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Friday, April 20, 2007

Human Genes for the Pyruvate Dehydrogenase Complex

The pyruvate dehydrogenase complex (PDC) catalyzes a very important metabolic reaction: the conversion of pyruvate to acetyl-CoA [Pyruvate Dehydrogenase Reaction]. The complex consists of three components: E1 a dimer of E1α and E1β polypeptides; E2, and E3 [The Structure of the Pyruvate Dehydrogenase Complex].

Each of them are encoded by separate genes so there are four human genes required. We'll see shortly that there are two additional genes for a total of six. The E3 subunit is shared with two other enzymes: 2-oxoglutarate dehydrogenase (a citric acid cycle enzyme) and 2-oxo acid dehydrogenase (a enzyme required for amino acid degradation) [Pyruvate Dehydrogenase Evolution].

The gene for E1α: is called PDHA1 and it's located on the X chromosome at p22.2-p22.1 [Entrez Gene = 5160]. There are more than three dozen alleles that give rise to symptoms ranging from mild lactic acidosis to developmental defects. The accumulation of lactate is due to the fact that it can't be converted to pyruvate because the defect in pyruvate dehydrogenase causes buildup of pyruvate in the cell [Pyruvate]. Males often die at an early age. (Note that males are homozygous for mutant alleles because the gene is on the X chromosome) [OMIM 300502]. Females are also affected because only one X chromosome is active and if it happens to be the one carrying the mutations the entire cell is affected [Calico Cats].

A testis specific copy of the E1α: gene is called PDHA2 and it's located on chromosome 4 (q22-q23) [Entrez Gene = 5161].

The gene for E1β: is called PDHB on chromosome 3 near p21.1-p14.2 [Entrez Gene = 5162]. There are only two known alleles that cause a problem. Both are homozygous lethals but only after birth. The infants have severe problems and fail to develop normally [OMIM 179060]. Death usually occurs within a year of birth. It's likely that other mutations are embryonic lethals so we never see them as genetic diseases [Most Metabolic Diseases Affect Unimportant Genes].

The gene for the E2 subunit is called DLAT (dihydrolipoamide s-acetyltransferase). It is located on the chromosome 11 at q23.1 [Entrez Gene = 1737 ]. Two alleles are known to cause problems but the patients respond well to dietary treatment [OMIM 608770]. It's very likely that more severe genetic defects are embryonic lethals.

The gene for the E3 subunit is called DLD [Entrez Gene = 1738]. It is located on chromosome 7 at q31-q32. There are many alleles of this gene and some of them cause genetic diseases. The phenotype results from a defect in amino acid metabolism and not from a defect in pyruvate dehydrogenase. Recall that the E3 subunit of PDC is shared with 2-oxo acid dehydrogenase, an enzyme required for the breakdown of branched chain amino acids. Deficiencies in the enzyme activity lead to accumulation of breakdown products that are secreted in the urine. This gives rise to a characteristic odor resembling maple syrup [OMIM 238331]. The particular genetic disease associated with the DLD genes is called maple syrup urine disease type III

There is one other minor component of the pyruvate dehydrogenase complex in humans. Protein X binds to E3. It is encoded by the PDHX gene on chromosome 11 (p13). There are no known alleles in the OMIM database.


Alex said...

Note that males are homozygous for mutant alleles because the gene is on the X chromosome

Shouldn't males be semantically-speaking, hemizygous, as opposed to homozygous?
And homozygous lethal should be...recessive lethal?

Back to studying!

Larry Moran said...

Yes, "hemizygous" is more correct.

No, I think there's a difference between "recessive" alleles and those that have a phenotype in the heterozygous state ("semi-dominant"). Most of these alleles are "dominant" or "semi-dominant" which means the genetic disease is manifest when only one copy is present. When both mutant alleles are present the patient does not survive. Thus the allele is a homozygous lethal but not a "recessive" lethal.

The complication is that your terminology could be only addressing the "lethal" phenotype. In that case it is not a dominant "lethal" so it must be a recessive "lethal." I prefer to avoid that. There's no ambiguity in "homozygous lethal." Everyone knows exactly what it means.