Isozymes of human phosphofructokinase: biochemical and genetic aspects.

Human PFK is under the control of three structural loci that encode muscle-type (M), liver-type (L), and platelet-type (P) subunits. These loci are differentially expressed in various human tissues, resulting in a tissue-specific isozyme distribution patterns. Random tetramerization of these subunits produces various homotetrameric and heterotetrameric isozymes distinguishable by ion-exchange chromatography and subunit-specific mouse monoclonal antibodies. Inherited PFK deficiency is associated with five clinically and biochemically identifiable groups. The largest and best defined of these consists of the patients with glycogenosis type VII (group I). This syndrome results from a total deficiency of the catalytically active M subunit; the molecular pathology of the other four syndromes remains to be elucidated. Subunit- and species-specific hybridoma antibodies to the PFK subunits have permitted not only precise immunochemical analysis of this complex isozyme system, but also chromosomal localization of the PFK loci. In addition, immunochemical homologies among vertebrate PFKs determined using monoclonal antibodies suggest both an ancient duplication of the ancestral PFK gene and the structural conservatism of vertebrate PFK subunits despite this early divergence. Using somatic cell hybrids and subunit-specific antibodies, the PFKM, PFKP, and PFKL loci have been assigned to chromosomes I (region cen leads to q32), 10p and 21, respectively. The localization of PFKL to chromosome 21 and the chromatographic demonstration of a specific increase in the L subunit in red cells from trisomy 21 individuals has thus resolved the controversy about whether the previously observed elevation in PFK activity in Down syndrome represented a gene dosage effect. PFK exhibits both quantitative increases and isozymic shifts secondary to the altered gene expression in neoplasia. Since these alterations are correlated with the rate of growth and not the cell type of origin, PFK appears to be not only a transformation-linked but also a progression-linked discriminant of malignancy.