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Flashcards in Heme Biosynthesis Deck (110):
1

Formed by linking 4 pyrole rings

Heme

2

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

-arangment of side chains is important to activity

Methyl, vinyl, or propionate

3

What are the major components of Heme?

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

4

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

cytochrome P450 class of enzymes

5

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

Liver Cytochrome P450

6

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

Water and Oxygen

7

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

Liver Cytochrome P450

8

What are the porhpyrin precursors and what are their characteristics?

Aminolevulinate(ALA) and Porphobilinogen (PBG)
-water soluble
-excreted and measured in urine
-biologically inactive

9

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

Porphyrinogens

10

Are porphyrinogens biologically active?

Yes

11

Excreted in urine

Uroporphryinogen

12

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

Coproporphyrinogen

13

Excreted and measured in feces

Stercoporphyrinogen

14

Molecules detected and measured in clinical laboratories

-Oxidized

Porphyrins

15

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

Absorb visible light

16

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

Reactive oxygen species

17

Heme biosynthesis takes place in the

Cytoplasm and mitochondria

18

How many enzymes catalyze heme biosynthesis?

8

19

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

Mitochondria

20

What have the highest rates of heme biosynthesis?

Bone marrow erythroid cells and the liver

21

85% of heme is synthesized in

Bone marrow erythroid cells

22

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

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

23

Mitochondira are progressively lost throughout erythroid maturation through

Autophagy

24

What is the committed step of heme biosynthesis?

Step 1:

Succinyl CoA + Glycine ---> delta ALA

25

The committed step of Heme biosynthesis is catalyzed by?

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

26

What happens in the first step of Heme biosynthesis?

-Committed step
-Highly regulated

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

27

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

Porphobilinogen (PBG)

28

The second step of heme biosynthesis is catalyzed by

-Zinc containing enzyme

ALA dehydratase (PBG synthase)

29

ALA dehydratase is inhibited by?

Lead

30

The first precursor to pyrrole is synthesized in the

2nd step

31

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

PBG deaminase

32

Once synthesized, hydroxymethylbilane has what two main fates?

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

33

Catalyzes an intramolecular rearrangement and ring closure

URO III synthase

34

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

Protoporphyrin IX

35

Protoporphyrin IX is converted into Heme by

Ferrochelatase

36

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

Ferrochelatase

37

Ferrochelatase is inhibited by

Lead

38

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

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

39

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

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

40

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

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

41

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

Heme, Hemin*, and hematin*

*pharmologically by stable forms of heme

42

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

Heme

43

What represses the transcription of ALAS?

Heme, Glucose, and Insulin

44

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

-a coactivator of nuclear receptors and transcription factors

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

45

Inhibit PCG-1α, thereby inhibiting ALAS transcription

Heme, Insulin, and Glucose

46

What are the "4M's" that induce transcription of ALAS 1?

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

47

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

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

48

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

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

49

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

Repression of translation of ALAS2

50

Describe how low iron cellular content through an IRE represses transcription

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

51

ALAS 1 catalyzes the first step of heme synthesis in the

Liver

52

ALAS 2 catalyzes the first step of heme synthesis in the

Erythroid cells

53

What are three abnormalities in Heme synthesis

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

54

Heterogeneous group of disorders with 2 common features

Sideroblastic Anemia

55

What are the two common features of sideroblastic anemia?

1.) Ring sideroblasts in the bone marrow
2.) Impaired heme biosynthesis

56

Abnormal normoblasts with excessive accumulation of iron in the mitochondria

Ring sideroblasts

57

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

Sideroblastic anemia

58

Sideroblastic anemia disturbs

Mitochondrial metabolism

59

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

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

60

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

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

61

Lead inhibits which two key enzymes in heme synthesis?

ALA dehydratas(ALAD) and Ferrochelatase

62

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

ALAD

63

How can you treat lead induced sideroblastic anemia?

-bind lead and help it be excreted in urine

Lead chelators

64

What is a moderate in severity presentation of lead poisoning?

Gingival and long bone lead lines

65

What is a more sever consequence of lead poisoning?

Renal failure

66

What are three ways we can diagnose lead poisoning?

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

67

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

ALAD inhibition

68

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

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

69

Pathologies stemming from defects in heme biosynthesis

Porphyrias

70

Most porphyrias behave as

Autosomal dominant genetic diseases

71

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

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

72

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

Enzyme

73

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

Acute Porphyria

74

Accumulation of porphyrinogens in the skin and tissues could indicate

Non-acute porphyria

75

The second most common type of porphyria

Acute intermittent Porphyria (AIP)

76

Acute intermitent Porphyria (AIP) is caused by a

Partial deficiency in PBG deaminase (PBGD)

77

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

Acute intermittent Porphyria (AIP)

78

Unlike other porphyrias, AIP does not result in

Skin lesions

79

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

Primary liver cancer

80

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

Heme

81

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

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

82

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

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

83

What are three treatment options for AIP?

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

84

What is the most common type of Porphyria?

Porphyria cutanea tarda (PCT)

85

PCT results from a deficiency of the hepatic enzyme

Uroporphyrinogen decarboxylase (UROD)

86

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

Porphyria cutanea tarda (PCT)

87

Genetic PCT is referred to as

Familial PCT

88

The clinical onset of PCT typically occurs during the

4th or 5th decade of life

89

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

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

90

What are some symptoms of PCT?

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

91

Blisters filled with clear fluid

Bullae

92

Purple-red suffusion facial skin

Heliotrope facial skin

93

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

Milia

94

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

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

95

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

Photosensitivity caused by porphyrias

96

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

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

97

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

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

98

How can PCT be detected in red blood cells?

UROD enzyme activity assay

99

What are two clinical treatments of PCT?

1.) Chelation with an iron chelator
2.) Phlebotamy (bleeding)

100

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

Phlebotamy

101

Erythropoetic Protoporphyria is caused by mutations in

Ferrochelatase

102

Has an autosomal dominant inheritance and is present in early childhood

-indicated by severe cutaneous photosensitivity

Erythropoetic Protoporphyria (EPP)

103

Later in life, EPP results in

Chronic liver disease

104

Iron inhibits

-Causes PCT

UROD

105

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

PCT

106

Iron inhibits

-Causes PCT

UROD

107

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

PCT

108

What role does vitamin B6 provide in heme biosynthesis?

Vitamin B6 is a cofactors for ALAS

109

Stimulates ALAS2 in erythroid cells

Iron

110

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

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

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