Transcript The Cell, 5e

Chapt. 44
Ch. 44 Biochemistry
of Erythrocytes
Student Learning Outcomes:
• 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)
Blood cells
Table 1 Blood cells (cells/mm3):
• 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,
Hematopoiesis
Hematopoiesis:
• Stem cells in bone marrow (1/105)
• Proliferate, differentiate, mature
by growth factors, hormones
signal transduction paths
• Myeloid, lymphoid lines
• Leukemias: immature cells
keep proliferating;
defined by cell type
Fig. 15
Anemia
Anemias: hemoglobin concentration is low:
• Normal Hb g/dL: men 13.5-17.5; women 11.5-15.5
Anemias classified by red blood cell morphology:
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
Erythrocyte metabolism
Erythrocyte metabolism:
Only glycolysis
• 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. 1
Heme synthesis
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
Fig. 2
Heme synthesis
Heme synthesis:
Glycine, succinyl CoA form
d-Aminolevulinic acid
(d-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
Heme synthesis
Heme synthesis begins with d-ALA:
• Decarboxylation by d-ALA synthase
• PLP is pyridoxal phosphate
• Dehydratase joins 2 d-ALA
• 4 pyrroles form porphyrinogen
Fig. 4
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 absorbed in ferrous state (Fe2+), oxidized by ferroxidase to
Fe3+ for transport
Apotransferrin binds Fe3+ = Transferrin
Stored as ferritin in cells
Heme stimulates synthesis of globin proteins from ribosomes
Iron metabolism
Iron metabolism:
• Transferrin carries Fe3+ to cells; stored as ferritin
• Transferrin taken up by R-mediated endocytosis
• Hemosiderin stores excess
Fig. 6
RE = reticuloendothelial
system
Degradation of hemoglobin
Heme is degraded to bilirubin:
• Bilirubin is congugated to glucuronate (more soluble),excreted
• Rbc only live ~120 days
• Globin is degraded to amino acids
Figs. 7,8
Red blood cells
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
Fig. 9
Cytoskeleton of erythrocyte
Erythrocyte cytoskeleton
• provides shape, structure, permits stretch
• 2-D lattice of proteins links to membrane proteins:
• spectrin (a, b)
• actin
• ankyrin
• band 4.1
• membrane proteins:
• glycophorin
• band 3 protein
•Mature rbc does not synthesize
new proteins
• Gets lipids from circulating LDL
Fig. 10 general side view; inside cell view up
Agents affect oxygen binding of hemoglobin
Agents affect oxygen binding of
hemoglobin:
•
•
•
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. 11,12, 14
Effect of H+ on oxygen binding to Hb
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
Fig. 13
Hematopoiesis
Hematopoiesis:
• Stem cells in bone marrow
• proliferate
• differentiate
• mature
• myeloid vs. lymphoid
• Stromal cells secrete
growth factors
• Cytokines signal via
membrane receptors
Fig. 15
Bone marrow
Bone marrow stromal cells secrete growth factors
Hematopoietc stem cells respond
Hematopoiesis involves cytokine signaling
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
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
Fig. 17
Hemoglobin genes
Hemoglobinopathies, hemoglobin switching:
• Order of genes parallels development, controls
• >700 mutant Hb (often base subsittution)
• HbS sickle cell (Hb b Glu6Val)
• HbC (Hb b Glu6Lys)
Both ↑ malaria resistance
Fig. 18
Thalassemias
Thalassemias: unequal production of a, b of Hb:
• need a:b 1:1
• a has 2 genes each chromosome; b only 1
• can have amino acid substitutions, promoter
mutations, gene deletions, splice
• Improper synthesis cause instability, or aggregation
b+ has some b; b0 makes none
• People offten survive if hereditary persistence of
fetal hemoglobin: HPFH (a2g2 = HbF)
• Treatments of b-thalassemia or sickle cell:
increase Hb g transcription
VI. Hemoglobin switching
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
a-globin locus about 100 kb; HS40 control region
b-globin locus has LCR control region
• Promoter of g 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
Fig. 19
Blood types reflect erythrocyte glycolipids
Blood group substances are glycolipids or
glycoproteins on cell surface of erythrocytes:
• 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. 30.16,17
Key concepts
Key concepts:
• Blood contains distinct cell types
• Erythrocytes transport O2 and return CO2 to lung
• Limited metabolism
• Heme synthesis in rbc precursos
• Oxygen binding
• Hematopoiesis from bone marrow
• Leukocytes include monocytes, polymorphonuclear
• Hemoglobin mutant proteins, expression
Review question
Review question:
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