|Topic:||6-Phosphofructo-1-Kinase (Phosphofructokinase-1, PFK-1): .|
|Details:||The next reaction of glycolysis involves the utilization of a second ATP to convert F6P to fructose 1,6-bisphosphate (F1,6BP). This reaction is catalyzed by 6-phosphofructo-1-kinase, better known as phosphofructokinase-1 or PFK-1. This reaction is not readily reversible because of its large positive free energy (ΔG0' = +5.4 kcal/mol) in the reverse direction. Nevertheless, fructose units readily flow in the reverse (gluconeogenic) direction because of the ubiquitous presence of the hydrolytic enzyme, fructose-1,6-bisphosphatase (F-1,6-BPase).
The presence of these two enzymes in the same cell compartment provides an example of a metabolic futile cycle, which if unregulated would rapidly deplete cell energy stores. However, the activity of these two enzymes is so highly regulated that PFK-1 is considered to be the rate-limiting enzyme of glycolysis and F-1,6-BPase is considered to be the rate-limiting enzyme in gluconeogenesis.
Functional PFK-1 enzymes are tetramers composed of various combinations of three different subunits encoded by three different genes. These genes encode the muscle subunit (PFKM gene), the liver subunit (PFKL gene) and the platelet subunit (PFKP gene). The PFKM gene is located on chromosome 12q13.11 and is composed of 30 exons that generate 18 alternatively spliced mRNAs that collectively encode eight different protein isoforms. The PFKL gene is located on chromosome 21q22.3 and is composed of 28 exons that generate two alternatively spliced mRNAs. These two PFKL mRNAs encode proteins of 830 amino acids (isoform a) and 780 amino acids (isoform b). The PFKP gene is located on chromosome 10p15.2 and is composed of 28 exons that generate 11 alternatively spliced mRNAs that collectively encode eight protein isoforms.
Fibroblasts also express the PFKP gene. The PFK-1 enzyme found in skeletal muscle is a homotetramer of the PFKM encoded proteins, whereas, the liver PFK-1 enzyme is a homotetramer of the PFKL encoded protein. Erythrocytes contain multiple PFK-1 enzymes that randomly contain both the M and L proteins such that one can find M4 and L4 homotetramers as well as M3L1, M2L2, and M1L3 heterotetramers.
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