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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
what handles heme degradation
reticulo-endothelial system
26
what happens to globin and heme during degradation
globin --> broken down into amino acids | heme --> removed for degradation
27
Heme oxygenase
removes the bridge between pyrrole rings of heme during degradation heme --> biliverdin
28
heme degradation - what does it require - what does it release - what happens to iron - what is synthesized
- requires oxygen - releases carbon monoxide - iron is oxidized from ferrous to ferric (2+ --> 3+) - biliverdin is synthesized
29
Biliverdin reductase
breaks the double bond in biliverdin and adds hydrogen ions to form bilirubin molecule
30
free/unconjugated/indirect bilirubin is soluble or insoluble | conjugated/direct bilirubin is soluble or insoluble
unconjugated: insoluble conjugated: soluble
31
what binds to bilirubin once its made to transport it | - and where is it transported
albumin | to the liver
32
how is conjugated bilirubin formed
hepatocyte microsomes conjugate BR with glucoronic acid making it soluble
33
UDP-glucose dehydrogenase (UDP-GD)
converts UDP-glucose into UDP-glucoronic acid in the start of conjugation of bilirubin
34
UDP glucoronyl transferase (UDP-GT)
conjugates free BR with UDP-glucoronic acid to form Br-monoglucoronide and diuronide ***rate limiting step in removal of bilirubin from the blood
35
urobilin
causes yellow color of urine | - urobilinogen is reabsorbed and processed by kidneys
36
stercobilin
causes brown color of feces | - urobilinogen undergoes further microbial reduction to stercobilin
37
how is urobilinogen formed
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
hyperbilirubinemia
jaundice; elevated levels of BR in the blood stream
39
normal blood levels of unconjugated BR
0.2 - 0.9 mg/dL
40
normal blood levels of conjugated BR
0.1 - 0.3 mg/dL
41
pre-hepatic jaundice
caused by increased production of unconjugated BR - excess hemolysis (hemolytic anemia) - internal hemorrhage - capacity of liver to uptake/conjugate/excrete BR is exceeded
42
findings of pre-hepatic jaundice - unconjugated BR levels - conjugated BR levels - ALT and AST levels - urobilinogen in urine? - direct BR in urine?
- 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
intra-hepatic jaundice
impaired hepatic uptake/conjugation/secretion of conjugated BR - generalized hepatic dysfunction - liver cirrhosis, viral hepatitis
44
findings of intra-hepatic jaundice - unconjugated BR levels - conjugated BR levels - ALT and AST levels - urobilinogen levels in urine - conjugated BR in urine?
- 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
post-hepatic jaundice
``` caused by problems with BR excretion possible causes: - obstruction to biliary drainage - cholangiocarcinoma - gall stones - infiltrative liver disease - lesions - drugs ```
46
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?
- 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
Neonatal jaundice - what kind of jaundice - enzymatic deficiency - elevation in what
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
neonatal jaundice can be aggracated by
premature birth
49
how can neonatal jaundice cause encephalopathy (kernicturus)
bilirubin diffuses into basal ganglia
50
phototherapy for jaundice
newborn is exposed to blue fluorescent light and bilirubin undergoes photoconversion to form more soluble isomers
51
how does intramuscular injection of tin-mesoporphyrin treat jaundice
inhibits heme oxygenase which prevents the formation of bilirubin
52
Crigler-Najjar syndrome type 1
``` 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
Crigler-Najjar syndrome type 2
mutation in UDP-GT (still have the enzyme but less activity; less severe than type 1) - 10% activity of enzyme
54
Gilbert Syndrome
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
Hepatitis - what is it - what can cause it - what biologically is occurring - two notable symptoms
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
red bruise - what breakdown level for Hb
heme
57
green bruise indicates what breakdown level for Hb
biliverdin
58
orange bruise - what breakdown level of Hb
bilirubin
59
reddish/brown bruise- what breakdown level of Hb
homosiderin
60
what is the rate limiting step in removal of bilirubin from the blood
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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