PCCA and PCCB: Case Study

Propionic acidemia is caused by mutations in PCCA or PCCB, alpha and beta subunits of propionyl-CoA hydroxylase. Here is the complex in its full glory. Pink blobs are susbtrates, indicating the position of the catalytic pocket.

Pccab sideview

And here are theside an the top views of the central PCCB hexamer:

Pccb hexamer side.small Pccb hexamer top.small

Given the high number of interfaces and ligand binding/catalytic sites, in which almost every residue participates, it would be reasonable to expect that the protein is very sensitive to mutation (that is, cannot tolerate mutations). Indeed, the comparative analysis shows remarkable conservation in sequence, from human to pufferfish (Z=exon boundary; colors in structural visualziations and here are unrelated):


Pcca alignment


Pccb alignment

By the heuristic estimating strategy we are using, this should be one of the most common inborn errors of the metabolism. However, it is not. Therrell at all quote atypical incidence of 4 cases per million in 2001-2010.

Are the mutations embryonic lethal? Or, completely conversely, can the organism circumvent the enzyme if it is completely absent from the system?