2012 Protein of the Year

pyruvate decarboxylase

Pyruvate decarboxylase (PDC) plays a particularly important role in ethanol fermentation in yeast and other microorganisms.  Glucose is first converted to pyruvate via glycolysis.  PDC, with help from its cofactors Mg²⁺ and thiamine pyrophosphate (TPP), then catalyzes the decarboxylation of pyruvate to acetaldehyde and carbon dioxide.  After PDC does this, alcohol dehyrdrogenase completes the two-step fermentation process and converts acetaldehyde to ethanol.  Therefore, PDC plays a crucial role in the regulation and production of ethanol, an infamous alcohol known throughout the world.

PDC is a homotetramer.  This is flawless symmetry at its best!  It occurs as a dimer of dimers.  The two dimers interact loosely to form a loose tetramer.  There are two active sites shared between the monomers of each dimer, thus resulting in a total of 4 active sites altogether.  The enzyme has parallel beta-sheets in a beta-alpha-beta structure.  Each dimer contains 563 residue subunits for a total of 2252 subunits in the entire tetramer.  Take a look at the two figures below to see this spectacular symmetry.

The figure below shows one of the four active sites of PDC.  Displayed are the cofactors Mg²⁺ and TPP, as well as key amino acids: Glu-51, Glu-477, Asp-444, and Asp-28.  Glu-51 and Glu-477 aid in cofactor binding (Glu-477 contributes solely to the stability of TPP. It's the lower-right corner Glu in the figure below).  Asp-444 and Asp-44 stabilize the Mg²⁺ ion.

To ensure that only pyruvate binds to the active site, two Cys-221 and two His-92 trigger a conformational change, which inhibits or activates the enzyme depending on the bound substrate (see figure below).  If the substrate is pyruvate, the enzyme is activated.  The conformational change is thought to involve a 1,2 nucleophilic addition, thus resulting in the formation of a thioketal, which transforms the enzyme from its inactive to active state.

Positions of His and Cys residues in respect to active sites (TPP and Mg) that participate in conformation changes when interacting with pyruvate substrate.

PDC is present in brewer’s and baker’s yeast.  The CO₂ produced by pyruvate decarboxylation in brewer’s yeast is responsible for the characteristic carbonation of champagne.  In baker’s yeast, the CO₂ produced mixes with fermentable sugar and causes the dough to rise.  Without PDC, we would not have the same champagne and beer that we humans adore, and our bread would look like this:

 

Without pyruvate decarboxylase, life would surely be one giant FAIL.

References

Baburina I, Dikdan G, Guo F, Tous GI, Root B, Jordan F (February 1998). "Reactivity at the substrate activation site of yeast pyruvate decarboxylase: inhibition by distortion of domain interactions". Biochemistry 37 (5): 1245–55. 

Dyda F, Furey W, Swaminathan S, Sax M, Farrenkopf B, Jordan F (June 1993). "Catalytic centers in the thiamin diphosphate dependent enzyme pyruvate decarboxylase at 2.4-A resolution". Biochemistry 32 (24): 6165–70. 

Nelson, D. L., & Cox, M. M. (2008). Lehninger: Principles of Biochemistry (5th ed., p. 547-549). New York, NY: W.H. Freeman and Company.