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Digging Deep in Biology: “Things Get Even More Complicated When You Look Closer”

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“As is often the case in biology,” the scientist and artist David Goodsell has observed, “things get even more complicated when you look closer.” And that is the truth.

Yesterday started out as an ordinary Tuesday. Then I set out to read a recent paper published in the journal Cell, “Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation,” by R Nagaraj et al. It reported something rather odd that caught my eye. Very early embryos (at the two- or four-cell stage in mouse or human respectively) undergo a critical transition: they have to go from relying on RNAs and proteins loaded into the egg before fertilization by the mother, to making their own RNA and protein.

The phenomenon is called embryonic genome activation. In order to activate their genomes, embryos have to remove maternal and paternal epigenetic modifications and create new ones appropriate to the embryonic genome.

Stop and think. That’s remarkable — there is a fair amount of information being imparted to the genome by these epigenetic changes, and we know little about how that happens. We do know according, to the authors, that

[s]uch major reprogramming of the genome requires metabolites such as α-ketoglutarate, essential for protein and DNA demethylation, acetyl-CoA required for protein acetylation, [and] ATP for phosphorylation of substrates.

Normally these metabolites are made by specialized enzymes that are part of the tri-carboxylic acid (TCA) cycle. The TCA cycle takes place in the mitochondria, specialized organelles that produce energy for the cell. The mitochondria take up a compound called pyruvate, which is then converted to acetyl-CoA by the enzyme pyruvate dehydrogenase (PDH), and the resulting acetyl-CoA enters the TCA cycle, to produce the other metabolites and ATP.

However, these early stage embryos are metabolically inactive relative to later stages. Their mitochondria are condensed and little enzyme activity is present. So where are the metabolites coming from? Pyruvate is absolutely required for development to proceed. It can come from the fluid in the oviduct — it can be imported by the embryo. PDH is also absolutely required for development. But where is PDH enzyme activity if not in the mitochondria? And what about the TCA cycle enzymes?

Here’s what caught my attention. The enzymes are localized in the nucleus at this early stage of development, where the metabolites are needed for reprogramming the genome, rather than the mitochondria. Now that would be surprise enough — enzymes that every undergrad biology student learns are in the mitochondria are found in the nucleus early in development. That’s remarkable. And now they’re involved in embryonic genome activation. But then I dug deeper.

It occurred to me to wonder how hard it would be to get those enzymes into the nucleus, so I looked up pyruvate dehydrogenase and found to my astonishment that it is not one enzyme but an enormous complex of three different enzymatic activities clustered together on a cube-shaped core of 24 units, or alternatively a dodecahedral core of 60 units. The enzymes work together to turn pyruvate into acetyl CoA in a three-step process, handing off to each other as the reaction proceeds. Look here to see pyruvate dehydrogenase described by David Goodsell.

Let me emphasize: this is a core enzymatic activity. The TCA cycle is important to the process by which cells make ATP, the energy currency of the cell. PDH is the link that connects glycolysis, the breakdown of sugars, to the TCA cycle. Without it cells would obtain much less energy from the breakdown of sugars. But it is also essential for embryonic development past the two- to four-cell stage (in mice and humans, and presumably other mammals).

It’s also essential for bacteria like E. coli, where it has a similar structure and three-step reaction. This is an ancient enzyme complex, yet of great sophistication.

How could early cells have assembled such a structure, bringing together separate enzyme activities to work cooperatively? Getting enzymes to assemble into multi-subunit structures is non-trivial, requiring multiple side-chain interactions and three-dimensional fit. Even further, the genes encoding these enzymatic activities of the PDH complex are clustered together into a single operon in E. coli. They are neighbors, side-by-side in E. coli’s genome, and co-expressed. Of course, that’s how an intelligent designer would do it. What’s the use of part of a complex? Make the enzymes together and assemble them into a factory to turn pyruvate into acetyl CoA — it’s much more efficient.

I started the day wondering about epigenetics, and uncovered some remarkable things — reprogramming genomes, apparently mobile enzyme complexes, and operons. Information, complexity and order. It was a not-so-ordinary Tuesday.

Update: Since I wrote this piece I discovered that according to Voet and Voet’s biochemistry textbook, PDH complex carries out five enzymatic activities to produce acetyl-CoA, not three, and they state that the PDH complex is the largest eukaryotic enzyme complex known.

Image: © Monkey Business — stock.adobe.com.