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MCM Test 2 > Heme Biosynthesis > Flashcards

Heme Biosynthesis Flashcards

1
Q

what is heme

A

a heterocyclic porphyrin ring with 4 pyrols (pyrols are a 5 membered ring)

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2
Q

what state is iron in in heme

A

Ferrous state

Fe2+

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3
Q

Iron in heme exists in ferrous state. what would happen if we oxidized it to ferric state

A

Hb inactivates

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4
Q

Heme is located in

A

myoglobin
Hb
cytochromes

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5
Q

Where is heme made?

A
  1. Liver

2. Erythroid cells of the bone marrow

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6
Q

What are the 3 stages of heme synthesis and where does this occur?

A

Phase 1- mitochondria
Phase 2- cytosol
Phase 3- mitochondria

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7
Q

If we have a defect in one stage of heme synthesis, this can cause ________

A

porphyrias

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8
Q

Step 1 of heme biosynthesis

A

ALA is made in the mT.

  1. Glycine + succinyl coA–> aminolevulinic acid (ALA)
    via ALA synthase

*Needs a vitamin b6 cofactor

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9
Q

aminolevulinic synthase

What co-factor does it need?

A

vitamin b6

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10
Q

What happens when there is a deficiency in vitamin b6?

A

If there is a deficiency in vit. B6

  1. Decreased heme synthesis
  2. RBCs are pale
  3. Increase in Fe stores

CAN CAUSE ANEMIA!

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11
Q

What are the two isoforms of ALASynthase

A

ALAS I and ALAS II
ALAS I–> ubiquitous
ALAS II–> only in erythroid in bone marrow.

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12
Q

What is special about ALAS II

A

Has a Fe response element in mRNA.

When Fe is present, it increases transcription and translation

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13
Q

What inhibits ALAS?

A

heme and hemin

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14
Q

What happens once we make ALA

A

Once we make ALA,

it will leave the MT and go into the cytosol so that we can begin phase 2

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15
Q

Phase 2 (general)

A

Occurs in the cytosol
Make porphyrin ring

4 steps

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16
Q

Phase 2

Step 3

A

ALA + ALA= PBG

via ALA dehydratase

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17
Q

Phase 2

Step 4

A

FOURRRRR PBG–> hydroxymethylbilane

via PBG deaminase

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18
Q

Phase 2

Step 5

A

hydroxymethylbilane –> UPR III

via UPR III co-synthase

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19
Q

Phase 2

Step 6

A

UPR III–> CPR III

via UPR decarboxylase

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20
Q

What produce now has all 4 porphryin rings?

A

CPR III

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21
Q

PBG

A

porphobillinogen

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22
Q

UPR III

A

uroporphyrinogen III

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23
Q

CPR III

A

coproporphyrinogen III

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24
Q

which has all 4 rings

A

CPR

coproporphyrinogen III

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25
Q

Which has 1 porphyrin ring?

A

PBG

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26
Q

Step 3

A

Occurs in the MT again

Create protoporphyrin IX and introduce iron to make heme

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27
Q

Step 7

A

CPR III moves into the mT

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28
Q

Phase 3

Step 8

A

CPR III–> protophoryinogen IX

via CPR oxidase

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29
Q

Phase 3

Step 9

A

protophoryinogen IX–> protoporphoryin IX

Via protophoryingoen oxidase

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30
Q

Phase 3

Step 10

A

Protoporphyrin IX + Fe2+–> HEME

via ferrochelatase

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31
Q

Lead poisoning will impact

A
  1. ALA dehydratase

2. Ferrochelatase

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32
Q

Lead poisoning leads to a build up of

A
  1. ALA

2. Protophorphyrin IX

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33
Q

Consequences of lead poisoning

A
  1. Production of heme is lowered, causing anemia

2 NRG production is impacted because cytochromes are not made

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34
Q

Porphyrias

A

INHERITED metabolic disorders caused by defects in heme synthesis

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35
Q

Types of porphyrias

A
  1. acute hepatic –> causes neurological sx

2. erythopoietic –> fucks with skin and photosensitivity

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36
Q

if its a hepatic porphyria, you will have what types of problems?

A

neurological

37
Q

Acute intermittent porphyria

Genetics:
Type of porphyria
Enzyme affected:
Effects:

A

Acute intermittent porphyria

Genetics: Autosomal dominant

Type of porphyria: Hepatic

Enzyme affected: PBG Deaminase (in the liver)

Effects: Excess ALA and PBG, neurological deficit

38
Q

Congenital Eythropoietic Porphyria

Genetics:
Type of porphyria
Enzyme affected:
Effects:

A

Genetics: Autosomal recessive

Type of porphyria: Erythropoietic

Enzyme affected: UPR III Synthase (in blood cells)

Effects: Increase in [UPR I] and its oxidation product [uroporphyrin I] (which produces red color in teeth/urine and skin photosensitivity)

39
Q

PCT (porphyria cutanea tarda)

Genetics:
Type of porphyria
Enzyme affected:
Effects:

A

Genetics: Autosomal dominant

Type of porphyria: Hepatoeythropoietic

Enzyme affected: UPR decarboxylase

Effects: increase in UPR III, wine red urine color

40
Q

Variegate porphyria (CELEBRITY PORPHYRIA)

Genetics:
Type of porphyria
Enzyme affected:
Effects:

A

Genetics: Autosomal Dominant

Type of porphyria: Hepatic

Enzyme affected: protoporphyrinogen IX oxidase

Effect: neurological sx

41
Q

Which porphyria is celebrity?

A

variegate

42
Q

What is the most common porphyria in the US?

A

PCT

porphyria cutanea tarda

43
Q

Congenital Erthrypoietic porphyria

ezyme affected

A

UPR III synthase

44
Q

Congenital Erthrypoietic porphyria

Results

A

Build up of

Uroporphyrinogen I and its oxidation product
uroporphyrin I.

Red urin, red fluorescence and skin photosentivity

45
Q

UDP glucouronic acid is the same thing as

A

UDP-glucourinate

46
Q

in the small intestine,

bilirubin diglucourinate is converted to

A

urobilinogen

47
Q

urobilinogen can then

A

Go to the kidney and be converted to urobilin (excreted as pee

Go to the large intestine –> stercobilin (red/brown)–> POOP

48
Q

Jaundice is also called

A

hyper[biliruben][emia]

49
Q

Jaundice

A

Jaundice occurs when we have high levels of bilirubin in the blood. we have an imbalane between production and excrecretion

50
Q

Unconjugated/indirect bilirubin is located

A

ALL before the liver

51
Q

Conjugated/direct bilirubin is located

A

in and after the liver

52
Q

Normal blood levels of unconjugated/indirect bilirubin

A

0.2-0.9

53
Q

Normal blood levels of conjugated/direct bilirubin

A

0.1-0.3

54
Q

What should we have more of in our blood

A. Unconjugated/indirect bilirubin
B. Conugated/direct bilirubin

A

Unconjugated/direct billirubin blood levels should be 0.2-0.9 mg/dL

55
Q

Jaundice is diagnosed based on

A

conjugation

56
Q

Thus, we have three types of jaundice

A
  1. pre-haptic
  2. haptic
  3. post-haptic
57
Q

Prehepatic jaundice

A

increase levels of unconjugated BR

Normal levels of conjugated BR

58
Q

in prehepatic jaundice, where do all of the problems exist/

A

BEFORE THE LIVER!!!

59
Q

Intrahepatic jaundice

A

can be caused by
Problems with :

  1. hepatic uptake of bilirubin (maybe a problem with the transporter that takes it up)
  2. Conjugations (perhaps with problem with the enzyme in the conjugation)
  3. secretion of the conjugated BR (maybe not being secreted into the gallbladder).
60
Q

Intrahepatic jaundice can be caused by

A

generalized hepatic dsyfunction such as

  1. Liver cirrhosis
  2. Criggler-Najjar syndrome
  3. Gilbert syndrome
61
Q

In intra-hepatic, how are levels of unconjugated/conjuguated?

A

They vary. it depeond on if the problem occured pre-conjugation or post-conjugation

62
Q

In intra-hepatic jaundice, what type of serum ASL and AST would we expect to see?

A

Liver enzymes would be high!

63
Q

In in-hepatic jaundice, how is everything in the GI?

A

Good.

Only problem is in the liver

64
Q

Post-hepatic jaundice will occur when?

A

When we have problem excreting our billirubin.

thus, we have decreased bile flow.

65
Q

Post-hepatic jaundice

______ blood levels of conjugated BR

A

high

66
Q

Post-hepatic jaundice

_________ serum AST and ALT levels

A

normal

67
Q

Post-hepatic jaundice

________ blood levels of unconjugated BR

A

slightly higher

68
Q

Describe the urine of people with post-hepatic jaundice

A

High amounts of conjugated BR in the urine,

so it will be dark.

69
Q

In people with Post-hepatic jaundice, is there urobilinogen in the pee?

A

No. We cannot break down out conjugated BR

70
Q

In people with post-hepatic jaundice, is there stercobilin in the feces?

A

No. We cannot break down our conjugated BR so their stool will be pool.

71
Q

People wilth Post-hepatic jaundice will have
_______ stool
_______ urine

A

PALE stool

DARK urine

72
Q

What is neonatal jaundice

A

Neonatal jaundice is also called physiological jaundice.

neonatal jaundice occurs when newborns have high levels of unconjugated/indirect/free BR in their blood cause they do not have mature enough hepatic pathways to conjugate and excrete their bilirubin. They have a deficiency in UDP- gluconyl transferase

so they have intra-hepatic

73
Q

Neonatal jaundice is also called

A

physiological jaundice

74
Q

In neonatal jaundice, there is a deficiency of _______

A

UDP-gluconyl transferase

75
Q

What is the tx for neonatal jaundice?

A

Phototherapy using a blue fluorescent light. This allows BR to undergo photo conversion to create more soluble isomers.

76
Q

Crigler-Najjar syndrome and Gilbert syndrome are what types of jaundice?

A

Intra-hepatic.

They are both due to problems with UDP-gluconyl transferase enzyme (which permits the conjugation of bilirubin.

77
Q

Neonatal jaundice is due to

A

deficient UDP-gluconyl transferase enzyme

78
Q

Which is worse: Crigler Najjar syndrom or Gilbert?

A

Criggler Najjar is worse because it is the COMPLETE absence of the UDP-GT enzyme

79
Q

Crigler Najjar syndrome

A

Intra-hepatic jaundice
Type 1 (BAD)–> because - caused by the complete absence of the UDP-GT enzyme.
Thus, severe hyperbilirubinemia.
BR will accumulate in the brains of babies and cause kernicturus (encephalopathy and brain damage)

80
Q

Kernicturus

A

Kernicturus is encephalopathy often caused by high amount of BR in the brain of babies. Kernicturus is often seen in Crigler Najjar syndrome

81
Q

Criggler-Najjar Syndrom Type II

A

a less worse (benign) form of Criggler Najjar.

The UDP-GT enzyme has a mutation but has 10% function. So its all good.

82
Q

Gilbert Syndrom

A

Intrahepatic jaundice
relatively common
2-10%
Results from a reduced activity of UDG-GT (has about 25% of its function)

83
Q

Hepatitis

A

Hepatitis is inflammation of the liver that leads to liver dysfunction.

People with Hep have increased levels of conjugated AND unconjugated BR in the blood

Thus, BR will accumulate in skin and eyes and cause a yellow discoloration

Urine is dark tea colored

84
Q

how do we get hepatitis

A

inflammation of the liver that leads to liver disorder

85
Q

What are our levels of BR in hepaptis

A

High levels of CONJUGATED and UNCONJUGATED!!!!!

86
Q

What is is the sequential breakdown of Hb

A 
Hb 
heme (red)
biliverdin (green)
Bilirubin (orange)
Iron (hemosiderin) (red/brown)
87
Q

Color of iron/hemosiderin

A

red brown

88
Q

color of billirubin

A

ORANGE!!!!

MCM Test 2 (12 decks)

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