Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Foundations Exam 2 > Heme Synthesis > Flashcards

Heme Synthesis Flashcards

1
Q

highest rate of heme synthesis are in _____ cells in _____ and _____

A

erythroid cells of bone marrow and liver

in liver: heme is mainly used by cytochrome p450 enzymes, and levels depend on demand (CYP enzymes are inducible)

erythroid cells: heme used for hemoglobin synthesis, relatively constant

*note that virtually all tissues synthesis heme though

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

how is heme used in the liver

A

used by cytochrome p450 enzymes

heme levels depend on demand (CYP enzymes are inducible)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

when does heme synthesis stop in erythrocyte life cycle

A

mature RBC lack organelles (including mitochondria), so heme synthesis stops when RBC mature

*reticulocytes: immature RBC that contain residual ribosomes/rRNA (account for 1-2% of total RBC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what is the rate-limiting step of heme biosynthesis?

A

first step:
succinyl CoA + glycine —> delta-aminolevulinic acid
via ALAS

ALAS (aminolevulinate synthase): requires PLP (vit B6 / pyridoxal phosphate)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

ALAS, the rate limiting step of heme biosynthesis (in the first step), requires _____

A

PLP (pyridoxal phosphate), aka Vitamin B6

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what is the difference between the 2 isozymes of ALAS?

A

ALAS - rate limiting first step enzyme of heme synthesis (requires PLP/Vitamin B6)

ALAS1: in liver, where heme levels change based on demand

ALAS2: in erythroid cells, where heme synthesis is relatively constant (for hemoglobin production)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what are 2 ways by which ALAS1 levels are regulated in the liver?

A

ALAS1: first step and rate-limiting step of heme synthesis in the liver (requires PLP/VitB6)

  1. negative feedback by heme (multiple mechanisms)
  2. insulin and glucose (carbohydrates) repress ALAS1 transcription
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what are the 4 M’s that can induce ALAS1 transcription in the liver?

A

remember that ALAS1 is first and rate limiting step of heme synthesis (requires PLP/VitB6)

induce transcription of ALAS1:
1. medication
2. menstruation
3. malnutrition
4. maladies (being sick, stress, etc)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

how do medications induce ALAS1 expression in the liver?

A

ALAS1 - first/rate limiting step of heme synthesis (requires VitB6/PLP)

medications induce synthesis of heme-containing cytochrome p450 —> increases heme demand

results in decrease in heme concentration in the cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

how is ALAS2 regulated in erythroid cells?

A

ALAS2 is first and rate limiting step of heme synthesis (requires PLP/VitB6)

low iron concentration: IRP (iron regulatory protein) binds IRE (iron response element), which blocks mRNA translation —> low production of ALAS2

high iron concentration: iron binds IRP (preventing it from binding IRE), uninhibiting translation —> increase ALAS2 production

[remember that ferritin is also regulated through IRE-IRP system, and downregulated when iron is low]

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

how would a vitamin B6 deficiency affect heme synthesis?

A

would decrease heme synthesis in both liver (ALAS1) and erythroid cells (ALAS2) because ALAS requires PLP/Vitamin B6

ALAS is first and also rate-limiting step of heme synthesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

sideroblastic anemia

A

ring sideroblasts: in bone marrow, nucleated erythroblasts with a ring of blue granules (due to iron-laden mitochondria) —> sign of impaired heme synthesis

mature RBC in circulation are microcytic (smaller) and hypochromic (pale) because of shortage of hemoglobin

[in blood smear, RBC look paler because the central pallor region is enlarged]

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

how does a blood smear of thalassemia look, and reminder of what thalassemia is caused by?

A

thalassemia: genetic mutation in either alpha or beta globin

blood smear - appears as hypochromic microcytic anemia (RBC are smaller and/or pale)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what is 1 hereditary and 3 acquired causes of sideroblastic anemias?

A

hereditary: X-linked ALAS2 mutation

acquired: drugs (isoniazid for TB), toxins (alcohol), Vitamin B6 deficiency (pyridoxine/PLP)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

X-linked sideroblastic anemia

what is a possible complication resulting from the body’s attempt to compensate?

what is the treatment?

A

XLR mutation in ALAS2 (rate-limiting step in heme synthesis in erythroid cells)

sideroblasts seen in bone marrow due to iron excess (blue granules)

iron overload occurs from reduced usage and increased absorption (compensation) —> heart and liver cirrhosis

treatment: pyridoxine (B6), since it is cofactor for ALAS2

symptoms: fatigue, dizziness, conjunctival/palm/nail pallor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

how does lead poisoning affect heme synthesis?

A

lead inhibits 2 key enzymes in heme synthesis:
1. ALAD (step 2) - more sensitive
2. Ferrochelatase (step 8)

*would see an increase in ALA (delta-aminolevulinic acid, product of ALAS - committed step) without increase in next product (PBG)

17
Q

heme is a common prosthetic group. what is its structure?

A

derivative of porphyria - cyclic, formed by 4 pyrrole rings linked by methenyl bridges

iron/Fe2+ found in center of heme

heme is also known as Fe protoporphyrin IX

18
Q

how does lead poisoning present?

A

headache, nausea, irritability, lethargy, anorexia, constipation/diarrhea (lead colic)

lead lines in gums, long bone

neuropathy (foot or wrist drop)

developmental delays, memory loss, learning difficulties

[remember that lead poisoning inhibits 2 enzymes in heme synthesis - ALAD and Ferrochelatase]

19
Q

how is lead poisoning diagnosed? (5)

A
  1. measure blood lead levels (BLL)
  2. accumulation of ALA without increase in PBG (steps in heme synthesis - lead blocks ALAD enzyme in between these)
  3. zinc protoporphyrin in RBC
  4. basophilic stippling in peripheral smear (looks like spots - rRNA aggregates in RBC)
  5. microcytic anemia (small RBC)
20
Q

other than removing the source of lead, what is a treatment of lead poisoning?

A

lead chelators

21
Q

what are the enzymes in heme biosynthesis? and where does heme biosynthesis take place in the cell?

challenge question

A

mitochondria;
1. ALAS (rate limiting)
cytosol:
2. ALAD (inhibited by lead)
3. PBGD
4. UROS
5. UROD
mitochondria:
6. CPOX
7. PPOX
8. FECH (inhibited by lead)

22
Q

porphyrias

A

rare inherited or acquired metabolic disorders caused by mutations in enzymes of heme biosynthesis

results in accumulation/excretion of heme precursors and/or porphyrins

clinical presentations differ - can be acute (triggered by something) or non-acute (constant symptoms), primary tissues involved differ

23
Q

how does solubility change throughout the heme synthesis pathway?

A

earlier in the pathway, intermediary products are water soluble and can be excreted in urine (porphyrin precursors)

as more decarboxylation steps occur, water solubility degrees as heme biosynthesis pathway progression —> excretion shifts from urine to bile (porphyrins - become colored by oxygen, so urine or bile may be colored)

24
Q

acute intermittent porphyria (AIP)

A

deficiency in hepatic PBG Deaminase (PBGD)
—> ALA and PBG accumulate (heme synthesis) —> neurotoxic

  • acute, so presents episodically
  • onset usually 20s/30s
  • 2nd most common porphyria

abdominal pain, neuropsychiatric symptoms, peripheral neuropathy, red urine (port-wine)

*5Ps: Pain (abdominal), Psychiatric, Peripheral neuropathy, Port-wine urine, PBGD deficiency

25
Q

what precipitating factors can cause an acute episode of AIP (acute intermittent porphyria)?

A

4 M’s that induce ALAS1 (first step of heme pathway, before PBG Deaminase which is deficient in AIP):
1. medication
2. menstruation
3. malnutrition
4. maladies

26
Q

what are 3 treatment options of acute intermittent porphyria (AIP)?

A

remember that AIP is PBGD deficiency

  1. avoid precipitating factors (4 M’s that induce ALAS)
  2. glucose (carb) loading - glucose/insulin repress ALAS1
  3. hemin/hematin: pharmacologically stable form of heme (inhibits ALAS1 via negative feedback)

*keep in mind that AIP only affects heme in liver, so anemia will not ensue from these treatments

27
Q

Porphyria Cutanea Tarda (PCT)

A

UROD (uroporphyrinogen decarboxylase) deficiency (heme synthesis pathway, step 5)

most common porphyria, onset 40’s/50’s

essentially an acquired disease, some people are just predisposed via genetic deficiency (“familial PCT”)

28
Q

what are 6 factors that can precipitate acquired PCT (porphyria cutanea tarda)

A
  1. liver iron overload - such as patients with hereditary hemochromatosis
  2. chronic liver disease
  3. Hep B/C/HIV
  4. alcohol

also, but less important:
5. sunlight
6. hydrochlorobenzene (fungicide)

29
Q

how does PCT (porphyria cutanea tarda) present?

how is it treated?

A

bullae filled with clear fluid on skin, chronic blistering, phototoxicity

phototoxicity due to tetrapyrrole intermediates of heme pathway that are light reactive —> ROS formation

treatments: avoid environmental exposures (alcohol, tobacco), sunscreen, iron chelator, phlebotomy (bleeding) - reduces iron load

30
Q

how is PCT diagnosed? (porphyria cutanea tarda) - 4

A
  1. coral red urine
  2. isocoproporhyrin in feces (remember later in heme pathway intermediates are not water soluble)
  3. 8-carboxyl or 7-carboxyl porphyrins in serum (indicates UROD defect)
  4. UROD enzyme activity assay or genetic analysis
31
Q

erythropoietic protoporphyria (EPP)

A

mutations in ferrochelatase (last step of heme pathway) —> increased levels of free protoporphyrin IX in RBC

early childhood presentation

severe cutaneous photosensitivity (non-blistering), burning/stinging pain with sunlight

chronic liver disease later in life

may have elevated protoporphyrin in stool, but not urine (at this part of pathway, intermediates no longer water soluble)

32
Q

deficiencies of enzymes earlier in the heme synthesis pathway are more likely to cause ______ symptoms, while deficiencies in enzymes later in the pathway are more likely to cause ______ symptoms

A

earlier in the pathway: neurological symptoms

later in the pathway: photosensitivity and sun explorer produces more severe cutaneous symptoms

33
Q

A blood smear shows microcytic and hypochromic RBC. In the bone marrow, erythroblasts show a ring of blue granules

this is indicative of what?

A

sideroblastic anemia - impaired heme synthesis

34
Q

A patient presents with conjunctival and nail bed pallor, fatigue, and dizziness. The patient has moderate cirrhosis of the heart and liver, which is determined to be caused from an iron overload. Erythroblasts in the bone marrow appear to have a ring of blue granules.

What is going on? How will you treat them?

A

X-linked sideroblastic anemia: XLR mutation in ALAS2 (in erythroid cells)

iron overload due to reduced usage and increased compensatory iron absorption (from diet)

treat them with vitamin B6 (pyridoxine)

35
Q

A patient presents with diarrhea, staining in their gums, foot drop, memory loss, and irritability. Urine analysis shows an increase in ALA. What is going on?

A

lead poisoning - causes increase in ALA without increase in PBG, because lead blocks ALAD enzyme in heme synthesis

staining in gums - lead lines
foot drop - neuropathy
diarrhea - lead colic

36
Q

Pt is a 32yo M presenting sudden onset of with neurovisceral pain, hallucinations and seizures, and peripheral neuropathy. Urine sample appears port-wine colored.

What is going on, and what is one dietary change that can be made to alleviate these symptoms?

A

AIP (acute intermittent porphyria) - deficiency in hepatic PBGD (step 3 of heme synthesis), onset in 20/30s

neurovisceral pain - abdominal
hallucinations/seizures - neuropsychiatric symptoms

urine would show accumulation of ALA or PBG

acute attack due to precipitating factors (4 M’s that induce ALAS1)

treat with carb loading - glucose/insulin repress ALAS1 transcription
(can also administer Hemin/Hematin)

37
Q

Pt is a 47yo F presenting with skin bullae filled with clear liquid and phototoxicity with skin fragility. Urine sample has coral red color and high level of uroporphyrins. Feces sample has high levels of isocoproporphyrin.

What is going on, and what is causing skin damage?

A

PCT (porphyria cutanea tarda): UROD deficiency (heme synthesis), presents 40/50s (essentially acquired)

precipitating factors: liver iron overload, chronic liver disease, Hep B/C/HIV, alcohol

tetrapyrrole intermediates react with light in skin —> ROS, skin damage

38
Q

Pt is a 4yo M with severe cutaneous photosensitivity, non-blistering. Pt complains of burning/stinging pain with sunlight. Urine porphyrin levels are normal.

What may be going on?

A

EPP (erythropoietic protoporphyria): mutations in ferrochelatase (heme synthesis, last step), presents in early childhood

chronic liver disease later in life

increased levels of free protoporphryin IX in RBC (not excreted into urine - but excreted in stool, so may see higher levels here)

39
Q

what is the deficiency, main clinical presentation, and age of onset for:
a. AIP
b. PCT
c. EPP

A

these are all porphyrias - deficiencies in enzymes for heme synthesis

a. AIP (acute intermittent porphyria): PBGD deficiency, 20s/30s, port-wine urine and acute attacks

b. PCT (porphyria cutanea tarda): UROD deficiency, 40s/50s, bullae on skin with blistering and coral-red urine

c. EPP (erythropoietic protoporphyria): mutation in ferrochelatase, early childhood, severe photosensitivity with blistering

Foundations Exam 2 (42 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions