Hexokinase (HK), the red cell enzyme with the lowest activity in the glycolytic pathway, catalyzes the initial step in the utilization of glucose and thus is required for both glycolysis and the pentose shunt and produces glucose 6-phosphate. The two HK isoenzymes, HK1 and HKR, are the product of a single gene HK-1 by use of an alternate translation initiation site. A single nucleotide polymorphism in HK-1 was strongly associated with reduced hemoglobin and hematocrit levels in a European population. HK deficiency is a rare cause of hereditary chronic nonspherocytic hemolytic anemia.
HK is proximal to the generation of 2,3-BPG and thus decreased levels of 2,3-BPG in HK deficiency lead to a left-shifted hemoglobin-oxygen dissociation curve and a more symptomatic anemia than comparable levels of anemia seen in patients with other RBC disorders. Splenectomy may be beneficial. A mouse model of HK deficiency demonstrates severe hemolytic anemia with extensive tissue iron deposition and marked reticulocytosis.
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