Metabolism of Red Blood Cells (RBCs)

Metabolism of Red Blood Cells (RBCs)Metabolism of Red Blood Cells (RBCs)

HMIM224HMIM224

Objectives of the LectureObjectives of the Lecture

1- Understanding the general structural & functional features of red 1- Understanding the general structural & functional features of red blood cells (RBCs).blood cells (RBCs).

2- Recognizing the main metabolic pathways occurring in RBCs with 2- Recognizing the main metabolic pathways occurring in RBCs with reference to their relations to functions of RBCs.reference to their relations to functions of RBCs.

3- Identifying some of the main & common diseases of RBCs as 3- Identifying some of the main & common diseases of RBCs as implication of defects of RBCs metabolism.implication of defects of RBCs metabolism.

4- Understanding the relation of characteristic features of structure 4- Understanding the relation of characteristic features of structure of membrane of RBCs.of membrane of RBCs.

5- Recognizing changes occurring in aging of RBCs.5- Recognizing changes occurring in aging of RBCs.

• The red blood cells (RBCs) are notnot true cells.

• RBCs contain nono nucleus or nucleic acids, and thus, can notnot reproduce.

• RBCs contain nono cell organelles (as mitochondria, Golgi, ER or lysosomes) and thus possess nono synthetic activities (no no protein biosynthesis, nono lipid synthesis & nono carbohydrate synthesis).

• RBCs must be able to squeeze through some tight spots in microcirculation.

For that RBCs must be easily & reversibly deformable

Introduction to the Red Blood Cells (RBCs)Introduction to the Red Blood Cells (RBCs)

• Red cells contain 35 % solids.• HemoglobinHemoglobin, the chief protein of the red cells.• Other proteins are present in combination with

lipids and oligosaccharide chains, forming the stroma and cell membrane.

• PotassiumPotassium, magnesiummagnesium, and zinczinc concentrations in red cells are much higher than in the plasma.

Biochemical composition of the RBCsBiochemical composition of the RBCs

HemoglobinHemoglobin

Functions of RBCsFunctions of RBCs

• RBCs have relatively simple functions simple functions as they have much simpler structure than most human cells.

• The major functions of RBCs are delivering oxygen to the tissues & disposal of carbon dioxide & protons formed by tissue metabolism.

This function is carried out by hemoglobinhemoglobin.

IntroductionIntroduction:• RBCs contain nono mitochondria, so there is nono

respiratory chain, nono citric acid cycle, and nono oxidation of fatty acids or ketone bodies.

• Energy in the form of ATP is obtained ONLYONLY from the glycolytic breakdown of glucose with the production of lactate (anaerobic glycolysis).

• ATPATP produced being used for keeping the biconcave

shape of RBCs & in the regulation of transport of ions & water in and out of RBCs.

Metabolism of RBCsMetabolism of RBCs

Metabolism of RBCs Metabolism of RBCs (cont.)

1- Glucose transport through RBC membraneGlucose transport through RBC membrane:

GlucoseGlucose is transported through RBC membrane glucose by a

facilitated diffusion by glucose transporters (GLUT-1GLUT-1).

Glucose transporters (GLUT-1) are independentindependent on insulin

i.e. insulin does not promote glucose transport to RBCS

2- GlycolysisGlycolysis:

Glucose is metabolized in RBCs through anaerobic glycolysis anaerobic glycolysis (that requires nono mitochondria and nono oxygen).

One molecule of glucose yields 2 molecules of ATP 2 molecules of ATP by one anaerobic

glycolytic pathway.

In addition, 2 molecules of lactate 2 molecules of lactate are produced.

LactateLactate is transported to blood & in the liver it is converted to glucose.

Metabolism of RBCs Metabolism of RBCs (cont.)

Anaerobic Anaerobic GlycolysisGlycolysis

Genetic defects in enzymes of glycolysisGenetic defects in enzymes of glycolysis:

Genetic defects of one of the enzymes of glycolysis in RBCs results in a reduced rate of glycolysis in RBCs & by this way will deprive RBCs of the onlyonly means for producing energy.

As a result, hemolytic anemia hemolytic anemia will be a consequence as RBCs will not be able to keep the biconcave flexible shape which allows it to squeeze through narrow capillaries with an end result of hemolysis (destruction of RBCs) .

95% of cases of genetic defects in glycolytic enzymes is caused by pyruvate pyruvate kinase deficiencykinase deficiency.

4% is caused by phosphoglucose isomerase deficiencyphosphoglucose isomerase deficiency.

Metabolism of RBCs Metabolism of RBCs (cont.)

3- Production of 2,3 bisphosphoglycerate (2, 3 BPG)Production of 2,3 bisphosphoglycerate (2, 3 BPG): In RBCs, some of glycolysis pathways aremodified so that 2, 3 bisphosphoglycerate , 3 bisphosphoglycerate is formed (by bisphosphoglycerate mutase).

2, 3 bisphosphoglycerate 2, 3 bisphosphoglycerate decreases affinity of HB for oxygen.So, it helps oxyhemoglobin to unload oxygen.

StoringStoring blood results in decrease of 2,3-BPG leadingto high oxygen affinity Hb.This leads to oxygen trap .

6-24 hours are needed to restore the depleted 2,3 BPGMaximum storage time for RBCs is 21-42 days

Metabolism of RBCs Metabolism of RBCs (cont.)

4- Pentose phosphate pathwayPentose phosphate pathway:

• RBCs contain an active pentose phosphate pathway (PPP) for glucose that supplies NADPHNADPH (PPP is the only source for NADPH in RBCs) (PPP is the only source for NADPH in RBCs)

• NADPHNADPH is important in keeping glutathioneglutathione in the reduced glutathione.

• Reduced glutathione Reduced glutathione plays a very important role in the survival of the red blood cells. (prevents oxidation of membrane)

• Glucose 6- phosphate dehydrogenase deficiency (G6PD DeficiencyGlucose 6- phosphate dehydrogenase deficiency (G6PD Deficiency): Glucose 6-phosphate dehydrogenase is the first enzyme of pentose phosphate

pathway & its deficiency leads to reduced production of NADPH ending in acute hemolytic anemia.

Metabolism of RBCs Metabolism of RBCs (cont.)

• The erythrocytes contain carboniccarbonic anhydraseanhydrase

Carbon dioxide combines with water only after it enters the red cells where hemoglobin, the most important buffer for the resulting carbonic acid, is present.

COCO22 + H + H22O O HCO HCO33-- + H + H++

• The red cell also contain rhodaneserhodanese enzyme responsible for the detoxication of cyanides.

Metabolism of RBCs Metabolism of RBCs (cont.)

• RBCs must be able to squeeze through some tight spots in microcirculation (capillaries). For that RBCs must be easily & reversibly deformable. Its membrane must be both fluidfluid & flexibleflexible .

• About 50% of membrane is protein, 40% is fat & up to 10% is carbohydrate.

• RBCs membrane comprises a lipid bilayer lipid bilayer (which determine the membrane fluidityfluidity), proteinsproteins (which is responsible for flexibilityflexibility) that are either peripheral or integral penetrating the lipid bilayer & carbohydratescarbohydrates that occur only on the external surface.

RBCs membrane structureRBCs membrane structure

• The membrane skeleton is four structural proteins that include & spectrinspectrin, ankyrinankyrin, protein 4.1 protein 4.1 & actinactin.

• SpectrinSpectrin is major protein of the cytoskeleton & its two chains ( & ) are aligned in an antiparallel manner

• & chains are loosely interconnected forming a dimer, one dimer interact with another, forming a

head to head tetramer.

• AnkyrinAnkyrin binds spectrinspectrin & in turn binds tightly to band 3band 3 securing attachment of spectrin to membrane.

• Band 3 is anion exchange protein permits exchanges of Cl- for HCO3+.

• ActinActin binds to the tail of spectrinspectrin & to protein 4.1 protein 4.1 which in turn binds to integral proteins, glycophorins A, B & C.

• Glycophorins A,B,C are transmembrane glycoproteinsglycoproteins;

• Defects of proteins may explain some of the abnormalities of shape of RBCs membrane as Defects of proteins may explain some of the abnormalities of shape of RBCs membrane as hereditary spherocytosishereditary spherocytosis & & elliptocytosiselliptocytosis..

Red Cell Membrane Structure Red Cell Membrane Structure (cont.)(cont.)

Changes in RBCs due to agingChanges in RBCs due to aging

Increased in old cells Decreased in old cells

Hb Glycosylated Hb Bisphosphoglycerate (BPG)

Membrane Osmotic fragilityNa+

Binding of IgG

Sialic acidK+

Lipids and Proteins

Enzymes G6PDPyruvate dehydrogenase

Others

GeneralCell densitySphericity

DeformabilityDisc like shape

AssignmentsAssignments

• Pyruvate kinase deficiencyPyruvate kinase deficiency

• Hereditary sphercytosisHereditary sphercytosis