Unit 4 - Hgb Synthesis Flashcards
What is 90% of the dry weight of RBCs?
Hemoglobin
What is most of internal RBC metabolism geared toward?
Maintaining Hgb function
What promotes gas exchange in the capillaries in RBCs?
RBC membrane structure and deformability
What kind of protein is hemoglobin?
Conjugated protein
What is the molecular weight of hemoglobin
~67,000
How much of the RBC does hemoglobin occupy?
1/3 the mass of the RBC
Moieties means
portions
What is heme made up of?
Iron + porphyrin ring
How many heme per RBC?
4 per molecule
What is globin made up of?
Protein portion
How many chains of globin in an RBC?
4 chains
2 chains of one type
2 chains of another type (a2B2)
How much hgb synthesis at pronormoblast stage?
Minimal
How much hgb synthesis at normoblast stage?
Maximum
What stage of RBC is producing the least amount of hgb synthesis?
Pronormoblast
What stage of RBC is producing the most amount of hgb synthesis?
Normoblast
What happens to mRNA production after nucleus is extruded?
No new mRNA is produced
What does the remaining mRNA in a reticulocyte do?
Continues hgb synthesis
Hgb from retic synthesis is ___ of total hgb in rbc
20-25%
Biochemical pathways for synthesis include
Heme portion
Global portion
Assembly of molecule
Different forms of hemoglobin
Normal human hgb types
Variant human hgb due to genetics
Chemically modified hemoglobin variants
Heme is also known as
Ferroprotoporphyrin
What is the heme structure
Ring structure of 4 pyrrole rings attached together at methylene bridges
What is the ring structure of heme called
Protoporphyrin
What are the 4 rings that join in a heme?
Pyrrole
What is it that holds the 4 pyrrole rings together in a heme group?
Methylene bridges
What is at the center of the protoporphyrn?
Ferrous iron
What form of iron cannot bind oxygen?
Ferric iron
What is heme considered in biochemical terms
A prosthetic group attached to a protein
What are globin chains
Protein chains folded into complex tertiary structure with a pocket to hold heme
Normal globin
variants are named by what?
Greek letters
What kind of structure is hemoglobin?
A tetramer of protein chains, 2 of each type
What are the heme moiety
Iron
Glycine
Succinyl Co-A
What are the global moiety
Amino acids
When does hemoglobin synthesis occur
Pronormoblast stage through reticulocyte stage
Where in the cell is heme produced
Mitochondria
Cytoplasm
Where in the cell is globin produced
Ribosomes
What is the rate limiting step and regulatory point of heme synthesis?
Glycine + succinyl CoA -> Delta ALA
What is the first step of heme synthesis?
Glycine + succinyl CoA –> Delta ALA
What is the second step of Heme synthesis?
Delta ALA moves into cytoplasm
What is the third step of Heme synthesis?
2 Delta ALA condense into pyrrole, porphobilinogen (PBG)
4 PBG form what kind of structure?
Linear structure
What are the two rings formed after porphobilinogen forms?
Uroporphyrinogen
Coproporphyrinogen
What happens after the formation of coproporphyrinogen in the cytoplasm?
Coproporphyrinogen returns to the mitochondria
What occurs once coproporphyrinogen returns to the mitochondria?
COP undergoes two oxidation steps
COP III –> Protoporphyrinogen IX
PRO IX –> Protoporphyrin IX
What is the final step of heme synthesis in the mitochondria?
Protoporphyrin IX –> Heme by inserting Fe++
Catalyzed by Ferrochelatase
Transferrin
Carrier protein in serum
How many iron does one transferrin carry?
2 Fe++ to cytoplasmic membrane of developing RBC
Once transferrin crosses RBC membrane, what occurs next?
Fe inserted into protoporphyrin IX
OR
Stored as ferritin or hemosiderin
Iron storage forms
Ferritin
Hemosiderin
What can cause iron deficiency anemia
Heme synthesis stops at protoporphyin
Insufficient hgb, small RBC
Porphyrias
Congenital defects of heme synthesis enzymes
Substrates
Accumulate
Prior to defect
Products
Insufficient
After defect
What can cause defects in heme synthesis
Congenital defects/Porphyrias
Lead poisoning
Accumulated substrates can cause what problems
Photosensitivity
Neuropathy
Red urine
Where does globin synthesis occur
On ribosomes
When does globin synthesis occur
Same time as heme synthesis
What stimulates globin synthesis
The presence of heme
Globin chains in an adult
Alpha
Beta
Delta
Gamma
Globin chains in embryo
Zeta
Epsilon
Each molecule of hemoglobin moiety
4 heme
2 globin chains (one type)
2 globin chains (another type)
Normal adul hemoglobin’s contain what globin chains
2 alpha
2 of either B, Y, d
Normal adults have a mixture of what types of hemoglobin
Hgb A1
Hgb A
Hgb F
Hgb A1 is composed of
a2 B2
What percent of hgb is A1? In an adult
92-95%
Hgb A1 subset
Glycosylated Hgb (aka Glycated Hgb)
How does Glycosylated/Glycated Hgb appear?
a2B2 + Glucose attached somewhere
Where is the glucose attached on Hgb A1c?
N-terminus of the beta chain
How long does the glucose remain attached to HgbA1c beta chain?
The rest of the RBCs life
Irreversible
What is an excellent indicator of long term blood glucose levels
Hgb A1c
What percent of total A1 hgb is hgbA1c?
4-6%
What is Hgb A2 comprised of?
a2 d2
What percent of total hgb in a normal adult is a2d2?
2-3% of total hgb in a normal adult
Hgb F composition
a2 Y2
What percent of Hgb is HgbF in a normal adult?
1-2%
Alpha gene on chromosome 16 –>
Alpha chain of 141 aa
Beta gene on chromosome 11 –>
beta chain of 146 aa
What can lead to an abnormal hemoglobin?
The substitution of even ONE amino acid
Where are embryonic hemoglobins detectable?
Yolk sac and liver
When should embryonic hemoglobins be undetectable?
~3 months gestation
Gower 1
Z2 e2
Gower 2
a2 e2
Portland
Z2 Y2
Hemoglobin F
a2 Y2
What percent of fetal hemoglobin if Hgb F?
90-95%
What form of hgb has higher oxygen affinity than A1?
HgbF
When does Hgb A1 synthesis begin?
~35 weeks gestation
How long does residual Hgb F production remain?
For life
When does adult pattern of hemoglobins appear?
1 year of age
