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BMS-I > Heme Synthesis > Flashcards

Heme Synthesis Flashcards

1
Q

How are porphyrins produced? What are side chains they can possess?

A

Linking 4 pyyrole rings

3 types of side chains: methyl, vinyl, propionate

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2
Q

What is another name for heme?

A

Fe Protoporphyrin IX

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3
Q

What is heme produced in the liver mainly used for?

A

Synthesis of CYPp450 enzymes.

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4
Q

Why are CYP enzymes important?

A 
Phase 1 Liver detox
Detoxify xenobiotic (toxicit/chemical/alcohols/carcinogens->convert to h20 and 02)
Bilirubin metabolism
Syn. Vit D
Cholesterol synthesis
Syn. Of bile and bile acids
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5
Q

What are the precursors to porphyrin? Are these molecules active?

A

ALA and PBG

Biologically inactive and water soluble (excreted in urine)

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6
Q

What are porphyrinogens? What form are they found in?

A

Larger molecules whose aq. Solubility varies based on number of COOH side chains
Biologically active
Reduced form.

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7
Q

Uro
Copro
Sterco

A

Urine
Feces/Urine
Feces

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8
Q

What are porphyrins? Why are they oxidized?

A

Molecules detected and measured in clinical laboratories (oxidized form)
-> oxidation creates conjugation system that allows molecules absorb visible light.

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9
Q

Why do oxidized porphyrins manifest clinically?

A

Release of absorbed energy produces ROS that damage tissue.

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10
Q

Where does Heme biosynthesis take place in the cell?

A

Both Cytoplasm and mitochondria

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11
Q

What steps of Heme syn. Occur in mitochondria?

A

1st step:
Generation of d-ALA from Succinyl CoA and glycine (via ALAS)

Last 2:
Coproprophyrinogen III —->Proroporphyrinogen (via copro oxidasse) —-> Protoporphyrin IX (via protopor oxidase) —->Heme (via Ferrochelatase+Fe2+)

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12
Q

What steps of hemesyn. occur in cytosol?

A

ALA —-> PBG (via ALAD)
PBG —-> hydroxymethylbilane (via PBGD)
Hydroxymethy…—->uroporphyrinogen III (uroporIII cosynthetase_

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13
Q

What two tissues have the highest rate of heme biosynthesis?

A

Bone marrow erythroid cells (constitutional)

Liver (depends on function desired)

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14
Q

Why do mature RBCs stop syn. Heme?

A

Lack mitochondria. (Progressive loss thru autophagy)

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15
Q

What is the committed and regulated step of Heme syn?

A

Succinyl CoA + glycine —-> ALA (via ALAS)

ALA formed in mitochondria, transported to cytoplasm.

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16
Q

What is difference btwn ALAS1 and ALAS2

A

Housekeeping (liver) ALAS1

Erythroid-specific - ALAS2

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17
Q

What is another name for ALAD (the enzyme responsible for converting ALA to PGB?

A

Porphobilinogen synthetase.

Cytoplasmic.

Zinc containing enzyme, 1st precursor to pyrole synthesized

INHIBITED BY LEAD

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18
Q

What does PBGD synthesize?

A

Hydroxymethylbilane

(Combination of 4 PBG) into a linear tetrapole.

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19
Q

What are the 2 pathways that Hydroxymethylbilane proceed thru?

A

Spontaneous (@ high [ ]) -> URO I —> COPROI

Uroporphyrinogen III (via URO III syn) —-> Coprophyrinogen (via URO III decarb)

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20
Q

Where is ferrochelatase found? What is it’s function?

A

Mitochondiral enzyme.
Adds Fe2+ to protoporphyrin IX to form Heme

INHIBITED BY LEAD (not as important as ALAD inhibition)

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21
Q

What is water solubility of ALA & PGB?

A

Water soluble. Excreted in urine

22
Q

Rank the solubility of Copro/Proto/and Uro porphyrins? Why is there solubility changing?

A
  1. Uro
  2. Copro
  3. Proto

Decarboxylation makes these porphyrins less and less soluble.

23
Q

What is the most important step of heme syn?

A

ALA synthase (committed step)

Succinyl CoA + glycine —-> ALA

24
Q

What ALAS is found in liver cells? Erythroids?

A

Liver: ALAS 1
Erythroids: ALAS2

25
Q

How is ALAS regulated in liver?

A

ALAS-1

  1. Allosteric feedback INHIBITION by HEME/(HEMIN/HEMATIN-stable oxidized forms of heme_
  2. Inhibition of new ALAS protein transport from cytosol to mitochondria
  3. Repression of transcription of ALAS by heme, insulin, glucose (carb loading)
26
Q

How can we induce transcription of ALAS1?

A

4M’S
1. Medication
(Barbituates, alcohol, steroids, SMX/TMP, erythromycin

  1. Menstruation (or any bleeding really)
  2. Malnutrition
  3. Maladies
27
Q

What happen if we take a drug that uses CYP enzymes to break down the medication?

A

Induces CYP enzymes leading to increased demand for heme.

B/c of this increased demand the [heme] in the cell decreases which then turns on transcription of ALAS

28
Q

How do we regulate ALAS in erythroid cells?

A

ALAS2

There is a repression of TRANSLATION of ALAS2 when [iron] cell via an iron response element.

Low iron, iron responsive element binds and prevents translation.

29
Q

If there is low IRON content in your erythroid cell, will you produce ALAS2?

A

NO. Iron is a positive feedback modulator. Your cells are saying why bother producing heme now, we don’t have the iron for it.

30
Q

What are the 2 common features of sideroblastic anemias? (@ erythroids)

A
  1. Ring sideroblasts in bone marrow (excessive iron accumulation)
  2. Mature RBCs appear with hypochromic, microcytic anemia. B/c shortage of Hgb
31
Q

What is an example of a hereditary Sideroblastic anemia?

A

Congenital X-linked (erythroid specific) d/t ALAS-2 mutation.

Disrupts overall heme production. Leads to accumulation of iron.

(Also Mitochondrial cytopathy)

32
Q

What are some types of acquired sideoblastic anemia?

A
  1. Drug Tx : ISONIAZID, ETHANOL
  2. Toxins: Lead (ALAD inhib)
  3. Nutritional: Pyridoxine deficiency

All lead to decreased heme formation which increases Fe deposits.

33
Q

What 2 enzymes in the heme syn. Pathway does Lead inhibit? Which one is more sensitive to effects of lead?

A
  1. ALAD - more sensitive
  2. Ferrochelatase
  3. Pyrimidine 5’-nucleotidase (not as important)
34
Q

How do we treat lead poisoning?

A

Lead chelators:

  1. Desferrioxamine mesylate
  2. Sodium Calcium edetate
  3. Penicillamine
35
Q

what are S/Sxs of Pb poisoning?

A

*important one, look for gingival and long bone lead line.

36
Q

How do we Dx Lead poisoning?***

A
  1. Accumulation of ALA in urine (b.c. ALAD inhibition)
  2. Zinc protoporphyrin in blood* (zn substitutes with iron)
  3. Basophilic stippling in peripheral smear***
37
Q

What is a porpyrias?

A

Pathology stemming from defects in heme biosynthesis. Most are autosomal dominant genetic diseases.

38
Q

What are some of porphyrias that we talk about in class?

A
  1. AIP (Acute intermittent porphyria -PBGD inhib)
  2. Porphyria Cutanea Tarda (PCT - UROD inhib)
    Has genetic and non-genetic factors
  3. Erythropoietic protoporphyria (EP - Ferrochelatase defic?)
39
Q

How do acute vs non-acute porphyrias differ?

A

Acute: accum. Of ALA + PBG +/- decrease of heme
Presents with Neuropsych s/sxs

Non-acute: accum. Of porphyrinogens in skin and tissues —>spontaneous oxidation or porphyrinogens to porphyrins—>photosensitivity

40
Q

What enzyme is inhib in AIP? How common is it?

A

Acute Intermittent Porphyria. 2nd most common.
Partial deficiency in PGBD

1-10/100,000

Presents with neurosymptoms d/t accumulation of ALA/PGB

41
Q

What are S/Sxs of AIP?

A

NO SKIN LESIONS

Only 10% develop diz, but all are at risk for liver diz

Peripheral neuropathy

W>M

42
Q

How do the 4M’s interplay with AIP?

A

4Ms increase transcription of ALAS b/c heme is being used.

This increases ALA/PGB precursors that cannot be broken down fast enough

43
Q

Qualify the color of PGB in urine

A

PGB oxidized to porphobilin –> dark brown ‘port-wine reddish color’

44
Q

How do we Tx AIP?

A
  1. Avoid precipitating factors (4M’s)
  2. Glucose loading
  3. Heme Tx (end the feedback loop)
45
Q

What porphyria results from deficiency of the UROD enzyme? How common is it?

A

Most common

Porphyria Cutanea Tarda (PCT)

Typically autosomal dominant w/ onset in 4th/5th decade

46
Q

How is UROD influenced environmentally?

A
  1. Alcohol
  2. Hepatic Iron overload
  3. Exposure to sunlight
  4. HBV/HCV/HIV
  5. Hydrochlorobenzene
47
Q

What are S/Sxs of PCT?

A

Exposed areas: Blisters (bullae), hair (hypertrichosis), milia,

DARK PINK FLUORESCING URINE

Uro: Coprophyrins 3-5:1

48
Q

What is pathology for skin lesions in PCT patients?

A

Spontaneous oxidation of porphyrinogens to porphryins in the skin

49
Q

How do we Tx PCT?

A

Remove enviromental UROD inhib (Alcohol/tobacco/ERT)
Sunscreen
Chelation with desferrioxamin
Phlebotomy (decreases iron stores)

*remember iron is a positive feedback modulator. If we have lots of iron, we will have lots of heme syn.

50
Q

What is enzyme is deficient in Erythropoietic protoporphyria? (EPP)

A

Ferrochelatase

Autosomal Dominant

Onset in early childhood, severe cutaneous sensitivity

BMS-I (17 decks)

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