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Heme Biosynthesis Flashcards

1
Q

Formed by linking 4 pyrole rings

A

Heme

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2
Q

What are the three types of side chains that can be attached to the pyrrole ring?

-arangment of side chains is important to activity

A

Methyl, vinyl, or propionate

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3
Q

What are the major components of Heme?

A
  1. ) 4-linked pyrrole
  2. ) 3 types of side chain
  3. ) Prosthetic group for proteins (tightly-bound cofactor)
  4. ) Chelated Fe2+
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4
Q

Heme produced in the liver is used mainly for the synthesis of the

A

cytochrome P450 class of enzymes

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5
Q

Responsible for phase I liver detoxification and for detoxifying xenobiotic sources of toxicity, chemicals, acohols, and carcinogens

A

Liver Cytochrome P450

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6
Q

When liver Cytochrome P450 detoxifies xenobiotic sources of toxicity, chemicals, acohols, and carcinogens, what does it convert them into?

A

Water and Oxygen

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7
Q

What is responsible for bilirubin metabolism, synthesis of vitamin D, cholesterol synthesis, and synthesis of bile and bile acids?

A

Liver Cytochrome P450

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8
Q

What are the porhpyrin precursors and what are their characteristics?

A

Aminolevulinate(ALA) and Porphobilinogen (PBG)

  • water soluble
  • excreted and measured in urine
  • biologically inactive
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9
Q

Larger molecules whose aqueous solubility varies in part based on the number of carboxylic acid side chains in the molecule

A

Porphyrinogens

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10
Q

Are porphyrinogens biologically active?

A

Yes

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11
Q

Excreted in urine

A

Uroporphryinogen

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12
Q

Much less water soluble than uroporphyrinogen and is excreted in the feces as well as in urine

A

Coproporphyrinogen

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13
Q

Excreted and measured in feces

A

Stercoporphyrinogen

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14
Q

Molecules detected and measured in clinical laboratories

-Oxidized

A

Porphyrins

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15
Q

The oxidation of porphyrins creates an extended conjugation system that allows the molecules to

A

Absorb visible light

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16
Q

Oxidation of porphyrins in the cell is dangerous because the release of the absorbed light produces

A

Reactive oxygen species

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17
Q

Heme biosynthesis takes place in the

A

Cytoplasm and mitochondria

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18
Q

How many enzymes catalyze heme biosynthesis?

A

8

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19
Q

The first and last two steps of heme biosynthesis take place in the

A

Mitochondria

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20
Q

What have the highest rates of heme biosynthesis?

A

Bone marrow erythroid cells and the liver

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21
Q

85% of heme is synthesized in

A

Bone marrow erythroid cells

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22
Q

85% of heme is synthesized in bone marrow erythroid cells because

A

Mature RBC’s lack mitochondria, thus heme synthesis stops upon maturity

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23
Q

Mitochondira are progressively lost throughout erythroid maturation through

A

Autophagy

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24
Q

What is the committed step of heme biosynthesis?

A

Step 1:

Succinyl CoA + Glycine —> delta ALA

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25
Q

The committed step of Heme biosynthesis is catalyzed by?

A

ALA synthase (ALAS 1 (liver) and ALAS 2 (erythroid cells))

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26
Q

What happens in the first step of Heme biosynthesis?

  • Committed step
  • Highly regulated
A

δ-ALA is formed in the mitochondria and transported to the cytoplasm

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27
Q

In the second step of Heme biosynthesis, 2 molecules of ALA condense to form

A

Porphobilinogen (PBG)

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28
Q

The second step of heme biosynthesis is catalyzed by

-Zinc containing enzyme

A

ALA dehydratase (PBG synthase)

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29
Q

ALA dehydratase is inhibited by?

A

Lead

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30
Q

The first precursor to pyrrole is synthesized in the

A

2nd step

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31
Q

In the third step of heme biosynthesis, 4 molecules of PBG are joined into an extended linear tetrapyrrole (hydroxymethylbilane). This reaction is catalyzed by?

A

PBG deaminase

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32
Q

Once synthesized, hydroxymethylbilane has what two main fates?

A
  1. ) Converted to Uroporphyrinogen III (URO III Synthase) then to Coproporphyrinogen III (URO III decarboxylase)
  2. ) At high concentrations, a spontaneous reaction occurs converting it to URO 1 and then COPRO 1
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33
Q

Catalyzes an intramolecular rearrangement and ring closure

A

URO III synthase

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34
Q

Following a series of decarboxylation and oxidation reactions, Coproporphyrinogen III is converted into

A

Protoporphyrin IX

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35
Q

Protoporphyrin IX is converted into Heme by

A

Ferrochelatase

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36
Q

A mitochondrial enzyme that adds an Fe2+ to protoporphyrin IX to form Heme

A

Ferrochelatase

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37
Q

Ferrochelatase is inhibited by

A

Lead

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38
Q

What are the three porphyrins generated in heme biosynthesis (and where are they excreted)

A
  1. ) Uroporphyrin (urine)
  2. ) Coproporphyrin (Urine and bile)
  3. ) Protoporphyrin (Bile)
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39
Q

Water solubility decreases due to decarboxylation steps as the pathway progresses towards heme. Thus excretion progresses from

A

Urine (uroporphyrin: 8 carboxylates) to bile (protoporphyrin: 2 carboxylates)

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40
Q

What are the three mechanisms of regulation of ALAS 1 (the committed step enzyme) in the liver?

A
  1. ) Allosteric feedback
  2. ) Inhibition of newly synthesized ALAS from cytosol to mitochondria
  3. ) Repression of transcription of ALAS
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41
Q

What provides allosteric feedback to regulate ALAS 1 in the liver?

A

Heme, Hemin, and hematin

*pharmologically by stable forms of heme

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42
Q

What inhibits the newly synthesized ALAS protein transport from cytosol to mitochondria?

A

Heme

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43
Q

What represses the transcription of ALAS?

A

Heme, Glucose, and Insulin

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44
Q

What serves as an activator to induce ALAS-1 transcription?

-a coactivator of nuclear receptors and transcription factors

A

Peroxisome proliferator-activated receptor ƴ coactivator 1α (PGC-1α )

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45
Q

Inhibit PCG-1α, thereby inhibiting ALAS transcription

A

Heme, Insulin, and Glucose

46
Q

What are the “4M’s” that induce transcription of ALAS 1?

A
  1. ) Medication
  2. ) Menstruation
  3. ) Malnutrition
  4. ) Maladies (stress, trips, exams)
47
Q

Certain medications are metabolized by cytochrome P450 enzymes, which are hem-containing proteins. What effect then do certain drugs have on heme synthesis?

A

Induce the synthesis of cytochrome P450, thus leading to an increased demand for heme

48
Q

The increased demand for heme caused by induced synthesis of Cytochrome P450 leads to

A

An overall decrease of heme in the liver and subsequent transcription of ALAS synthase and heme synthesis

49
Q

Low iron cellular content through and iron response element sequence (IRE) results in the

A

Repression of translation of ALAS2

50
Q

Describe how low iron cellular content through an IRE represses transcription

A

The IRE forms a translational blockade that prevents iron from binding translational machinery

51
Q

ALAS 1 catalyzes the first step of heme synthesis in the

52
Q

ALAS 2 catalyzes the first step of heme synthesis in the

A

Erythroid cells

53
Q

What are three abnormalities in Heme synthesis

A
  1. ) Sideroblastic anemia
  2. ) Lead (Pb) poisoning
  3. ) Porphyias
54
Q

Heterogeneous group of disorders with 2 common features

A

Sideroblastic Anemia

55
Q

What are the two common features of sideroblastic anemia?

A
  1. ) Ring sideroblasts in the bone marrow

2. ) Impaired heme biosynthesis

56
Q

Abnormal normoblasts with excessive accumulation of iron in the mitochondria

A

Ring sideroblasts

57
Q

Results in mture red blood cells that are smaller than normal (microcytic) and appear pale (hypochromic) because of the shortage of hemoglobin

A

Sideroblastic anemia

58
Q

Sideroblastic anemia disturbs

A

Mitochondrial metabolism

59
Q

What is the major hereditary sideroblastic anemia and what is it’s etiology (cause)

A

Congenital X-linked sideroblastic anemia: caused by ALAS-2 mutation

60
Q

What are three ways to aquire sideroblastic anemia (SA)?

A
  1. ) Drugs (isoniazid for tuberculosis or ethanol)
  2. ) Toxins (lead)
  3. ) Nutritional (pyridoxine deficiency)
61
Q

Lead inhibits which two key enzymes in heme synthesis?

A

ALA dehydratas(ALAD) and Ferrochelatase

62
Q

Which is more sensitive to the effects of lead, Ferrochelatase or ALAD

63
Q

How can you treat lead induced sideroblastic anemia?

-bind lead and help it be excreted in urine

A

Lead chelators

64
Q

What is a moderate in severity presentation of lead poisoning?

A

Gingival and long bone lead lines

65
Q

What is a more sever consequence of lead poisoning?

A

Renal failure

66
Q

What are three ways we can diagnose lead poisoning?

A
  1. ) Accumulation of ALA in urine
  2. ) Zinc protoporphyrin (ZPP) in the blood
  3. ) Basophilic stippling in peripheral smear
67
Q

The accumulation of ALA in the urine, which indicates lead poisoning, is due to

A

ALAD inhibition

68
Q

The presence of Zinc protoporphyrin (ZPP) in the blood, which indicates lead poisoning, is due to the fact that

A

In the absence of iron, iron can not be chelated into protoporphyrin IX, so Zn substitutes for Fe

69
Q

Pathologies stemming from defects in heme biosynthesis

A

Porphyrias

70
Q

Most porphyrias behave as

A

Autosomal dominant genetic diseases

71
Q

What are three porphyrias in heme biosynthesis and which steps do they occur?

A
  1. ) Acute intermittent porphyria (step 3)
  2. ) Porphyria cutanea tarda (step 5)
  3. ) Erythropoietic protoporphyria (step 8)
72
Q

Clinical presentations of Porphyrias differ. They could be presented by a deficient

73
Q

The accumulation of heme biosynthesis intermediates such as ALA and PBG could indicate

A

Acute Porphyria

74
Q

Accumulation of porphyrinogens in the skin and tissues could indicate

A

Non-acute porphyria

75
Q

The second most common type of porphyria

A

Acute intermittent Porphyria (AIP)

76
Q

Acute intermitent Porphyria (AIP) is caused by a

A

Partial deficiency in PBG deaminase (PBGD)

77
Q

The accumulation of ALA and/or PBG can result in peripheral neuropathy and nerovisceral symptoms, which indicate

A

Acute intermittent Porphyria (AIP)

78
Q

Unlike other porphyrias, AIP does not result in

A

Skin lesions

79
Q

Only 10% of people with AIP develop disease, but all are at risk for

A

Primary liver cancer

80
Q

Clinical expression of AIP occurs in response to 4Ms that decrease the livers concentration of

81
Q

What is the consequence of the decrease in cellular levels of heme seen in AIP?

A

Feedback inhibition on ALA synthase is reduced, resulting in more heme biosynthesis

82
Q

With AIP, your urine becomes a dark-brown color. This is the result of

A

PBG in urine which gets oxidized to porphobilin upon being exposed to air

83
Q

What are three treatment options for AIP?

A
  1. ) Avoid precipitating factors (4Ms)
  2. ) Glucose loading
  3. ) Administer HEmin/Hematin (inhibit ALAS synthase)
84
Q

What is the most common type of Porphyria?

A

Porphyria cutanea tarda (PCT)

85
Q

PCT results from a deficiency of the hepatic enzyme

A

Uroporphyrinogen decarboxylase (UROD)

86
Q

Essentially an aquired disease, but some individuals have a genetic (autosomal dominant) deficiency of UROD, which contributes to its development

A

Porphyria cutanea tarda (PCT)

87
Q

Genetic PCT is referred to as

A

Familial PCT

88
Q

The clinical onset of PCT typically occurs during the

A

4th or 5th decade of life

89
Q

What types of factors can influence the expression of UROD and subsequently cause PCT?

A

Alcohol, Hepatic iron overload, sunlight, hep B or C, hydrochlorobenzene

90
Q

What are some symptoms of PCT?

A
  1. ) Bullae
  2. ) Hypertrichosis
  3. ) Heliotropic facial skin
  4. ) sclerodermoid plaque on scalp
91
Q

Blisters filled with clear fluid

92
Q

Purple-red suffusion facial skin

A

Heliotrope facial skin

93
Q

Tiny white bumps or small cysts on the skin which can also represent PCT

94
Q

What causes one of the major signs and symptoms or porphyrias: photosensitivity?

A

The ring shaped intermediates which are reactive w/ light and form oxygen radicals

95
Q

Leads to local tissue damage (on sun exposed skin) including itching and burning sensations and rash-like appearance

A

Photosensitivity caused by porphyrias

96
Q

One of the ways to detect PCT is through the coral red fluoresence of urine, caused by

A

Uroporphyrin to cproporphyrin ratios ranging from 3:1 to 5:1

97
Q

To detect PCT, the fractionation of serum porphyrins can be performs. What would indicate PCT?

A

A predominance of 7-8 carboxyl porphyrin fractions reflecting a UROD defect

98
Q

How can PCT be detected in red blood cells?

A

UROD enzyme activity assay

99
Q

What are two clinical treatments of PCT?

A
  1. ) Chelation with an iron chelator

2. ) Phlebotamy (bleeding)

100
Q

Reduces iron stores, which improves heme synthesis disturbed by iron mediated inhibition of UROD

A

Phlebotamy

101
Q

Erythropoetic Protoporphyria is caused by mutations in

A

Ferrochelatase

102
Q

Has an autosomal dominant inheritance and is present in early childhood

-indicated by severe cutaneous photosensitivity

A

Erythropoetic Protoporphyria (EPP)

103
Q

Later in life, EPP results in

A

Chronic liver disease

104
Q

Iron inhibits

-Causes PCT

105
Q

Which is the only Porphyria that can be acquired and is not genetic?

106
Q

Iron inhibits

-Causes PCT

107
Q

Which is the only Porphyria that can be acquired and is not genetic?

108
Q

What role does vitamin B6 provide in heme biosynthesis?

A

Vitamin B6 is a cofactors for ALAS

109
Q

Stimulates ALAS2 in erythroid cells

110
Q

When an enzyme of heme biosynthesis is inhibited, what is actually excreted and detected to show inhibition?

A

Porphyrins. The inhibition causes accumulation of porphyrinogen, which is oxidized to porphyrin and then excreted

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