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Heme/Lymph > Heme Synthesis & Hemoglobin > Flashcards

Heme Synthesis & Hemoglobin Flashcards

1
Q

What are the functions of heme?

A
  1. Transport of oxygen (hemoglobin, myoglobin)
  2. Electron transport (respiratory cytochromes)
  3. Oxidation-reduction reactions (cytochrome P450 enzymes)
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2
Q
  • Where are the major sites of heme synthesis?
  • Where else is heme synthesized?
  • What cannot synthesize heme?
A
  • Major Sites:
    • bone marrow ⇒ hemoglobin (6-7g hemoglobin are synthesized each day)
    • liver ⇒ cytochrome P450 enzymes (drug detoxificaton)
  • However, heme is also required for other important cellular proteins and is synthesized in virtually all cells,
  • mature erythrocytes do not synthesize heme (lack mitochondria)
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3
Q
  • What are porphyrins?
  • What is the structure of heme?
A
  • Porphyrins: cyclic tetrapyrroles capable of chelating to various metals to form essential prosthetic groups for various biological molecules
  • Heme is predominantly a planar molecule
    • porphyrin derrivative + a single ferrous ion (Fe2+ = reduced form of iron)
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4
Q

Heme = ?

  • What is heme oxidized to?
A

Heme = Ferroprotoporphyrin IX

  • Ferroprotoporphyrin IX (heme) is rapidly autooxidized to ferriprotoporphyrin IX (“hemin”; contains ferric Fe3+ iron)
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5
Q

7 major steps of heme biosynthesis:

  • The 1st and last 3 steps occur in the ….
  • The intermediate steps occur in the ….
A
  • The 1st and last 3 steps occur in the mitochondrion
  • The intermediate steps occur in the cytosol
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6
Q

What is the committed step of heme synthesis?

A

Step 1: condensation of glycine and succinyl-CoA with decarboxylation, to yield 5-aminolevulinate (ALA)

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7
Q

**Step 1 **of heme synthesis:

  • **Reaction: **
  • **Enzyme: **
  • **Location: **
  • **Cofactor: **
A
  • Reaction: condensation of glycine and succinyl-CoA with decarboxylation, to yield 5-aminolevulinate (ALA)
  • Enzyme: 5-aminolevulinate synthase (ALAS)
  • Location: ALAS is localized to the inner mitochondrial membrane
    • encoded by a nuclear gene family
    • must be imported into the mitochondrion
  • Cofactor: pyridoxal phosphate (PLP) dependent enzyme (vitamin B6)
    • Condensation with succinyl-CoA takes place while the amino group of glycine is in Schiff base linkage to the PLP aldehyde
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8
Q

What are the **isoforms **of ALAS?

A

Two isoforms of ALAS:

  1. ALAS1 is the liver isoform
  2. ALAS2 is the erythroid/reticulocyte isoform
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9
Q

Describe the regulation of ALAS1:

A
  • Feedback inhibition by heme or hemin regulates heme biosynthesis in the liver
  • Heme (hemin) exerts multiple regulatory effects on hepatic heme biosynthesis by inhibiting ALAS1 synthesis at both transcriptional and translational levels, as well as its mitochondrial import
  • drugs or metabolites can increase ALAS1 activity
    • **increase the synthesis of cytochrome P450 enzymes **⇒ increasing the demand for heme
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10
Q

Describe the regulation of ALAS2:

A
  • Heme biosynthesis in erythroid cells is NOT regulated by feedback repression of ALAS2 by heme
  • In reticulocytes (immature RBCs), **heme stimulates synthesis of globin **and ensures that heme & globin are synthesized in the correct ratio for assembly into hemoglobin
  • Drugs that cause a marked elevation in ALAS1 activity, such as phenobarbital, do not affect ALAS2
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11
Q

Step 2 of heme biosynthesis:

  • Reaction:
  • **Enzyme: **
  • **Cofactor: **
  • **Location: **
  • Complication:
A
  • Reaction: condensation of two molecules of ALA to form one molecule of porphobilinogen (PBG)
    • ​first pathway intermediate that includes a pyrrole ring
  • Enzyme: ALA dehydratase (ALAD)
  • Cofactor: Zn2+
    • lead and other heavy metals can displace the Zn2+ and eliminate catalytic activity
  • Location: cytosol
  • Complication: lead poisoning
    • increase ALA in urine
    • clinical manifestations that mimic acute porphyrias
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12
Q

Effects of **lead poisoning: **

  • Heme synthesis:
  • Neurologic symptoms:
A
  • Inhibition of ALA dehydratase (aka, porphobilinogen synthase) by lead (Pb2+) results in elevated blood ALA
    • as impaired heme synthesis leads to de-repression of transcription of the ALAS gene
  • ALA is toxic to the brain, perhaps due to:
    • Similar ALA & neurotransmitter GABA (γ-aminobutyric acid) structures
    • ALA autoxidation generates reactive oxygen species (ROS)
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13
Q

Step 3 of heme synthesis:

  • Reaction:
  • Enzyme:
  • Coenzyme:
  • **Location: **
A
  • **Reaction: **
    • Step 1: head-to-tail condensation of 4 porphobilinogen molecules to form hydroxymethylbilane (linear tetrapyrrole)
      • Each condensation ⇒ liberation of one ammonium ion
    • Step 2: hydroxymethylbilane ⇒ uroporphyrinogen III
  • Enzyme: porphobilinogen deaminase (PBGD) or uroporphyrinogen I synthase
  • Coenzyme: uroporphyrinogen III cosynthase
  • Location: cytosol
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14
Q

What is the role of uroporphrinogen III cosynthase?

A
  • The tetrapyrrole can spontaneously cyclize to form uroporphyrinogen I (nonenzymatic) which IS NOT in the normal pathway for heme biosynthesis
  • However, PBGD is tightly associated with a second enzyme uroporphyrinogen III cosynthase (UROS)
    • no enzymatic activity alone
    • serves to direct the stereochemistry of the condensation reaction to yield the uroporphyrin ogen III isomer which IS on the pathway for heme biosynthesis
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15
Q

**Step 4 **of heme synthesis:

  • Reaction:
  • **Enzyme: **
  • Location:
A
  • Reaction: uroporphyrinogen III ⇒ coprophorphyrinogen III
    • decarboxylation of acetate side chains to methyl groups
  • Enzyme: Uroporphyrinogen decarboxylase (UROD)
  • Location: cytosol
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16
Q

Step 5 of heme synthesis:

  • Reaction:
  • Enzyme:
    • What is being converted?
  • Location:
    • What does this imply?
A
  • Reaction: Coproporphyrinogen III ⇒ protoporphyrinogen IX
    • transported into the intermembrane space
  • Enzyme: coproporphyrinogen III oxidase (CPO)
    • converts specific propionic acid side chains to vinyl groups
  • Location: intermembrane space of the mitochondrion
    • implying that its product or protoporphyrin IX must cross the inner mitochondrial membrane because heme is formed within the inner membrane
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17
Q

Step 6 of heme synthesis:

  • **Reaction: **
  • **Enzyme: **
  • **Location: **
A
  • **Reaction: **protoporphyrinogen IX ⇒ protoporphyrin IX (moving double bonds)
  • Enzyme: protoporphyrinogen IX oxidase (PPO)
  • Location: mitochondrion
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18
Q

Step 7 of heme synthesis:

  • **Reaction: **
  • **Enzyme: **
  • **Location: **
A
  • Reaction: Insertion of Fe2+ into protoporphyrin IX to generate HEME
  • ​​Enzyme: ferrochelatase
  • Location: mitochondrion
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19
Q
  • What can inhibit Step 7 of heme synthesis?
  • What will result in a brillant flourescent complex?
A
  • Ferrochelatase is inhibited by lead (lead poisoning; increase protoporphyrin in urine) and is also inhibited during iron deficiency (anemia)
  • In the absence of Fe2+:
    • ​ferrochetalase can insert Zn2+ into the protoporphyrin ring to yield a brilliantly fluorescent complex
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20
Q

What are porphyrias?

A

inherited genetic or acquired (rarely) disorders resulting from deficiency in specific enzymes of the porphyrin/heme biosynthetic pathway

21
Q
  • How are porphyrias classified?
  • What is the pattern of inheritance?
A

Either hepatic or erythroid

  • reflect the principal sites of heme biosynthesis
  • depend on the site of expression of the enzyme defect
  • Inheritance: autosomal dominant
    • Except congenital erythropoietic porphyria (autosomal recessive)
22
Q
  • What causes symptoms seen in porphyrias?
  • What is the difference in location of the defect (early vs. late)?
A
  • Accumulation of intermediates upstream from the enzyme defect **results in the clinical symptoms **associated with the various porphyrias
  • Defects early in the biosynthetic pathway (accumulation of ALA, prophobilinogen) result in neurologic dysfunction
  • Defects later in the pathway (accumulation of cyclic tetrapyrroles, but not prophobilinogen) result in sunlight-induced cutaneous lesions:
    • in the presence of molecular oxygen, UV irradiation of cyclic tetrapyrroles generates reactive oxygen species that can produce cellular damage
23
Q

What are the acute porphyrias?

  • Definiton:
  • Symptoms:
  • Examples:
A
  • Periodic acute attacks
  • Symptoms: abdominal pain, neurologic deficits, psychiatric symptoms, and reddish-colored urine.
  • Examples:
    1. Doss porphyria (ALA dehydratase deficiency)
    2. Acute intermittent porphyria
    3. Hereditary coproporyphyria
    4. Variegate porphyria
24
Q

What are chronic porphyrias?

A
  • Dermatologic diseases that may or may not include the liver and nervous system
  • Examples:
    1. Congenital erythropoietic porphyria (Gunther’s disease)
    2. Erythropoietic porphyria/protoporphyria
    3. Porphyria cutanea tarda
25
Q
  • What enzymes are particularly sensitive to lead poisoning?
  • What will be seen in the urine during lead poisoning?
A
  • Ferrochelatase and ALA dehydratase are particularly sensitive to lead poisoning
  • Protoporphyrin and ALA accumulate in the urine
26
Q

What is the function of hemoglobin?

A
  • Hemoglobin is a specialized protein designed to transport oxygen (O2) from the lungs, a region of high O2concentration, **to peripheral **tissues, **where oxygen is low
  • Metabolism in the peripheral tissues generates CO2 and H+ that are transported back to the lungs, in part, by hemoglobin.
  • O2 has very low solubility in plasma
  • As a consequence, >98% of the O2 that reaches tissues is carried in red blood cells (RBCs) bound to Hemoglobin
27
Q

How is CO2 transport different from O2 transport?

A
  • RBCs contain carbonic anhydrase which catalyzes the rapid reversible hydration of CO2 to carbonic acid (H2CO3).
  • H2CO3 then rapidly and spontaneously dissociates to bicarbonate (HCO3-) and a H+
  • CO2 and HCO3- are soluble in plasma and RBC cytosol
    • most of the CO2 made in tissues returns to the lungs as those species
    • about 14% of the CO2 made is carried bound to Hb
28
Q
  • What is the structure of hemoglobin?
  • What is hemoglobin related to?
  • Which form of Fe can bind O2?
  • Which form of iron cannot bind O2? What is it called?
A
  • **Hemoglobin is a heterotetrameric protein **(αβ)2
  • Both subunits are evolutionarily related to myoglobin
    • a monomeric protein abundant in muscle that is designed to store O2
    • myoglobin: 1 heme groups
    • hemoglobin: 4 heme groups
  • Fe2+ is the ferrous form of iron that is capable of binding O2
  • Fe3+ is the ferric form of iron that CANNOT bind O2 and is present in an INACTIVE form
    • methemoglobin (metHb)
29
Q

Describe the cooperative binding curve for oxygen:

A
  • Myoglobin gives a normal binding curve which is hyperbolic in shape
  • Hemoglobin shows sigmoidal cooperative binding of oxygen
    • direct result of its more complex subunit structure
  • **P50: **partial pressure of oxygen yielding 50% saturation of binding
    • analogous to Km for the binding of substrates to enzymes
30
Q

What kind of cooperativity does hemoglobin exhibit for oxygen?

A

Sequential cooperativity for oxygen binding:

  • binding of oxygen to one subunit induces a conformational change that is partially transmitted to adjacent subunits
  • transmission of the partial conformational change induces an increased affinity for oxygen by these adjacent subunits
    • R=relaxed=high affinity; T=taut=low affinity
31
Q

What happens if CO binds to hemoglobin?

A
  • Carbon monoxide (CO) has ~250-fold higher affinity for Hb than does O2
  • When bound to the heme group of one subunit, it causes all four subunits to “lock” in the R conformation
    • ​limiting oxygen release in peripheral tissues
32
Q

How Does O2 Binding Change the Conformation of a Hb Subunit?

A

Without O2 bound:

  • heme Fe2+ is pulled away from the plane of the porphyrin ring by a His residue of the Hb polypeptide chain
    • a His ring N is bound to the Fe2+

When O2 binds:

  • it pulls the Fe2+ back into the plane of the ring
    • moves the His residue and its whole section of the polypeptide chain
  • That in turn causes the Hb subunits to shift relative to one another to an arrangement that favors the R-conformation
33
Q

Allosteric Regulation of O2 Binding to Hemoglobin:

  • Reduces affinity:
  • Increases affinity:
A
  • **Reduces affinity: **
    • ​H+, CO2, and 2,3-diphosphoglycerate (DPG) ALL can bind to Hb
    • leftward curve shift
  • Increases affinity:
    • **high O2 **
    • causes H+, DPG and CO2 to dissociate from Hb
    • rightward curve shift
34
Q

__ and ___ are heterotropic negative allosteric effectors that decrease the affinity of Hb for O2

A

H+ and CO2 are heterotropic negative allosteric effectors that decrease the affinity of Hb for O2

35
Q

When would you want H+ and CO2 to be high in the blood?

A

During catabolism

  • In the blood of tissues, CO2 and H+ are high
  • HbO2 will release its O2 load ⇒catabolism can continue
36
Q

______ is a positive homotropic allosteric effector of O2 binding

A

Oxygen is a positive homotropic allosteric effector of O2 binding

37
Q

Desribe the Bohr effect:

A

**Reciprocal relationship between O2 and H+ binding **

  • Oxygen is a negative allosteric effector of H+ and CO2 binding
  • Changes in H+ binding result from a shift in the pKa of specific residues (mostly histidines) due to microenvironment effects triggered by conformational changes in the hemoglobin molecule
38
Q

_______________ is a negative allosteric effector of O2 binding

A

2,3-diphosphoglycerate is a negative allosteric effector of O2 binding

39
Q

How does 2,3-DPG alter O2 affinity for Hb?

A
  • **2,3-DPG binds to a specific site in a central cavity​ between the β subunits **
    • Binding is by ionic interactions
  • Special regulatory mechanisms exist in RBCs to control the concentration of 2,3-DPG in order to fine tune the affinity of hemoglobin for O2 in response to changes in metabolism and environment
40
Q

2 important things to notice about the effect of 2,3-DPG on the O2 binding curves:

A
  1. Without any 2,3-DPG
    • ​​Hb would be much more like myoglobin
    • 2,3-DPG stabilizes the T-state, making it easier for Hb to release O2
  2. 2,3-DPG levels increase at high altitudes
    • Because there is less O2 at high altitudes, tissues tend to become somewhat hypoxic
    • By increasing the concentration of 2,3-DPG ⇒ RBC adapt to hypoxia ⇒ easier for O2 to dissociate from Hb
      • anemia and smoking also cause an increase in 2,3- DPG
    • Changes in 2,3-DPG occur over hours and days
      • takes most people a few days to adapt to high altitude
      • exercise or strenuous activity will be difficult until then
41
Q
A
42
Q

How does temperature affect cooperative O2 binding?

A

↑ temp = ↓O2 affinity

↓ temp = ↑ O2 affinity

43
Q
  • Each chromosome __ has two α-globin genes
  • Each chromosome __ has a single β-globin gene
A
  • Each chromosome 16 has two α-globin genes
    • a person has 4 total, each is active and codes ~1/4 of expressed α-globin subunit
  • Each chromosome 11 has a single β-globin gene
44
Q

What are the levels of Hb in normal adult red blood cells?

A
  • ~95% HbA (α2β2)
  • ~3% HbA2 (α2δ2)
  • ~2% HbF (α2γ2)

Note: all forms have an α-globin

45
Q
  • What is the most common hemoglobinopathy?
  • What is the pattern of inheritance?
A
  • most common hemoglobinopathy ⇒ sickle cell anemia
  • pattern of inheritance ⇒ autosomal recessive
46
Q

What causes sickle cell anemia?

A
  • Caused by a point mutation in the adult β-globin gene that causes **substitution of valine (Val) for **glutamic acid (Glu) at amino acid 6
  • Patient’s RBCs containing mainly hemoglobin S (HbS)
    • ​two normal adult α-globin subunits and two sickle adult β-globin subunits.
  • Valine is hydrophobic and its presence creates a sticky patch on deoxyHb
    • leads to polymerization of Hb tetramers into long chains
    • intracellular fibers cause the sickle cell shape and reduced deformability of the RBCs
    • leads to problems in their passage through the microcirculation
47
Q

Rate and extent of polymer formation in a circulating SS RBCs depends primarily on three independent variables:

A
  1. degree of deoxygenation
    • which can be affected by subtle changes in pH, ionic strength and temperature
    • Deoxygenated HbS forms insoluble polymers
  2. intracellular hemoglobin concentration
  3. relative amount of HbF present
    • HbF inhibits polymerization owing to a GLU residue at position 87 of the gamma chain, which prevents a critical lateral contact in the sickle cell fiber
    • HbF decreases with post-partum age but varies from 1-30% of total Hb in sickle cell individuals
48
Q

Define thalassemia syndromes:

A

a heterogeneous group of disorders caused by inherited mutations that decrease the synthesis of adult hemoglobin HbA (α2β2)

49
Q

What are the major categories of thalassemias?

A
  1. β-Thalassemias
    • Caused by mutations that diminish the synthesis of β-globin chains
  2. α-Thalassemias
    • Caused by mutations that result in reduced or absent synthesis of α-globin chains

Heme/Lymph (18 decks)

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