Evolution of a bifunctional enzyme: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.
The bifunctional rat liver enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (ATP:D-fructose-6-phosphate 2-phosphotransferase/D-fructose-2,6-bisphosphate 2-phosphohydrolase, EC 2.7.1.105/EC 3.1.3.46) is constructed of two independent catalytic domains. We present evidence that the kinase and bisphosphatase halves of the bifunctional enzyme are, respectively, structurally similar to the glycolytic enzymes 6-phosphofructo-1-kinase and phosphoglycerate mutase. Computer-assisted modeling of the C-terminal bisphosphatase domain reveals a hydrophobic core and active site residue constellation equivalent to the yeast mutase structure; structural differences map to length-variable, surface-located loops. Sequence patterns derived from the structural alignment of mutases and the bisphosphatase further detect a significant similarity to a family of acid phosphatases. The N-terminal kinase domain, in turn, is predicted to form a nucleotide-binding fold that is analogous to a segment of 6-phosphofructo-1-kinase, suggesting that these unrelated enzymes bind fructose 6-phosphate and ATP substrates in a similar geometry. This analysis indicates that the bifunctional enzyme is the likely product of gene fusion of kinase and mutase/phosphatase catalytic units.
Bazan
J F
JF
Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
Fletterick
R J
RJ
Pilkis
S J
SJ
D000135:Acid Phosphatase / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D001731:Bisphosphoglycerate Mutase / Q000235:genetics; D006801:Humans; D008961:Models, Structural; D008969:Molecular Sequence Data; D025481:Phosphofructokinase-2; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D010770:Phosphotransferases / Q000235:genetics*; D011487:Protein Conformation; D012689:Sequence Homology, Nucleic Acid; D012984:Software
D010770:Phosphotransferases; D025481:Phosphofructokinase-2; D000135:Acid Phosphatase; D010744:Phosphoric Monoester Hydrolases; D001731:Bisphosphoglycerate Mutase