Hemoglobin (Week 7)

Fe2+, prosthetic, outside

Heme

• Ringed molecule with __ center

• Acts as a __ group (cofactor)

• Groups are exposed on __ of the Hb molecule

protein, 4

Globin

• Is the __ component of Hb

• Has __ polypeptide chains total

3

Average lifespan of a red blood cell is _ months

Decrease, rightward

A decrease in pH → __ O2 affinity → __ward shift to oxygen dissociation curve

5, 8

Concentration of 2,3-BPG in normal blood is about _ mmol/L

and concentration in blood from individuals at higher altitudes is _ mmol/L

2,3-BPG, increases, decreases, readily

People adapted to higher altitudes have a higher concentration of __ (Hb molecule)

• __ oxygen dissociation curve and __ affinity of hemoglobin for oxygen

• Oxygen is less bound and can __ release in tissues from help of this enzyme

Mitochondria, cytosol

Heme synthesis occurs with enzymes from the __ and __ (organelles) of the cell

Synthetase, dehydrase, porphobilinogen

In first step of Heme synthesis

• Delta-aminoevulinate __ forms product enzyme delta-aminolaevulinic acid __

• Then delta-aminolaevulinic acid dehydrase forms __from ALA

Heme, protoporphyrin, ferrochelatase

In second step of Heme synthesis

• Formation of __ from __ ring + Fe

• Iron is inserted into protoporphyrin by enzyme __

Lead

Inhibits function of ALA dehydratase/porphobilinogen synthetase and ferrochelatase

Ferrochelatase, ALA d, products, hemoglobin

Lead inhibition of __ is more severe than inhibition of __ (enzymes)

• Inhibition of later stage enzyme causes __ to precipitate

• Result Effect - __ cannot carry oxygen

Heme, photo, red-purple, abdominal, neuropsych

Porphyrias (General)

• Resulting from defects in __ synthesis enzymes

• General Sx include __sensitivity, __-__ urine, skin discoloration, __ pain, __ological disorders

ALA-d, toxicity, tissues

Delta-ALA Dehydratase Porphyria

• Deficiency in __ enzyme → Accumulation of ALA 

  • To RBCs and hepatocytes

• Causes porphyria __ to various __ (systemic sx)

Uroporphyrin I synthase, drugs

Acute Intermittent Porphyria

• Deficiency of __ __ __ enzyme

• Triggered by __ (i.e. barbiturates, antiepileptics)

• Sx - Dark red urine “wine”, abdominal pain, psych symptoms

uroporphyrinogen decarboxylase, 40s-50s, alcohol, sunlight

Porphyria Cutanea Tarda

• Deficiency of __ __ enzyme

• Clinical onset during __ age range; Related to __ use, __ exposure

• Sx - Painful blistering skin lesions that develop on sun-exposed skin, photosensitivity, skin fragile and peeling

protoporphyrinogen oxidase, nongenetic

Variegate Porphyria

• Deficiency of __ __ (enzyme)

• __ factors - drugs, diet, fasting, stress

• Sx - abdominal pain, vomiting, diarrhea, constipation, skin

Skin, sun, scarring, pigment, hair

Emphasized skin sx with variegate porphyria

• __ damage, skin sensitivity to __, __, changes in __ation, increased __ growth

RBCs, protoporphyrins, childhood

Erythropoietic Protoporphyria

• Enzyme deficiency in __ (erythrocytes)

• Accumulated __

• Presents in early __

• Sx - extreme photosensitivity, potential liver disease

ALA d, ferrochelatase, zinc

Lead Poisoning

• Interferes with (2 enzymes) ___ and ___ → Decrease heme synthesis

• Increased use of __ over iron

• Sx - Mimics porphyria, anemia, neurotoxicity, developmental delays, abdominal pain, constipation

Macrophage, Biliverdin, bilirubin, liver

Degradation of Heme

• Heme is taken up by the __ (immune cell) to form __ → forms __

• Bilirubin transferred to __ as bilirubin-albumin complex

Insoluble, indirect, unconjugated

Water-__ (soluble/insoluble) bilirubin / __ (direct/indirect) bilirubin / __ (conjugated/unconjugated) bilirubin

is premature

Soluble, direct, conjugated

Water-__ (soluble/insoluble) bilirubin / __ (direct/indirect) bilirubin / __ (conjugated/unconjugated) bilirubin

is excreted from body via feces/urine

UPD g transferase

Bilirubin is made more soluble by conjugation with glucuronic acid from UDP- glucuronic acid

catalyzed by enzyme Bilirubin UDP _lucuronosyl __

1

Jaundice is observable yellowing from serum bilirubin level higher than _ mg/dL

Pre-hepatic Jaundice

Too much unconjugated bilirubin, not at liver yet

Hepatic Jaundice

Enzymes missing, unconjugated + conjugated bilirubin, transport disturbances of conjugated bilirubin

Post-hepatic Jaundice

Too much conjugated bilirubin past liver (i.e. gallstones)

Polycythemia

Rate of RBC synthesis greater than RBC destruction rate

Anemia

Rate of RBC destruction greater than RBC synthesis rate

Hemoglobinemia

Release of free hemoglobin in plasma

Hemoglobinuria

Release of free hemoglobin in urine

Nephrotic

Excess level of free hemoglobin is __ to the body (i.e. hemolytic transfusion reactions)

16, 11

Alpha-globin chains are made on chromosome __

Beta-globin chains are made on chromosome __

Thalassemia

Disruption of balanced gene expression between alpha and beta globin chains

Silent Thalassemia

If one of 4 genes is defective, silent carrier

Alpha-Thalassemia Minor

 If 2 alpha-globin genes defective, have trait with mild anemia

Bart’s Hemoglobin

• If 3 alpha-globin genes are defective

• Marked anemia, useless oxygen carriers to remaining globins

Hydrops fetalis

If 4 alpha-globin genes are defective; Still-birth

Beta-thalassemia minor

one defective B-globin gene (trait)

Beta-thalassemia major

both genes defective (Colley anemia)

Colley anemia sx

Severe anemia, growth retardation, organomegaly, enlarged skull

(Beta Thalassemia outcome)

immature, age

Hemoglobin synthesis occurs in __ RBCs in the bone marrow

Globin gene expression varries with __

Point, traits, disease

• Abnormal Hb (sickle cell) can be formed if there is a __ mutation in Hb s

  • Heterozygous mutation - sickle cell __

  • Homozygous mutation - sickle cell __

Flexibility, hypoxic, crises

Sickle Cell Disease

• Reduces the __ of RBC membrane and “sickling”

• Result - __ tissue injury from micro-vascular occlusions

  • Sx - painful muscle aches and pains → from tissue damage and occlusive “__”

Bilirubin, jaundice

Patients with sickle cell disease can have a high __ count and visible __ (symptom) from hemolysis

Methemoglobin

Fe3+ made instead of Fe2+ in heme groups (Hb derivative)

Sulfa hemoglobin

• Sulfur-containing drugs binds to hemoglobin

• Takes away space for RBC to carry oxygen

(Hb derivative)

Glycohemoglobin

• Excess extracellular glucose means sugar binds to hemoglobin

• Common in DM; Takes away space for RBC to carry oxygen

(Hb derivative)

d-ALA synthase

What is the rate limiting enzyme for the heme synthesis pathway?

Hepatic

The jaundice type Gilbert's syndrome is classified as which type of jaundice?