The Molecular History of Eukaryotic Life  Phospholipases and Sphingomylinase 


David Nelson  Dec. 13, 2000

	Phospholipases are active members of signal transduction pathways.  PI specific 
Phospholipase C (PI-PLC) generates diacylglycerol and inositol triphosphate (IP3), each 
of which have effects in the cell.  The structures of PI-PLCs of a bacterium and a 
eukaryote have now been solved.  Though the sizes are quite different, 30-35kDa for 
bacteria and 85-150kDa for eukaryotes, the catalytic domain of the eukaryotic protein is 
made from distinct parts of the sequence that come together to form a (beta alpha)8-
barrel.  The first half of the barrel contains the catalytic conserved amino acids and it 
is highly conserved in the structure, but not in sequence.  The second half of the barrel 
is where the substrate binding pocket is.  This part is not as conserved, since the 
preferences of the enzymes are different.  One difference is a catalytic Ca in eukaryotes 
that is replaced by an Arg residue in bacteria.  The catalytic domains of both preserve a 
similar fold and similar mechanism, therefore, they must be descended from a common 
ancestor.  

	Sphingomylinase cleaves sphingomylin to release ceramide, a mediator of stress 
responses.  Ceramide activates several proteins including ceramide activated protein 
kinase, ceramide activated protein phosphatase and protein kinase C zeta.  Ceramide 
signaling has numerous effects, but often they end in apoptosis (programmed cell death).  
The classical apoptosis pathway does not exist in yeast, yet the ceramide stress response 
is found in yeast.  Therefore, the linkage of ceramide responses to apoptosis seems to be 
acquired after animals diverged from fungi.

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