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MCM Exam II > Heme Synthesis > Flashcards

Heme Synthesis Flashcards

1
Q

heme has a heterocyclic _____ with ____ present in the center

A

porphyrin ring with iron present in the center

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2
Q

porphyrin rings have 4 _____ containing _____ connected by ____

A

5-membered rings (pyrrole rings) containing nitrogen connected by single carbon bridges

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3
Q

iron is present in what state while bound to Hb

A

ferrous (Fe2+)

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4
Q

what does the oxidation to the ferric state of oxygen do

A

inactivates hemoglobin

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5
Q

where does the biosynthesis of heme primarily occur

A

liver and erythroid cells of bone marrow

- in the mitochondria

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6
Q

what occurs in phase 1 of heme biosynthesis and where does it occur

A

synthesis of ALA from glycine + succinyl CoA

- in the mitochondria

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7
Q

what occurs in phase 2 of heme biosynthesis and where does it occur

A

2 ALA –> PBG
4 PBG –> hydroxymethylbilane –> UPP III –>
CPPP III
- in the cytosol

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8
Q

what occurs in phase 3 of heme biosynthesis and where does it occur

A 
two oxidation reactions:
CPPP III --> PPP IX
PPP IX --> PP IX
insertion of Fe2+:
--> heme
- in the mitochondria
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9
Q

why does deficiency in B6 cause anemia

A

B6 is needed in phase 1 of heme synthesis as a cofactor for ALA synthase glycine + succinyl CoA into ALA

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10
Q

ALA synthase 1 vs ALA synthase 2

A

ALAS1: ubiquitous
ALAS2: only in erythroid cells of bone marrow, has an iron response element in mRNA

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11
Q

ALA synthase

A

enzyme that converts succinyl CoA + glycine –> ALA

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12
Q

how does the concentration of iron affect ALA synthase

A

presence of iron increases its translation and transcription

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13
Q

what is ALA synthase inhibited by

A

heme and hemin

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14
Q

enzyme that catalyzes ALA –> PBG

A

ALA dehydratase

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15
Q

enzyme that catalyzes PBG –> HMB

A

PBG deaminase

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16
Q

enzyme that catalyzes PP IX –> heme

A

ferrochelatase

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17
Q

how does lead poisoning occur

A

inactivation of ALA dehyratase (converts ALA –> PBG) and ferrochelatase (PP IX –> heme)

  • ALA dehyratase contains zinc (metalloenzyme)
  • ferrochelatase contains iron (metalloenzyme)
  • lead replaces the metal to inhibit the enzyme
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18
Q

why do lead poisoning symptoms occur

A

lead poisoning leads to an accumulation of both ALA and protoporphyrin IX

  • ALA is neurotoxic and contributes to neurological symptoms
  • heme production is lowered –> anemia
  • cytochromes aren’t being synthesized –> low energy (fatigue)
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19
Q

porphyrias

  • what are they
  • cause by what
  • acute hepatic porphyrias are characterized by
  • erythropoietic porphyrias are characterized by
A

inherited metabolic disorders

  • caused by defects in heme synthesis
  • acute hepatic: neurological symptoms
  • erythropoietic: skin, photosensitivity
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20
Q

acute intermittent porphyria

  • enzyme defect
  • type of porphyria
  • reaction inhibited
A

defect in PBG deaminase in liver
- hepatic porphyria
(PBG –> hydroxymethylbilane)

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21
Q

congenital erythropoietic porphyria

  • enzyme defect
  • causes buildup of
  • type of porphyria
  • reaction inhibited
A

defect in UPP III synthase in erythrocytes
- build up of UPP 1 and oxidation product UP 1
- erythropoietic porphyria
(HMB –> UPP III)
- SX: red urine, red teeth, RBC destruction, skin photosensitivity

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22
Q

porphyria cutanea tarda

  • enzyme defect
  • type or porphyria
  • reaction inhibited
A

defect in UPP decarboxylase
- hepatoerythropoietic porphyria
(UPP III –> CPPP III)

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23
Q

variegate porphyria

A

defect in PPP oxidase
(hepatic porphyria)
(PPP IX –> PP IX)

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24
Q

symptoms of variegate porphyria

A
  • being a celebrity
  • abd pain, delirium, hallucinations, convulsions
    ex: king george III, queen anne, vincent van gogh
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25
Q

what handles heme degradation

A

reticulo-endothelial system

26
Q

what happens to globin and heme during degradation

A

globin –> broken down into amino acids

heme –> removed for degradation

27
Q

Heme oxygenase

A

removes the bridge between pyrrole rings of heme during degradation
heme –> biliverdin

28
Q

heme degradation

  • what does it require
  • what does it release
  • what happens to iron
  • what is synthesized
A
  • requires oxygen
  • releases carbon monoxide
  • iron is oxidized from ferrous to ferric (2+ –> 3+)
  • biliverdin is synthesized
29
Q

Biliverdin reductase

A

breaks the double bond in biliverdin and adds hydrogen ions to form bilirubin molecule

30
Q

free/unconjugated/indirect bilirubin is soluble or insoluble

conjugated/direct bilirubin is soluble or insoluble

A

unconjugated: insoluble
conjugated: soluble

31
Q

what binds to bilirubin once its made to transport it

- and where is it transported

A

albumin

to the liver

32
Q

how is conjugated bilirubin formed

A

hepatocyte microsomes conjugate BR with glucoronic acid making it soluble

33
Q

UDP-glucose dehydrogenase (UDP-GD)

A

converts UDP-glucose into UDP-glucoronic acid in the start of conjugation of bilirubin

34
Q

UDP glucoronyl transferase (UDP-GT)

A

conjugates free BR with UDP-glucoronic acid to form Br-monoglucoronide and diuronide
***rate limiting step in removal of bilirubin from the blood

35
Q

urobilin

A

causes yellow color of urine

- urobilinogen is reabsorbed and processed by kidneys

36
Q

stercobilin

A

causes brown color of feces

- urobilinogen undergoes further microbial reduction to stercobilin

37
Q

how is urobilinogen formed

A

BR-diglucuronide is released into gall bladder as bile which is secreted into small intestine in response to food –> undergoes microbial reduction in intestine into urobilinogen

38
Q

hyperbilirubinemia

A

jaundice; elevated levels of BR in the blood stream

39
Q

normal blood levels of unconjugated BR

A

0.2 - 0.9 mg/dL

40
Q

normal blood levels of conjugated BR

A

0.1 - 0.3 mg/dL

41
Q

pre-hepatic jaundice

A

caused by increased production of unconjugated BR

  • excess hemolysis (hemolytic anemia)
  • internal hemorrhage
  • capacity of liver to uptake/conjugate/excrete BR is exceeded
42
Q

findings of pre-hepatic jaundice

  • unconjugated BR levels
  • conjugated BR levels
  • ALT and AST levels
  • urobilinogen in urine?
  • direct BR in urine?
A
  • elevated blood levels of unconjugated or indirect BR
  • normal conjugated BR
  • normal ALT and AST
  • urobilinogen present in urine
  • direct BR is absent in urine
43
Q

intra-hepatic jaundice

A

impaired hepatic uptake/conjugation/secretion of conjugated BR

  • generalized hepatic dysfunction
  • liver cirrhosis, viral hepatitis
44
Q

findings of intra-hepatic jaundice

  • unconjugated BR levels
  • conjugated BR levels
  • ALT and AST levels
  • urobilinogen levels in urine
  • conjugated BR in urine?
A
  • variable increases in unconjugated and conjugated BR depending on cause
  • increased ALT and AST
  • urobilinogen levels normal in urine
  • conjugated BR detected in urine
45
Q

post-hepatic jaundice

A 
caused by problems with BR excretion
possible causes:
- obstruction to biliary drainage
- cholangiocarcinoma
- gall stones 
- infiltrative liver disease
- lesions
- drugs
46
Q

findings of post-hepatic jaundice

  • unconjugated BR levels
  • conjugated BR levels
  • AST and ALT levels
  • ALP levels
  • conjugated BR in urine?
  • urobilinogen in urine?
  • stercobilin in feces?
A
  • elevated blood levels of conjugated BR
  • small increases in unconjugated BR
  • normal AST and ALT
  • elevated ALP
  • conjugated BR present in urine (dark urine)
  • no urobilinogen in urine
  • no stercobilin in feces (pale feces)
47
Q

Neonatal jaundice

  • what kind of jaundice
  • enzymatic deficiency
  • elevation in what
A

also called “physiological jaundice”

  • immature hepatic metabolic pathways are unable to conjugate and excrete bilirubin, so there is an elevation in unconjugated bilirubin
  • deficiency in UDP-GT enzyme
48
Q

neonatal jaundice can be aggracated by

A

premature birth

49
Q

how can neonatal jaundice cause encephalopathy (kernicturus)

A

bilirubin diffuses into basal ganglia

50
Q

phototherapy for jaundice

A

newborn is exposed to blue fluorescent light and bilirubin undergoes photoconversion to form more soluble isomers

51
Q

how does intramuscular injection of tin-mesoporphyrin treat jaundice

A

inhibits heme oxygenase which prevents the formation of bilirubin

52
Q

Crigler-Najjar syndrome type 1

A 
deficiency of UDP-GT
- severe hyperbilirubinemia
- BR accumulates in the brains of babies
--> encephalopathy (kernicturus) and brain damage
Tx: blood transfusions
- phototherapy
- heme oxygenase inhibitors
- oral calcium phosphate and carbonate
- liver transplant
53
Q

Crigler-Najjar syndrome type 2

A

mutation in UDP-GT (still have the enzyme but less activity; less severe than type 1)
- 10% activity of enzyme

54
Q

Gilbert Syndrome

A

reduced activity of UDP-GT

  • 2% - 10% of population
  • 25% of enzyme activity
  • serum bilirubin is less than 6 mg/dL but may increase with fasting/stress/alcohol
55
Q

Hepatitis

  • what is it
  • what can cause it
  • what biologically is occurring
  • two notable symptoms
A

inflammation of the liver

  • many causes (viral infection, alcoholic cirrhosis, liver cancer)
  • increased levels of unconjugated and conjugated bilirubin in the blood
  • bilirubin accumulates in skin and sclera
  • dark colored urine
56
Q

red bruise - what breakdown level for Hb

A

heme

57
Q

green bruise indicates what breakdown level for Hb

A

biliverdin

58
Q

orange bruise - what breakdown level of Hb

A

bilirubin

59
Q

reddish/brown bruise- what breakdown level of Hb

A

homosiderin

60
Q

what is the rate limiting step in removal of bilirubin from the blood

A

UDP glucoronyl transferase enzymes in liver conjugate free bilirubin with UDP-glucuronic acid –> bilirubin-monoglucuronide and diglucuronide (BR-MGC and BR-DGC)

MCM Exam II (14 decks)

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