Heterogeneity of the molecular lesions in inherited phosphofructokinase deficiency.

Abstract

A B S T R A C T Human phosphofructokinase (PFK; EC 2.7.1.11) exists in tetrameric isozymic forms. Muscle and liver contain the homotetramers M4 and L4, whereas erythrocytes contain five isozymes composed of M (muscle) and L (liver) subunits, i.e., M4, M3L, M2L2, ML3, and L4. Inherited defects of erythrocyte PFK are usually partial and are described in association with heterogeneous clinical syndromes. To define the molecular basis and pathogenesis of this enzymopathy, we investigated four unrelated individuals manifesting myopathy and hemolysis (glycogenosis type VII), isolated hemolysis, or no symptoms at all.The three symptomatic patients showed high-normal hemoglobin levels, despite hemolysis and early-onset hyperuricemia. They showed total lack of muscle-type PFK and suffered from exertional myopathy of varying severity. In the erythrocytes, a metabolic crossover was evident at the PFK step: the levels of hexose monophosphates were elevated and those of 2,3-diphosphoglycerate (2,3-DPG) were depressed, causing strikingly increased hemoglobin-oxygen affinity. In all cases,

Use of Mathematical Models for Predicting the Metabolic Effect of Large-Scale Enzyme Activity Alterations. Application to Enzyme Deficiencies of Red Blood Cells

“…Diseases caused by phosphofructokinase defects are predominantly related to the lack or instability of one of the subunit types (M, L) forming the enzyme tetramer (Valentine and Paglia, 1984). Since the five isoenzymes normally found in red blood cells substantially differ in their kinetic constants for ATP and DPG inhibition, lack of one subunit leads to a drastic change in PFK kinetics but a moderate activity decrease to 40-60% (Vora et al, 1983), which cannot be simulated by varying V,,, alone. The discrepancies for GPI and TPI deficiencies are probably due to the remarkable instability of almost all abnormal enzyme variants (Tanaka and Zerez, 1990).…”

“…Calculated range of disease Properties of deficient enzymes Number of References diseased minimum range of minimum enzyme unstable kinetic change in persons survival chronic normal activity variants change isoenzyme activity disease activity Tanaka, 1990;Valentine, 1983;Board, 1978;Rijksen, 1983;Miwa, 1985;Paglia, 1981;Necheles, 1970Tanka, 1990Paglia, 1974;Zanella, 1980;Neubauer, 1990;Arnold, 1973Tanka, 1990Vora, 1983;Valentine, 1984 ;Fogelfeld, 1990Kishi, 1987Miwa, 1981 ;Valentine, 1984Eber, 1979Valentine, 1984;Rosa, 1985 ;Zanella, 1985Waller, 1974Tanaka, 1990Maeda, 1991 ;Fujii, 1980Fujii, , 1992Valentine, 1984Schroter, 1965Rosa, 1973Rosa, , 1978Buc, 1974;Rosa, 1989;Tanaka, 1990 Syllm- Rapoport, 1965…”

Point Mutations That Reduce Erythrocyte Resistance to Oxidative Stress

“…Three PFK isoenzymes, encoded by separate genes, have been identified in mammals: muscle-type (PFKM), liver-type (PFKL), and platelet-type (PFKP), all of which are expressed in a tissue specific manner. Skeletal muscle expresses only PFKM homotetramers, liver mainly PFKL homotetramers, while erythrocytes contain PFKM and PFKL heterotetramers (Vora et al, 1983). Inherited deficiency of muscle PFK is known to occur in man and dog (Vora et al, 1983;Skibild et al, 2001).…”

“…Skeletal muscle expresses only PFKM homotetramers, liver mainly PFKL homotetramers, while erythrocytes contain PFKM and PFKL heterotetramers (Vora et al, 1983). Inherited deficiency of muscle PFK is known to occur in man and dog (Vora et al, 1983;Skibild et al, 2001). PFK deficiency was the first recognized disorder that directly affects glycolysis.…”

Characterization of the enzymatic defect in late-onset muscle phosphofructokinase deficiency. New subtype of glycogen storage disease type VII.

“…Inherited deficiency of muscle PFK is known to occur in man and the dog (4)(5)(6). In man, the enzyme deficiency is associated with a heterogeneous group of clinical syndromes characterized by myopathy and/or hemolysis or asymptomatic state (4,5).…”