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BMS > Heme Biosynthesis (Flipped Classroom) > Flashcards

Heme Biosynthesis (Flipped Classroom) Flashcards

1
Q

Highest rate of heme biosynthesis?

A

Bone marrow erythroid cells (85%)

  • constant turnover of erythroid cells
  • mature RBCs lack mitochondria, heme synthesis stops when RBCs mature
  • also produced in liver
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2
Q

Heme produced in liver mainly for

A

Synthesis of CYP450 class of enzymes

Function of enzymes:

1) phase I liver detoxification
2) detoxify xenobiotic stuff/chemicals/etc to H2O,O2
3) bilirubin metabolism (product of heme breakdown!)
4) synthesis of: cholesterol, bile/bile acids, vitamin D

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3
Q

Porphyrin precursors

A

1) ALA (Aminolevulinic acid)
2) PBG (Porphobilinogen)

~molecules before we make the first pyrrole molecule~

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4
Q

Porphyrins

A
  • H2O soluble
  • excreted & measured in urine
  • biologically inactive
  • OXIDIZED (conjugation system, allows molecules to absorb visible light)–>release of energy products ->ROS that damage tissues
  • COLORED
  • these accumulate in urine and we can measure them to distinguish between different types of porphyrias (spectrophometric & fluorescent properties)
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5
Q

Porphyrinogens

A

-4 pyrrole molecules
—–>condensed in reduced form, colorless
-biologically ACTIVE
-large
-aqueous solubility depends on # of carboxylic acid side chains
Ex: least soluble: 2C, protoporhyrin excreted in feces

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6
Q

Uro-

A

Urine

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7
Q

Copro-

A

Feces

-much less water soluble and is excreted in feces as well as in urine

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8
Q

Sterco-

A

-feces

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9
Q

Committed and regulated step of heme biosynthesis

1) location?
2) enzyme/cofactors required?

A

Succinyl CoA+ glycine –> d-ALA

1) mitochondria
2) ALAS (d-aminolevulinic acid synthase), pyridoxal phosphate (inhibited by Fe)

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10
Q

ALAS1

A

Housekeeping & liver

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11
Q

ALAS2

A

Erythroid specific

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12
Q

When is 1st pyrrole molecule made in heme biosynthesis?

  • location?
  • Enzyme?
  • inhibited by?
  • H20 soluble?
A

D-ALA—> PBG

-cytoplasm

Enzyme: d-ALA dehydrase (ALAD) aka PBG synthase

  • contains zinc
  • inhibited by Pb
  • H20 soluble, excreted in urine (for following, H20 solubility decreases bc of decaboxy steps; excreted in bile)
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13
Q

Mitochondrial enzymes in heme biosynthesis

A

ALAS, coproporphyrinogen oxidase, protoporhyrinogen oxidase, ferrochelatase

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14
Q

Ferrochelatase is inhibited by

A

Pb

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15
Q

Allosteric feedback inhibition of. ALAS by

A

Heme
–>inhibition of newly synthesized ALAS protein transport from cytosol to mitochondria

Insulin, glucose, carbohydrate loading

Drugs: hemin, he matin (pharmacological analogs of heme, oxidized analogs of Fe3+)

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16
Q

Induction of transcription of ALAS1 by:

A

4M’s

1) medication (barbs, alcohol, steroids, sulfa antibiotics); these are metabolized by CYP450 enzymes
2) menstruation (any bleeding)
3) malnutrition (starvation, dieting)
4) maladies (stress, trips, exams, infection)
* **somehow these decrease HEME so that is why ALAS1 transcription is induced!!!

Less heme –> promote its synthesis

17
Q

What induces ALAS-1 transcription?

A

Peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1A)

—> insulin, glucose, heme inhibits it!

PGC-1a is a coactivator of nuclear receptors & transcription factors

18
Q

Regulation of ALAS2 in _____ cells

A

Regulation of ALAS2 in erythroid cells

There is a repression of translation by low iron content

  • translational repression of ALAS2 by IRE in 5’ UTR
  • dec Fe promotes binding of IRP to IRE –> ALAS2 mRNA translation is inhibited
  • inc FE promoted unimpressed translation; nothing bound to IRE, ALAS2 mRNA translation good to GO
  • ->ensures ALAS2 made only when sufficient iron available for heme synthesis
19
Q

2 common features of sideroblastic anemia

A

1) ring sideroblastic in bone marrow (due to excessive accumulation of iron in mitochondria)
2) impaired heme biosynthesis

20
Q

What do mature RBCs look like in sideroblastic anemia?

A

1) microcytic (smaller than normal)

2) hypo chromic (pale due to shortage of hemoglobin)

21
Q

Congenital X-Linked Sideroblastic Anemia

A
  • hereditary
  • erythroid specific
  • ALAS2 mutation
  • —->reduced production of heme and excessive accumulation of iron in cells
22
Q

Mitochondrial Cytopathy (sideroblastic anemia)

A
  • hereditary

- abnormality in mitochondrial DNA (mtDNA)

23
Q

Myelodysplasia

A
  • acquired sideroblastic anemia

- mtDNA point mutations

24
Q

Drugs that result in acquired sideroblastic anemia

A
  • isoniazid (for tuberculosis)
  • —–> decrease active form of pyridoxal phosphate

-Ethanol

25
Q

Toxins & nutritional stuff that can cause an acquired sideroblastic anemia

A

Toxin: lead (inhibited ALAD, aka PBG synthase)

Nutritional: pyridoxine deficiency (required for ALAS)

26
Q

What 2 key enzymes does LEAD inhibit of heme synthesis

A

1) ALAD (d-ALA –> PBG)
2) Ferrochelatase (Protoporphyrin IX —> Heme)

**** ferrochelatase is less sensitive than ALAD to the effects of lead

27
Q

Treatment of lead poisoning

A

-lead chelators

—>Bind lead & lead is excreted in urine

Chelators:

1) desferrioxamine mesylate
2) sodium calcium edetate
3) penicilliamine

28
Q

Mechanism of lead poisoning

A

Inhibits ALAD and ferrochelatase

—> accumulation of ALA

29
Q

Deficiency in Acute intermittent Porphyria

A

PBG-Deaminase aka hydroxymethylbilance synthase of uroporphyrinogen I synthase

30
Q

Deficiency in Porphyria Cutanea Tarda

A

Uroporphyrinogen decarboxylase

31
Q

Deficiency in Erhythropoietic Protoporphyria

A

Ferrochelatase

32
Q

Substrate accumulation in AIP

A

PBG

Solubility increase –> greater neurological symptoms

33
Q

Substrate accumulation in PCT

A

Uroporphyrinogen

Photo sensitivity increase

-blister formation, hypertrichosis for skin with highest sun exposure

34
Q

Substrate accumulation in Erhythropoietic Protoporphyria

A

Protoporphyrin IX

Extreme cutaneous photo sensitivity burning stinking pain w sunlightq

35
Q

Treatment of AIP

A

He matin/hemin, glucose

Want to inhibit ALAS

36
Q

Treatment of PCT

A

Phlebotomy, Chelation

Want to reduce Fe2+ stores, reduce UROD inhibition

37
Q

Treatment for EPP

A

Sun avoidance

38
Q

What inducers heme synthesis

A

P450 drugs, Alcohol, etc.

4Ms

BMS (7 decks)

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