Friday, April 20, 2007

Pyruvate Dehydrogenase Evolution

Before discussing the origin of the pyruvate dehydrogenase complex (PDC) we need a little background information. There are three different reactions catalyzed by enzyme complexes resembling the pyruvate dehydrogenase complex. For example, one of the reactions of the citric acid cycle is the conversion of 2-oxoglutarate (α-ketoglutarate) to succinyl-CoA. As you can see from the reaction below it is very similar to the pyruvate dehydrogenase reaction. The main difference is that the substrate, 2-oxoglutarate, has five carbons while pyruvate only has three. The part of the molecule that reacts is the top part with a carboxyl (-COO-) that is lost as CO2 and a keto (-C=O) that ends up being attached to coenzyme A via a sulfhydryl linkage.

It should come as no surprise that this reaction is catalyzed by an enzyme called 2-oxoglutarate dehydrogenase (OGDH, also known by its old name: α-ketoglutarate dehydrogenase) (EC that's almost identical to pyruvate dehydrogenase. In fact, both PDC and OGDH evolved from a common ancestral enzyme. We know that the citric acid cycle enzyme is a late comer because many species of bacteria don't have it. Indeed, they don't even have a citric acid cycle.

So we need to look elsewhere if we are going to find the source of PDC. The most primitive enzymatic reaction is almost certainly one that's required in amino acid metabolism.1 In this case it's a reaction involved in the degradation of the branched chain amino acids; leucine, valine, and isoleucine. Look at the pathway below.

The first step in the degradation is the removal of the amino group (-NH3+) and its replacement with an oxygen to form a keto (-C=O) group. This creates three similar 2-oxo acids (α-keto acids) all of which resemble 2-oxoglutarate and pyruvate. All three of the 2-oxo (α-keto) acids are acted upon by the same enzyme called branched chain 2-oxoacid dehygrogenase (OADH, BCOADH, α-ketoacid dehydrogenase) (EC to create an acyl-CoA product. This is the same reaction as that catalyze by the pyruvate dehydrogenase complex except that the R group in pyruvate is -CH3 while in the case of the branched chain dehydrogenase it's a three, four, or five carbon branched structure.

BCOADH is found in all species. It is the most "primitive" enzyme. Like PDC it has a complex structure with three different subunits. E1 catalyzes the decarboxylation reaction. E2 catalyzes the formation of acyl-CoA—it has the lipoamide swinging arm. E3 catalyzes the oxidation of the lipoamide and the reduction of NAD+.

It looks like the "primitive" BCOADH could also catalyze the oxidative decarboxylation of pyruvate. In fact some of the modern enzymes still have residual activity towards the other substrates. Over time, the genes for some of the subunits duplicated and the two enzymes (PDC and BCOADH) diverged as they became more specialized for their modern substrates.

We can see the result if we look at the phylogenetic tree for the E2 subunit (below). This figure is from a paper by Scharrenberger & Martin (2002). They use a slightly different nomenclature (PDH=pyruvate dehydrogenase complex). This is an unrooted tree so you can't really tell which enzyme came first but, as I explained above, there is good reason to believe that the E2 from PDC and the E2 from OGDH evolved from the E2 gene for BCOADH via successive duplications.

Recall that the E2 subunits form the core of the complex (left). They contain the lipoamide swinging arm that carries substrate to three different active sites. The E3 subunits of the three enzymes are identical. There is only one E3 gene and it supplies the dihydrolipoamide dehydrogenase activity for BCOADH, PDC, and OADH.

The situation with the E1 subunit is more complicated. This is the part of the enzyme that recognizes the different types of substrate (e.g. pyruvate, 2-oxo acids, 2-oxoglutarate) so it makes sense that the three enzymes have different E1 subunits. All the eukaryotic versions of the PDC E1 subunit are related to the E1 subunit from BOADH. So are most of the bacterial versions. Other bacterial versions of the PDC E1 subunit are not related to those of the other enzymes (Schreiner et al. 2005).

The conclusion from the molecular data is that the pyruvate dehydrogenase complex evolved from the branched chain 2-oxo acid complex about 2 billion years ago. Subsequently, in some bacterial lineages a different E1 subunit replaced the one that's homologous to the BCOADH subunit. The α-proteobacteria and cyanobacteria lineages that gave rise to mitochondria and chloroplast respectively, retained the PDC E1 subunit that is related to BCOADH enzymes. This explains the eukaryotic versions of PDC.

1. This is a common theme in the evolution of metabolic enzymes. The evidence suggests strongly that amino acid metabolism is more ancient than most carbohydrate metabolism.

Schreiner, M.E., Fiur, D., Holatko, J., Patek, M. and Eikmanns, B.J. (2005) E1 enzyme of the pyruvate dehydrogenase complex in Corynebacterium glutamicum: molecular analysis of the gene and phylogenetic aspects. J Bacteriol. 187:6005-18.

Schnarrenberger, C. and Martin, W.. (2002) Evolution of the enzymes of the citric acid cycle and the glyoxylate cycle of higher plants. A case study of endosymbiotic gene transfer. Eur J Biochem. 269:868-83.


  1. The article reveals complexity that could never have happened by chance. Evolutionists believe in miracles.

    Many people, when they can't provide evidence for their theory, adopt the strategy of falsehood. Such is the case with many of those who have fallen victim to the propaganda of renowned evolutionists.

    If evolutionists want to end the arguments all they have to do is, get their brilliant heads together and assemble a 'simple' living cell. This should be possible, since they certainly have a very great amount of knowledge about what is inside the 'simple' cell.

    After all, shouldn't all the combined Intelligence of all the worlds scientist be able the do what chance encounters with random chemicals, without a set of instructions, accomplished about 4 billion years ago,according to the evolutionists, having no intelligence at all available to help them along in their quest to become a living entity. Surely then the evolutionists scientists today should be able to make us a 'simple' cell.

    If it weren't so pitiful it would be humorous, that intelligent people have swallowed the evolution mythology.

    Beyond doubt, the main reason people believe in evolution is that sources they admire, say it is so. It would pay for these people to do a thorough examination of all the evidence CONTRARY to evolution that is readily available: Try The evolutionists should honestly examine the SUPPOSED evidence 'FOR' evolution for THEMSELVES.

    Build us a cell, from scratch, with the required raw material, that is with NO cell material, just the 'raw' stuff, and the argument is over. But if the scientists are unsuccessful, perhaps they should try Mother Earth's recipe, you know, the one they claim worked the first time about 4 billion years ago, so they say. All they need to do is to gather all the chemicals that we know are essential for life, pour them into a large clay pot and stir vigorously for a few billion years, and Walla, LIFE!

    Oh, you don't believe the 'original' Mother Earth recipe will work? You are NOT alone, Neither do I, and MILLIONS of others!

  2. If there ever was an outstanding argument from ignorance, the above comment is it. Not only can't the commenter distinguish between science ('evolutionists', 'propaganda'), he can't discuss the science on the table.

    Please explain why then biology predicts a nested hierarchy (of a phylogenetic tree) and finds it, it isn't clear evidence for the science in question?

    This unrooted E2 tree has 34 branches, which means the ability of finding it (and, I assume, a few almost as likely alternatives) without leaving unconnected branches is a verified falsifiable prediction with an imprecision on the order of 10^-43. (According to the Phylogenetic Trees Calculator on )

    The commenter can put his/hers hands over the eyes and go "la-la-la". The rest of us will put another couple of clear examples on the "evidence" pile.

    Here is a fun picture of the amount of "la-la-la" one must make in order to reject the main part of biology:

    A course estimate of a 100 biology papers on evolution each year for 150 years, each with 10 pages (and 10 such evidences as above), will now yield a pile of evidence on paper 30 m high containing more than ~ 100 000 verified predictions. (At 0.2 mm/page)

    But I expect the real numbers may be couple of magnitudes larger.

  3. Hi. I'd love your opinion on one issue: Pyruvate Dehydrogenase is intra-mitochondrial in eukaryotes, and is a main constituent of the envelope of Mycobacteria. With the common perception of mitochondria originating from a prokaryote who became intra-cellular to eukaryotes, it stands to reason to entertain the notion that pyruvate dehydrogenase came along with it (see this for further thoughts:
    My question is - what would such a scheme mean for Acetyl CoA biosynthesis? Could eukaryotes have gotten along before?