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PA Biochem > L2: Heme Synthesis and Degradation > Flashcards

L2: Heme Synthesis and Degradation Flashcards

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1
Q

What is heme?

A

Final product of the porphyrin biosynthetic pathway consisting of one ferrous (Fe2+) ion in protoporphyrin IX

Heme serves as a prosthetic group for hemoglobin, myoglobin, cytochromes, catalase, nitric oxide synthase, and peroxidase.

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2
Q

Where are the major sites of heme biosynthesis?

A

Erythrocyte-producing bone marrow cells (~85%) and liver (~15%)

Heme synthesis in erythroid cells is relatively constant, while in the liver it varies based on intracellular needs.

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3
Q

What are the structural features of porphyrins that are clinically relevant?

A
  1. Side chains 2. Distribution of side chains 3. Type classification

These features affect the function and relevance in various diseases.

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4
Q

What side chains are found in Uroporphyrin?

A

Acetate (-CH2-COO-) and propionate (-CH2-CH2-COO-)

Uroporphyrin is one of the types of porphyrins with specific side chains.

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5
Q

What side chains are found in Coproporphyrin?

A

Methyl (-CH3) and propionate side chains

Coproporphyrin is another type of porphyrin characterized by its specific side chains.

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6
Q

What side chains are found in Protoporphyrin IX (and heme)?

A

Vinyl (-CH=CH2), methyl, and propionate groups

Protoporphyrin IX is crucial for heme production and has distinct side chains.

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7
Q

How can porphyrin side chains be arranged?

A

Symmetrically or asymmetrically around the four pyrrole rings

Type III porphyrins have asymmetric substitution of side chain order.

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8
Q

What type of porphyrins exist in healthy humans?

A

Type III porphyrins

Type III porphyrins are typically found in normal physiological conditions.

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9
Q

What can Type I porphyrins indicate?

A

They can form and accumulate in some diseases of abnormal heme synthesis

The presence of Type I porphyrins can be a marker for certain pathological conditions.

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10
Q

What are porphyrinogens?

A

Chemically-reduced, colorless precursors of porphyrin

They serve as intermediates in heme biosynthesis between porphobilinogen and oxidized protoporphyrins.

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11
Q

Where do the formation of ALA & Protoporphyrin IX occur?

A

In mitochondria

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12
Q

In which cellular locations do the formation of porphobilinogen & Uroporphyrinogen occur?

A

In the cytosol

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13
Q

What types of cells perform heme biosynthesis?

A

Liver and bone marrow erythropoietic stem cells

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14
Q

Why are mature erythrocytes unable to synthesize heme?

A

They do not have mitochondria

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15
Q

What is the rate-limiting step in heme biosynthesis?

A

Formation of δ-aminolevulinic acid (ALA)

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16
Q

Which two substances provide all carbon and nitrogen atoms in the porphyrin molecule?

A
  • Glycine
  • Succinyl coenzyme A
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17
Q

What enzyme combines glycine and succinyl coenzyme A to form ALA?

A

ALA synthase

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18
Q

What coenzyme is required by ALA synthase?

A

Vitamin B6 (pyridoxal phosphate)

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19
Q

What does ALA dehydratase condense to form?

A

Porphobilinogen

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20
Q

What ion in ALA dehydratase makes it senstive to heavy metals?

A

Zinc

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21
Q

What heavy metal can inhibit ALA dehydratase?

A

Lead

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22
Q

How many porphobilinogen molecules are condensed to form hydroxymethylbilane?

A

Four

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23
Q

What is the first tetrapyrrole produced in the biosynthesis pathway?

A

Hydroxymethylbilane

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24
Q

What is produced when uroporphyrinogen III undergoes decarboxylation?

A

Coproporphyrinogen III

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25
What happens to proprionate side chains in coproporphyrinogen III during heme formation?
They are decarboxylated to vinyl groups
26
What is oxidized to form protoporphyrin IX?
Protoporphyrinogen IX
27
What element binds at the center of protoporphyrin IX to form heme?
Iron (Fe2+)
28
What enzyme enhances the rate of iron incorporation into protoporphyrin IX?
Ferrochelatase
29
What condition can inhibit ferrochelatase and decrease heme biosynthesis?
High blood lead levels
30
What is the role of heme in the regulation of ALA synthase genes?
Heme functions as a repressor of the ALA synthase genes (ALAS) in the liver.
31
What happens to heme when its synthesis exceeds the availability of globins?
Excess heme is converted to hemin with the oxidation of ferrous (Fe2+) to ferric (Fe3+).
32
How does hemin affect hepatic ALA synthase activity?
Hemin inhibits hepatic ALA synthase activity by decreasing ALAS1 mRNA stability and reducing its import into mitochondria.
33
What effect do low iron levels have on ALA synthase activity in erythroid precursor cells?
Low iron levels reduce ALA synthase activity by repressing ALAS2 mRNA translation.
34
Which class of drugs can increase hepatic ALA synthase activity?
Barbiturates, such as Phenobarbital, can increase hepatic ALA synthase activity.
35
What is the role of the microsomal cytochrome P450 (CYP450) mono-oxygenase system?
The CYP450 system is involved in the hydroxylation and detoxification of aromatic and aliphatic compounds.
36
What happens to heme levels when CYP450 proteins are synthesized in response to drug exposure?
Utilization of heme increases and hepatic heme (and hemin) levels decrease.
37
What is the process called when ALA synthesis increases due to low heme levels?
De-repression.
38
How does lead exposure affect heme biosynthesis?
Lead inhibits enzymes in heme biosynthesis, such as ALA dehydratase and ferrochelatase.
39
How does lead inhibit ALA dehydratase?
Lead replaces the zinc in ALA dehydratase, resulting in decreased heme synthesis and elevated ALA.
40
What is the result of lead inhibiting ferrochelatase?
Lead prevents the incorporation of Fe2+ into Protoporphyrin IX, resulting in decreased heme synthesis and accumulation of Zn protoporphyrin (ZPP).
41
What are porphyrias?
Porphyrias are rare, inherited (or sometimes acquired) heme biosynthesis enzyme deficiencies.
42
What is a common feature of all types of porphyrias?
Decreased heme synthesis, but usually not anemia.
43
What does heme do as an end-product inhibitor in porphyrias?
Decreased heme results in increased ALA synthase activity via de-repression.
44
What is the significance of the name 'porphyria'?
The name refers to the purple-colored urine seen in some patients due to the abnormal presence of pigment-like porphyrins.
45
What are the two inheritance patterns of porphyrias?
Autosomal dominant and autosomal recessive ## Footnote An example of an autosomal recessive porphyria is Congenital erythropoietic porphyria.
46
How are porphyrias classified?
Erythropoietic and hepatic ## Footnote Hepatic porphyrias can be further classified as chronic or acute. (blood and liver)
47
What are the common symptoms associated with ALA and porphobilinogen accumulation?
Abdominal and neuropsychiatric disturbances (type of porphyria) ## Footnote Symptoms often arise upon administration of drugs that induce CYP450 pathway synthesis.
48
What is the most common porphyria?
Porphyria cutanea tarda (PCT) ## Footnote 20% of cases are familial due to autosomal dominant mutations.
49
What causes photosensitivity in porphyrias?
Porphyrin-mediated formation of superoxide radicals ## Footnote Reactive oxygen species can cause oxidative damage to cell membranes.
50
What factors can influence the clinical expression of familial PCT?
Hepatic iron overload, exposure to sunlight, alcohol ingestion, hepatitis B or C, HIV infections ## Footnote These factors may cause decreased UROD activity.
51
What characterizes acute hepatic porphyrias?
Acute attacks of gastrointestinal, neuropsychiatric, and motor symptoms ## Footnote Some may exhibit photosensitivity.
52
What is the result of decreased heme synthesis in hepatic porphyrias?
Depletion of cells of the ALAS1 end-product inhibitor ## Footnote This causes de-repression of ALAS1 synthesis.
53
What are the symptoms of erythropoietic porphyrias?
Skin rashes and blisters ## Footnote Symptoms appear early in childhood due to accumulation of porphyrin intermediates.
54
What deficiency leads to erythropoietic protoporphyria?
Ferrochelatase deficiency ## Footnote This leads to protoporphyrin IX accumulation.
55
What enzymes are involved in the heme biosynthetic pathway for porphyrias?
Uroporphyrinogen decarboxylase (UROD) and ALA dehydratase and Ferrocheltase ## Footnote Deficiencies in these enzymes are linked to various porphyrias.
56
True or False: Porphyrias only exhibit symptoms in adulthood.
False ## Footnote Symptoms of erythropoietic porphyrias appear early in childhood.
57
Fill in the blank: Porphyrias are classified as __________ or hepatic.
erythropoietic
58
What is the primary treatment for hepatic porphyrias?
Symptom management through intravenous injection of hemin (e.g., Panhematin) ## Footnote Hemin is a heme derivative used to manage symptoms of porphyrias.
59
How can 10% glucose injections affect porphyrin biosynthesis?
They can decrease porphyrin biosynthesis by the liver.
60
What are the management strategies for erythropoietic porphyrias with photosensitivity?
Avoidance of sunlight, phlebotomy, and ingestion of β-carotene.
61
What is the lifespan of a red blood cell (RBC)?
Approximately 120 days.
62
What system is responsible for the degradation of RBCs?
Reticuloendothelial System (RES) or Mononuclear phagocyte system (MPS). Liver, spleen, lymph nodes
63
What percentage of heme degradation comes from hemoglobin in mature RBCs?
Approximately 85%.
64
What is bilirubin?
A breakdown product of heme.
65
What enzyme catalyzes the formation of bilirubin from heme?
Microsomal Heme oxygenase.
66
What two products are released during the oxidation of heme?
Ferric iron and carbon monoxide.
67
What is the role of Billiverdin reductase?
It reduces biliverdin to form bilirubin.
68
What are bile pigments?
Bilirubin and its derivatives.
69
How does unconjugated bilirubin travel in plasma?
It must be noncovalently bound to albumin.
70
What can displace bilirubin from albumin?
Anionic drugs such as sulfonamides and salicylates.
71
What happens when bilirubin reaches the liver?
It dissociates from albumin and enters hepatocytes.
72
What enzyme catalyzes the conjugation of bilirubin?
Bilirubin glucuronyltransferase.
73
What is the solubility difference between unconjugated and conjugated bilirubin?
Conjugated bilirubin is 20,000 X more soluble than unconjugated bilirubin.
74
What is the liver's capacity for conjugating bilirubin per day?
3000 mg of bilirubin per day.
75
What transporters are involved in the secretion of bilirubin into bile?
MRP2/ABCC2 transporters.
76
What happens to bilirubin diglucuronide in the intestine?
It is hydrolyzed and reduced by bacteria to yield urobilinogen.
77
What color compound is formed when urobilinogen is converted in the kidney?
Yellow urobilin.
78
What gives feces their characteristic brown color?
Stercobilin, formed from the oxidation of urobilinogen by intestinal bacteria.

PA Biochem (4 decks)

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