Chapter 17: Pyruvate Kinase Deficiency & Disorders of Glycolysis – Key Vocabulary

Essential vocabulary flashcards summarizing enzymes, genetic defects, clinical features, biochemical mechanisms, and key concepts from Chapter 17 on pyruvate kinase deficiency and related glycolytic disorders.

Embden–Meyerhof Pathway (EMP)

The anaerobic glycolytic pathway used by erythrocytes to generate ATP; defects in any of its enzymes can cause congenital nonspherocytic hemolytic anemias (CNSHAs).

Congenital Nonspherocytic Hemolytic Anemia (CNSHA)

Group of hereditary hemolytic anemias caused by enzyme defects in erythrocyte glycolysis, characterized by hemolysis without spherocytes and with normal mean osmotic fragility.

Hexokinase (HK) Deficiency

Autosomal-recessive enzyme defect reducing the first step of glycolysis; causes chronic hemolysis, low 2,3-BPG, high O₂ affinity, and partial response to splenectomy.

Glucose-6-Phosphate Isomerase (GPI) Deficiency

Second-step glycolytic defect leading to hemolytic anemia ± neurologic dysfunction; shows thermal-labile enzyme, high substrate/product ratio, and autosomal-recessive inheritance.

Phosphofructokinase (PFK) Deficiency (Tarui Disease)

Defect of muscle (M) PFK subunit causing exercise-induced myopathy with secondary hemolysis; erythrocytes have low PFK activity and high 2,3-BPG.

Aldolase A Deficiency

Rare erythro-muscular defect causing hemolytic anemia ± myopathy or mental retardation; due to thermolabile aldolase A mutations.

Triose Phosphate Isomerase (TPI) Deficiency

Severe autosomal-recessive disorder with hemolytic anemia, progressive neuromuscular disease, low ATP, high DHAP, and shortened survival.

Glyceraldehyde-3-Phosphate Dehydrogenase (G3PD) Deficiency

Partial reduction of G3PD activity that usually does not cause hemolysis; significance remains uncertain.

Phosphoglycerate Kinase (PGK) Deficiency

X-linked enzymopathy producing hemolytic anemia, neurologic signs, or myopathy; males severely affected, females variable due to lyonization.

2,3-Bisphosphoglycerate Mutase (BPGM) Deficiency

Loss of enzyme that forms 2,3-BPG; red cells lack 2,3-BPG, oxygen affinity increases, and compensatory polycythemia develops without hemolysis.

Monophosphoglycerate Mutase (MPGM) Deficiency

Rare erythroid isozyme defect sometimes uncovered in hereditary spherocytosis; may aggravate hemolysis by lowering ATP formation distally.

Enolase Deficiency

Marked decrease of erythrocyte enolase activity; typically asymptomatic but may precipitate acute hemolysis after oxidant drugs such as nitrofurantoin.

Pyruvate Kinase (PK) Deficiency

Most common glycolytic enzymopathy (autosomal recessive); causes lifelong hemolytic anemia, high 2,3-BPG, low ATP, reticulocytosis, and variable benefit from splenectomy.

R-PK and L-PK Subunits

Isoforms encoded by the PKLR gene; R type in red cells, L type in liver—mutations can affect both tissues.

Adenosine Triphosphate (ATP) in Red Cells

Sole energy currency produced via EMP; depletion leads to cation pump failure, membrane rigidity, and premature hemolysis.

2,3-Bisphosphoglycerate (2,3-BPG)

Erythrocyte metabolite that lowers hemoglobin’s oxygen affinity; elevated in PK and PFK deficiencies, reduced in HK deficiency and BPGM deficiency.

Basophilic Stippling

Ribosomal RNA aggregates in erythrocytes; prominent in pyrimidine-5′-nucleotidase deficiency and lead poisoning.

Pyrimidine-5′-Nucleotidase (P-5′-N) Deficiency

Common nucleotide-metabolism defect causing hemolytic anemia with marked basophilic stippling, high pyrimidine nucleotides, and high GSH.

Adenylate Kinase (AK) Deficiency

Erythrocyte enzyme defect (AK1 gene) that impairs AMP⇌ADP balance; associated with moderate hemolysis and sometimes mental retardation.

Adenosine Deaminase (ADA) Overproduction

Autosomal-dominant excess of ADA activity leading to low adenosine nucleotides, decreased ATP, and chronic hemolytic anemia.

Embden–Meyerhof vs. Hexose Monophosphate (HMP) Shunt

EMP provides ATP; HMP shunt supplies NADPH for antioxidant defense—stimulation tests help distinguish glycolytic from G6PD defects.

Thermolabile Enzyme

Mutant protein that rapidly loses activity at body temperature; common mechanism in GPI, TPI, aldolase, PGK, and PK variants.

Autohemolysis Test

Old screening assay measuring spontaneous hemolysis of glucose-free erythrocytes after 48 h; limited value for diagnosing glycolytic defects.

Splenectomy in Glycolytic Enzymopathies

Often reduces hemolysis (PK, HK, GPI, PGK deficiencies) but rarely cures; efficacy varies with enzyme and patient.

Reticulocyte ATP Generation

Immature red cells can synthesize ATP via oxidative phosphorylation; compromised in PK deficiency under hypoxic splenic conditions.

Crystallographic Domains of PK (A, B, C)

Three-domain structure where the active site lies between A & B, metal binding in A, and allosteric fructose-1,6-diphosphate binding in C.

Right-Shifted Oxyhemoglobin Curve

Decrease in hemoglobin’s oxygen affinity (higher P₅₀) due to elevated 2,3-BPG; partially offsets anemia in PK or PFK deficiencies.

Left-Shifted Oxyhemoglobin Curve

Increase in oxygen affinity (lower P₅₀) seen in HK or BPGM deficiencies where 2,3-BPG is low, predisposing to tissue hypoxia and polycythemia.

Therapeutic Iron Overload in PK Deficiency

Chronic transfusions and ineffective erythropoiesis can raise body iron; monitored by ferritin and treated with chelators.

Lead-Induced Acquired P-5′-N Deficiency

Lead inhibits P-5′-N causing basophilic stippling and occasional hemolysis; reversible with chelation therapy.

Downeast Anemia (Mouse)

Murine model of HK1 mutation producing severe hemolysis, reticulocytosis, splenomegaly, and iron overload—useful for pathophysiologic studies.

Tarui Disease (GSD Type VII)

Systemic PFK M-subunit deficiency presenting with exercise intolerance, myoglobinuria, hyperuricemia, and mild hemolytic anemia.

Arginine to Gln Mutation (PK G1529A)

Common European PKLR missense change (Arg510Gln) causing unstable PK protein and variable anemia severity.

Fructose-1,6-Diphosphate (FDP) Activation

Allosteric effector that converts PK kinetics from sigmoidal to hyperbolic, increasing catalytic efficiency.

Rapoport-Luebering Shunt

Side pathway converting 1,3-BPG to 2,3-BPG then to 3-PG, bypassing ATP generation at the PGK step.

Gardos Channel

Ca²⁺-activated K⁺ channel in erythrocytes; overactive when ATP is low, leading to K⁺ loss, dehydration, and rigidity.

Hyperventilation-Induced Hemolysis (Dog PFK-D)

Unique canine phenomenon where alkalosis triggers rupture of low-2,3-BPG erythrocytes in PFK-deficient dogs; not seen in humans.

Allosteric Regulation

Modulation of enzyme activity by binding of effectors at sites other than the active site; crucial for PK, PFK, and BPGM function.

Therapeutic Approaches in PK Deficiency

Include splenectomy, folic-acid supplementation, transfusions, experimental gene or bone-marrow therapy, and small-molecule PK activators (e.g., AG-348).

Basenji Dog PK Deficiency

Natural animal model of severe frameshift PKLR mutation leading to anemia, used for transplantation and gene-therapy studies.

Pentose Phosphate Pathway (PPP) Impairment

Secondary failure of NADPH-producing pathway noted in some HK, GPI, and P-5′-N defects, compromising oxidative protection.