Transcarboxylase: one of nature's early nanomachines.
The enzyme transcarboxylase (TC) catalyzes an unusual reaction; TC transfers a carboxylate group from methylmalonyl-CoA to pyruvate to form oxaloacetate and propionyl-CoA. Remarkably, to perform this task in Propionii bacteria Nature has created a large assembly made up of 30 polypeptides that totals 1.2 million daltons. In this nanomachine the catalytic machinery is repeated 6-12 times over using ordered arrays of replicated subunits. The latter are sites of the half reactions. On the so-called 12S subunit a biotin cofactor accepts carboxylate, - CO2- , from methylmalonyl-CoA. The carboxylated-biotin then translocates to a second subunit, the 5S, to deliver the carboxylate to pyruvate. We have not yet characterized the intact nanomachine, however, using a battery of biophysical techniques, we have been able to derive novel,and sometimes unexpected, structural and mechanistic insights into the 12S and 5S subunits. Similar insights have been obtained for the small 1.3S subunit that acts as the biotin carrier linking the 12S and 5S forms. Interestingly, some of these insights gained for the 12S and 5S subunits carry over to related mammalian enzymes such as human propionyl-CoA carboxylase and human pyruvate carboxylase, respectively, to provide a rationale for their malfunction in disease-related mutations.
Carey
Paul R
PR
Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44120, USA. paul.carey@case.edu
Sönnichsen
Frank D
FD
Yee
Vivien C
VC
D000214:Acyl Coenzyme A / Q000737:chemistry; D001419:Bacteria / Q000201:enzymology; D001426:Bacterial Proteins / Q000737:chemistry; D001703:Biophysics / Q000379:methods*; D019878:Carboxyl and Carbamoyl Transferases / Q000378:metabolism / Q000502:physiology*; D002384:Catalysis; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D043586:Methylmalonyl-CoA Decarboxylase / Q000737:chemistry; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D009154:Mutation; D036103:Nanotechnology; D062907:Oxaloacetic Acid / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011766:Pyruvate Carboxylase / Q000737:chemistry; D019289:Pyruvic Acid / Q000737:chemistry; D013059:Spectrum Analysis, Raman
D000214:Acyl Coenzyme A; D001426:Bacterial Proteins; D010455:Peptides; C015357:methylmalonyl-coenzyme A; D062907:Oxaloacetic Acid; C009061:propionyl-coenzyme A; D019289:Pyruvic Acid; D019878:Carboxyl and Carbamoyl Transferases; C021580:Methylmalonyl-CoA carboxytransferase; D011766:Pyruvate Carboxylase; D043586:Methylmalonyl-CoA Decarboxylase