Acetyl-CoenzymeA (acetyl-CoA) is a central compound of metabolism and an essential building block for the synthesis of fatty acids and amino acids. When cells are growing on glucose, the glucose is broken down to pyruvate, which in turn is converted into acetyl-CoA (by pyruvate dehydrogenase) that is then fed into the Kreb’s cycle within mitochondria. An alternative mechanism of generating acetyl-CoA is to use the enzyme acetyl-CoA synthetase, an enzyme that attaches coenzyme A to acetate with the expenditure of ATP.

Yeast have two versions of enzyme acetyl-CoA synthetase, where the 600 amino-acid length proteins share about 60% sequence identity and catalyze the same basic reaction.
One version is called Acs1p and when scientists knocked out this gene, nothing much happens. But when the other version, known as Asc2p is knocked out, yeast shut down about 70% of their genes and then die. What’s going on?

Researcher Jef Boeke discovered that Asc2p does not reside in the mitochondria, as we might expect such a metabolic gene to do, but instead is found in the nucleus (Takahashi H, McCaffery JM, Irizarry RA, Boeke JD. 2006. Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. Mol Cell. 23:207-17). As this press release explains:

But why would an enzyme involved in generating energy live in the “wrong” part of the cell? A closer look at the chromosomal and non-chromosomal parts of the cell showed that although the enzyme itself is found only in the former, the chemical made by it is found in both places.

The question remained as to why the enzyme Asc2p and its chemical product, known as acetyl-CoA, are found near chromosomes.

Chromosomes contain both DNA, which contains genes, and proteins around which the DNA is wrapped for storage and support.

In addition to being used for energy, the acetyl part of acetyl-CoA also is used in controlling how tightly DNA is wrapped in the chromosomes. More acetyl on chromosomes leads to looser wrapped DNA. And locations along chromosomes that contain looser wrapped DNA appear to be regions where genes are turned on.

Even though cells that lack Asc2p can produce acetyl-CoA due to the presence of Asc1p and Pyruvate Dehydrogenase, they still die. In such cells, the acetyl-CoA is not being produced in the right place and the right amounts to facilitate chromosome function.

This is yet another experiment that highlights the importance of location and kinetics in living cells. The information needed to form a cell consists of more than the pieces and parts and their thermodynamic descriptions. We also need to specify where many of those pieces and parts belong. In the case of yeast, if you remove one rather basic metabolic gene from its proper location, it results in the collapse of the entire genome and thus the cell.