Enzyme Deficiencies Flashcards
Increased red cell destruction, or hemolysis, is one classification of anemia. The causes of hemolysis are either extrinsic or intrinsic. They are:
- Antibody-mediated destruction
- Mechanical trauma
- Infections of red cells
- Toxic or chemical injury
- Membrane lipid abnormalities
- Sequestration
- Acquired genetic defects
- Inherited genetic defects
several major metabolic pathways that converge in the red blood cell
- glycolysis
- hexose monophosphate shunt/pentose phosphate pathway (PPP)
- glutathione synthesis
- adenosine salvage/metabolism
purpose of the erythrocytes pathways is to:
(a) generate ATP to supply the Na-K-ATPase pump with energy to transport ions across the cell membrane in order to maintain the flexible, biconcave disc shape of the red blood cell.
(b) produce 2,3 bisphosphoglycerate (BPG) to facilitate O2 release in tissues due to its ability to reduce the O2 affinity for hemoglobin.
(c) generate the reducing equivalent, NADPH, which will be used to maintain glutathione in its reduced state.
(d) synthesize glutathione which can protect the RBCs against a range of oxidative stressors and chemical insults.
(e) to salvage pentose sugars for entry into the PPP
During metabolism, powerful reactive oxygen species (ROS) are produced in blood cells and other cells
- superoxide
- hydrogen peroxide
- peroxyl radicals
- hydroxyl radicals
Enzymes that catalyze the conversion of the ROS into lesser ROS intermediates or H2O
- superoxide dismutase
- catalase
- glutathione peroxidase
Enzyme that converts methemoglobin back to hemoglobin
- methemoglobin reductase (aka cytochrome b5 reductase)
methemoglobinemia molecular basis
- deficiency in methemoglobin reductase (aka cytochrome b5 reductase)
- caused by either an acquired or inherited defect in methemoglobin reductase
- occurs in individuals who have inherited hemoglobin M
Can also be caused by toxic compounds:
- primaquine
- pamaquine
- chloroquine
Fava beans can induce through:
- vicine
- divicine
- covicine
- isouramil
Methemoglobinemia symptoms
- exhibit “chocolate cyanosis” because their skin and mucous membranes have a brownish-blue coloration and their blood is tinged brown
- Other symptoms are related to the degree of tissue hypoxia, including anxiety, headaches, dyspnea, coma and death
Methemoglobinemia treatment
- Methylene blue or ascorbic acid are reducing agents that get oxidized as Fe3+ gets reduced
Glucose-6-phosphate dehydrogenase
- catalyzes a reaction in the pentose phosphate pathway (PPP) to produce NADPH
NADPH
- electrons are destined to be utilized by cells for reductive biosynthetic and detoxification reactions
- acts as an electron donor and it catalyzes the reduction of glutathione in order to degrade H2O2, a ROS intermediate
- PPP is the only pathway to produce NADPH
Glucose-6-phosphate dehydrogenase enzyme deficiency
- Deficiencies in the G6PD enzyme cause a hereditary, X-linked disease that is characterized by hemolytic anemia
- G6PD deficiencies (aka “Favism”) are highly prevalent in the Middle East, tropical Africa and Asia and parts of the Mediterranean
- Individuals who have this deficiency exhibit an increased resistance to Plasmodium falciparum malaria
- Since the PPP is the only pathway to produce NADPH, the RBCs lacking G6PD become very susceptible to oxidative damage exposure
(a) decreased cellular detoxification of free radicals
(b) insufficient production of NADPH under oxidative stress leading to damage and hemolysis of red cells
(c) diminished ability to form NADPH to maintain the pool of GSH
(d) formation of denatured proteins from sulfhydryl oxidation and attachment of insoluble Heinz bodies (inset) to RBC membranes that are plucked out by macrophages (“bite cells”)
(e) rigidity of RBCs that are removed by macrophages eventually causing hemolytic anemia
Glucose-6-phosphate dehydrogenase enzyme deficiency symptoms
- Usually asymptomatic except in response to an oxidant stress which usually manifests as hemolytic anemia within 2-3 days after
- Severe symptoms include formation of Heinz bodies in RBCs, jaundice, hematuria and dark-colored urine
Pyruvate kinase enzyme deficiency
- most common of the hemolytic anemias that result from a deficiency in a glycolytic enzyme
- second only to G6PD deficiency as an enzymatic cause of hemolytic anemia
- inherited disease that is autosomal recessive
- most prevalent among people of European descent and is often diagnosed among the Old Order Amish population of Pennsylvania due to intermarriages within a closed community
- confers resistance to most severe forms of malaria
- affects cellular integrity; PK deficient RBCs have decreased cellular ATP concentrations due to a reduced rate of glycolysis, and compensatory accumulation of 2,3 BPG
Pyruvate kinase enzyme deficiency symptoms
- jaundice
- mild to moderate splenomegaly
- Decreased ATP concentration
- Inability to synthesize ATP required to maintain RBC metabolism, ion gradients and cell shape leads to hemolytic anemia.
- Increased 2,3-bisphosphoglycerate concentration.
- Compensatory accumulation of 2,3 BPG that binds Hb and decreases its affinity for O2 to promote delivery to tissues (acts as a shunt in the glycolytic pathway to allow for transport of O2)
