Download Describe the structure/ function of blood cell types

Chapt. 44
Blood cells
Table 1 Blood cells (cells/mm3):
Ch. 44 Biochemistry
of Erythrocytes
Student Learning Outcomes:
• Erythrocytes
carry oxygen
5.2 x 106 men
4.6 x 106 women
• Neutrophils
4300
granules; phagocytic, O2 burst kills
• Lymphocytes
2700
immune response, B- and T-cells, NK
• Monocytes
500
macrophages for bacteria, damage
• Eosinophils
230
granules destroy parasites (worms)
• Basophils
40
• granules hypersensitivity, allergic
histamine, proteases,
• Describe the structure/ function of blood cell types:
• Erythrocytes, leukocytes, thrombocytes
• Explain the metabolism of the red blood cell
• Explain basics of hematopoiesis from bone marrow
• Describe some errors of hemoglobin function,
anemias, hemoglobin switching
• Describe the structure/ function of blood group
antigens (Ch. 30)
Hematopoiesis
Anemia
Hematopoiesis:
• Stem cells in bone marrow (1/105)
Anemias: hemoglobin concentration is low:
• Normal Hb g/dL: men 13.5-17.5; women 11.5-15.5
• Proliferate, differentiate, mature
by growth factors, hormones
signal transduction paths
• Myeloid, lymphoid lines
• Leukemias: immature cells
keep proliferating;
defined by cell type
Anemias classified by red blood cell morphology:
Fig. 15
Rbc morphology
Microcytic,
hypochromic
functional deficit
impaired Hb
synthesis
Macrocytic
normochromic
impaired DNA
synthesis
Normocytic
normochromic
red cell loss
possible cause
thalassemia, lead,
iron deficiency
vit B12 or folic acid
deficient, erythroleukemia
acute bleeding,
sickle cell defects
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Erythrocyte metabolism
Erythrocyte metabolism:
Heme synthesis
Only glycolysis
Heme synthesis in erythrocyte precursor:
• Heme = porphryn ring, coordinated to Fe
• Complexed to proteins in hemoglobin, myoglobin and
cytochromes; most common porphryn in body
• 4 pyrrole rings with –CH- joining
• Various side chains
• Heme is red color
• ATP for Na+/K+, Ca2+
• HMP shunt makes NADPH
G6PD is 1st enzyme
Lifetime rbc by G6PD activity
• 2,3-BPG modulates O2 binding
• Need Fe2+ Hb bind O2;
If ROS made Fe3+, NADH can reduce
Fig. 2
Fig. 1
Heme synthesis
Heme synthesis
Heme synthesis begins with δ-ALA:
Heme synthesis:
• Decarboxylation by δ-ALA synthase
• PLP is pyridoxal phosphate
• Dehydratase joins 2 δ-ALA
• 4 pyrroles form porphyrinogen
Glycine, succinyl CoA form
δ-Aminolevulinic acid
(δ
δ-ALA)
Each heme needs 8 of each
Final step is Fe2+
Heme regulates:
inhibit 1st enzyme
repress synthesis
Porphyria diseases from
defective enzymes
intermediates accumulate
photosensitive, toxic products
Fig. 3
Fig. 4
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Sources of iron and heme
Iron is essential from diet – 10-15 mg/day recommended
Iron is not readily absorbed from many sources
Iron in meats is form of heme, readily absorbed
Nonheme iron of plants not as easily absorbed becauuse other
compounds precipitate iron
Iron metabolism
Iron metabolism:
• Transferrin carries Fe3+ to cells; stored as ferritin
• Transferrin taken up by R-mediated endocytosis
• Hemosiderin stores excess
Iron absorbed in ferrous state (Fe2+), oxidized by ferroxidase to
Fe3+ for transport
Apotransferrin binds Fe3+ = Transferrin
Stored as ferritin in cells
Fig. 6
Heme stimulates synthesis of globin proteins from ribosomes
Degradation of hemoglobin
RE = reticuloendothelial
system
Red blood cells
Heme is degraded to bilirubin:
• Bilirubin is congugated to glucuronate (more soluble),excreted
• Rbc only live ~120 days
• Globin is degraded to amino acids
Erythrocyte cell membrane:
• Red disc, pale center
• Biconcave shape
Maximizes surface area
• 140 um2 vs. 98 um2 sphere
•
• Deforms to enter tissues
• Spleen destroys damaged
red blood cells
Figs. 7,8
Fig. 9
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Cytoskeleton of erythrocyte
Agents affect oxygen binding of hemoglobin
Erythrocyte cytoskeleton
• provides shape, structure, permits stretch
• 2-D lattice of proteins links to membrane proteins:
Agents affect oxygen binding of
hemoglobin:
• spectrin (α, β)
• actin
• ankyrin
• band 4.1
• membrane proteins:
• glycophorin
• band 3 protein
•Mature rbc does not synthesize
new proteins
• Gets lipids from circulating LDL
•
•
•
2, 3-BPG (glycolysis intermediate) binds
between 4 subunits of Hb, lowers affinity
for O2, releases O2 to tissues
Proton (Bohr) effect: ↑H+ lowers affinity of
Hb for O2:
CO2 can bind to Hb (not only bicarbonate)
Fig. 10 general side view; inside cell view up
Fig. 11,12, 14
Effect of H+ on oxygen binding to Hb
Hematopoiesis
Effect of H+ on oxygen binding to Hemoglobin:
• Tissues: CO2 released → carbonic acid, H+
• H+ bind Hb → release O2 to tissues
• Lungs reverse: O2 binds H+Hb → release H+
• H2CO3 forms, releases CO2 to exhale
Hematopoiesis:
• Stem cells in bone marrow
• proliferate
• differentiate
• mature
• myeloid vs. lymphoid
• Stromal cells secrete
growth factors
• Cytokines signal via
membrane receptors
Fig. 13
Fig. 15
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Bone marrow
Hematopoiesis involves cytokine signaling
Bone marrow stromal cells secrete growth factors
Hematopoietc stem cells respond
Growth factors signal through membrane receptors:
• Ligand causes receptors to aggregate
• Activates JAK (kinases) by phosphorylation (cytoplasmic RTK)
• JAK phophorylates cytokine receptor on Tyr
• Other signaling molecules bind, including STAT (signal
transducer and activator of transcription) → nucleus transcription
• Also RAS/Raf/MAP kinase activated
• Overactive signal → cancer
• Transient signal:
SOCS silences
Figs. 16; 11.15
Erythropoiesis
Hemoglobin genes
Erythropoiesis:
Erythropoietin from kidney increases red blood cell
proliferation (if low oxygen)
• Reticulocytes still have ribosomes, mRNA to make Hb
Mature in spleen, lose ribosomes
• Make 1012 rbc/day
• Anemia if not
appropriate diet
• Iron, vitamin B12, folate
Hemoglobinopathies, hemoglobin switching:
• Order of genes parallels development, controls
• >700 mutant Hb (often base subsittution)
• HbS sickle cell (Hb β Glu6Val)
• HbC (Hb β Glu6Lys)
Both ↑ malaria resistance
Fig. 17
Fig. 18
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Thalassemias
VI. Hemoglobin switching
Thalassemias: unequal production of α, β of Hb:
• need a:b 1:1
• α has 2 genes each chromosome; β only 1
• can have amino acid substitutions, promoter
mutations, gene deletions, splice
• Improper synthesis cause instability, or aggregation
β + has some β; β0 makes none
• People offten survive if hereditary persistence of
fetal hemoglobin: HPFH (α2γ2 = HbF)
• Treatments of β-thalassemia or sickle cell:
increase Hb γ transcription
Hemoglobin switching:
• embryo blast synthesis yolk
• fetus liver synthesis
• adult bone marrow
Multiple genes for Hb
Order of genes parallels
development
Problems if deletions,
other mutations
Problems if imbalance
Fig. 18
Transcription factors control Hb switching
Blood types reflect erythrocyte glycolipids
α-globin locus about 100 kb; HS40 control region
Blood group substances are glycolipids or
glycoproteins on cell surface of erythrocytes:
β-globin locus has LCR control region
• Promoter of γ gene has many transcription factors that bind;
HPFH mutations often map promoter
• Mutated repressor (CDP) or site
• SSP and SP1 compete for binding near TATA
• Glycosyltransferases add sugars, detemine blood type
• Two alleles (three choices) iA, iB, i
• Produced in Golgi, lipid part of membrane of vesicle, fuses
and carbohydrate extends extracellular
Fig. 19
Fig. 30.16,17
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Key concepts
Review question
Key concepts:
• Blood contains distinct cell types
• Erythrocytes transport O2 and return CO2 to lung
• Limited metabolism
• Heme synthesis in rbc precursos
• Oxygen binding
Review question:
• Hematopoiesis from bone marrow
• Leukocytes include monocytes, polymorphonuclear
• Hemoglobin mutant proteins, expression
1. A compensatory mechanism to allow adequate oxygen
delivery to tissues at high altitudes, where oxygen
concentrations are low, is which of the following?
a. Increase in 2,3-bisphosphoglycerate synthesis by rbc
b. Decrease in 2,3-bisphosphoglycerate synthesis by rbc
c. Increase in hemoglobin synthesis by rbc
d. Decrease in hemoglobin synthesis by rbc
e. Decreasing the blood pH
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