagram had no idea what he was drawing and did a botched-up copy/paste job with all those NAD+ → NADH reactions. There must be something wrong with the way Nature handles proofreading.

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    1. Not that this excuses the authors (who are ultimately responsible for what gets published under their names), but yes, I suspect an error on the part of the artist. Unlike "lesser" journals where figures are published as the authors submit them, Nature feels the need to recreate them in a more polished form. I've been on genome papers published there where we had to explain why certain "improvements" to our figures weren't really such.

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  3. Ooh! Ooh! My cell biology were just grilled on the citric acid cycle, so they should know this stuff. I might steal this diagram, put it on the final exam while telling them it's hot from the pages of Nature...and the exam question will be to list all the things wrong with it.

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  4. That should be, "my cell biology students"

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  5. P.S. I'm not even going to mention that FADH2 is NOT a product of enzyme-catalyzed β-oxidation.

    Thank goodness you didn't!

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  6. "The authors argue that, among other things, methylation of histones is regulated by changes in the concentrations of some citric acid cycle metabolites. I find it difficult to imagine that the concentrations of the citric acid cycle intermediates could change significantly enough to act as allosteric effectors but that's not what grabbed my attention. "

    They do, Isocitrate dehydrogenase-produced 2-oxoglutarate is required for dioxygenase activity. Activity that is involved in, say, cytosine demethylation. But there's a small problem in the citric acid cycle thing. There are three isocitrate dehydrogenase (IDH) genes in the cell.

    And the one involved in 2-oxoglutarate production for epigenetic purposes is cytoplamic. Oops. It's not involved in the cycle (which is the reason why it can be mutated in cancers like glioblastoma multiforme).

    So oops for that hypothesis.

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  7. Why is FADH2 not produced through beta-oxidation? I was thinking the first step of beta oxidation that converts acyl-CoA to Enoyl-CoA via the Acyl-CoA dehydrogenase needed FAD as electron acceptor giving as in the end FADH2...
    http://www.ncbi.nlm.nih.gov/books/NBK22581/

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    1. FAD is a covalently-bound prosthetic group. The enzyme cannot catalyze another reaction until FADH2 is oxidized in an electron transport chain. The complete reaction requires a complex of subunits and the terminal electron acceptor is Q. The free product of the reaction is QH2.

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  8. Should this be called a biochemical just-not-so-story?

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  9. this is the greatest thing of all time.

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  10. did this get corrected then? When accessed now, the figure is different.
    ...my 2 cents regarding your comment about the levels of intermediary metabolites changing sufficiently to influence transcription. This has been a controversial hypothesis since the early 2000s, because as you stated, the dogma is that redox does not change levels. And especially in the case of NAD+:NADH, where the steadystate ratio under homeostasis, is ~700:1, it is hard to imagine how redox could meaningfully influence NAD+ levels. However, in the particular case of NAD+, the emerging picture is that its levels are compartmentalized in the cell and locally regulated. The discovery of NAD+consumers (Sirtuins, ADP-ribosylases such as Parp1, cADP-ribosylases) that can only use NAD+ as a cosubstrate, further fuel the idea that nuclear or cytopplasmic levels are dynamic and under flux. Additionally, in mammals, both paralogous biosynthetic enzymes as well as NAD+ consumers that harbor distinct subcellular localizations, suggest that local NAD+ levels are regulated.

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