Фосфофруктокиназа 2 және фруктозо-бисфосфатаза 2 ферменттерінің құрылымы мен функциясы

Class of enzymes

Phosphofructokinase 2 (6 phosphofructo 2 kinase, PFK 2) or fructose bisphosphatase 2 (FBPase 2), is an enzyme indirectly responsible for regulating the rates of glycolysis and gluconeogenesis in cells. It catalyzes formation and degradation of a significant allosteric regulator, fructose 2,6 bisphosphate (Fru 2,6 P2) from substrate fructose 6 phosphate. Fru 2,6 P2 contributes to the rate determining step of glycolysis as it activates enzyme phosphofructokinase 1 in the glycolysis pathway, and inhibits fructose 1,6 bisphosphatase 1 in gluconeogenesis. Since Fru 2,6 P2 differentially regulates glycolysis and gluconeogenesis, it can act as a key signal to switch between the opposing pathways. This enzyme participates in fructose and mannose metabolism. The enzyme is important in the regulation of hepatic carbohydrate metabolism and is found in greatest quantities in the liver, kidney and heart. In mammals, several genes often encode different isoforms, each of which differs in its tissue distribution and enzymatic activity. PFK 2 is known as the "bifunctional enzyme" because of its notable structure: though both are located on one protein homodimer, its two domains act as independently functioning enzymes. One terminus serves as a kinase domain (for PFK 2) while the other terminus acts as a phosphatase domain (FBPase 2). In mammals, genetic mechanisms encode different PFK 2 isoforms to accommodate tissue specific needs. While general function remains the same, isoforms feature slight differences in enzymatic properties and are controlled by different methods of regulation; these differences are discussed below.

The monomers of the bifunctional protein are clearly divided into two functional domains. The kinase domain is located on the N terminal. It consists of a central six stranded β sheet, with five parallel strands and an antiparallel edge strand, surrounded by seven α helices. The PFK 2 domain appears to be closely related to the superfamily of mononucleotide binding proteins including adenylate cyclase. On the other hand, the phosphatase domain is located on the C terminal. It resembles the family of proteins that include phosphoglycerate mutases and acid phosphatases. The domain has a mixed α/ β structure, with a six stranded central β sheet, plus an additional α helical subdomain that covers the presumed active site of the molecule. While this central catalytic core remains conserved in all forms of PFK 2, slight structural variations exist in isoforms as a result of different amino acid sequences or alternative splicing. With some minor exceptions, the size of PFK 2 enzymes is typically around 55 kDa.

Gene PFKB4, located on chromosome 3, expresses PFK 2 in human testis tissue. PFK 2 enzymes encoded by PFK 4 are comparable to the liver enzyme in size at around 54kDa, and like the muscle tissue, do not contain a protein kinase phosphorylation site. This isoform has been particularly implicated as being modified and hyper expressed for prostate cancer cell survival.

Because this enzyme family maintains rates of glycolysis and gluconeogenesis, it presents great potential for therapeutic action for control of metabolism particularly in diabetes and cancer cells. The control of PFK 2/FBP ase2 activity was found to be linked to heart functioning, particularly for ischemia, and the control against hypoxia. Researchers hypothesize that this responsive characteristic of the PFK 2 genes may be a strong, evolutionary physiological adaptation. Lastly, the Pfkfb2 gene encoding PFK2/FBPase2 protein is linked to the predisposition to schizophrenia.