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biochem term 2 quiz 4 > porphyrin metabolism > Flashcards

porphyrin metabolism Flashcards

1
Q

porphyrins

A

cyclic compounds that bind metal ions tightly
most important = heme
formed by linkage of 4 pyrrole rings through methenyl bridges
two double bonds are conjugated throughout system
ones in humans have asymmetrical rings - can have symmetrical ones in disorders

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2
Q

heme

A

iron-binding compound responsible for:

- O2 transport in blood and muscle
- electron transport in mitochondria
- metabolism of fat-soluble compounds in the liver
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3
Q

pyrrole rings

A

form porphyrins
each ring has two side chains which are distributed around entire porphyrin molecule
Roman numerals specify the arrangement of side chains - asymmetrical when porphyrin is produced under normal physiological conditions

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4
Q

central pocket

A 
of a porphyrin
can be occupied by a metal ion
iron is in heme
cobalt is in cobalamine (vitamin B12)
magnesium is in the chlorophyll in plants
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5
Q

physiological roles of heme proteins (list)

A

as mitochondrial cytochromes - in electron transport chain
in Hb and Mb to transport O2
as catalases
in cytochrome P450 proteins - drug metabolism
removal of H2O2 - catalase

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6
Q

heme proteins as mitochondrial cytochromes

what inhibits?

A

generate membrane H+ gradient required for ATP synthesis via electron transport chain
cyanide poisoning causes irreversible inhibition of mitochondrial cytochrome a3

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7
Q

heme in cytochrome P450 enzymes

A

needed for metabolism of fat-soluble compounds, formation of cholesterol, steroids, and arachidonic acid metabolites

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8
Q

heme in catalase

A

antioxidant enzyme hydrolyzes H2O2

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9
Q

steps in heme synthesis

A

1: ALA synthase catalyzes condensation of glycine and succinyl CoA to make delta-aminolevulinic acid (ALA)
2: ALA dehydrase condenses two molecules of ALA to make pyrrole compound porphobilinogen (PBG)
3: hydroxymethylbilane synthase condenses four molecules of PBG to make hydroxymethylbilane
4: uroporphyrinogen synthase catalyzes ring closure of hydroxymethylbilane to make uroporphyrinogen I
5: uroporphyrinogen III cosynthase isomerizes the D ring side chains of uroporphyrinogen I to make uroporhyrinogen III
6: decarboxylation and oxidation reactions convert uroporphyrinogen III to protoporphyrin IX
7: ferrochelatase catalyzes introduction of iron into protoporphyrin IX to make heme

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10
Q

where is heme synthesized?

A

primarily by liver and bone marrow specific isoforms of the necessary enzymes

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11
Q

ALA synthase

A

enzyme that catalyzes the first step of heme synthesis
condenses glycine and succinyl CoA to make delta-aminolevulininc acid (ALA)
releases CoA and CO2
irreversible reaction
hemin, oxidized form of heme (Fe3+), and glucose suppress transcription of ALA synthase gene - allows negatative feedback

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12
Q

what suppresses ALA synthase?

A

hemin, oxidized form of heme, and glucose

note: these suppress the synthesis of the mRNA, not the activity of the enzyme

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13
Q

ALA dehydrase

A

enzyme responsible for second step of heme synthesis = pyrole compound
condenses 2 molecules of ALA to make porphobilinogen (PBG)
releases two H2O
lead inhibits

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14
Q

hydroxymethylbilane synthase

A

enzyme responsible for 3rd step in heme synthesis
condenses 4 molecules of PBG to make hydroxymethylbilane
regulate reaction
second rate-limiting step
releases 4NH3

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15
Q

uroporphyrinogen synthase

A

enzyme responsible for 4th step in heme synthesis

catalyzes ring closure of hydroxymethylbilane to make uroporphyrinogen I - symmetrical

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16
Q

uroporphyrinogen III cosynthase

A

enzyme responsible for 5th step in heme synthesis
isomerizes the D ring side chains of uroporphyrinogen I to make uroporphyrinogen III - so that it’s not a symmetrical heme and can be used biologically

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17
Q

uroporphyrinogen III

A

molecule made in 5th step of heme synthesis by enzyme uroporphyrinogen III cosynthase from uroporphyrinogen I
common precursor for chlorophyll, cobalamine, and heme in organisms that make those compounds
several steps make it into protoporphyrin IX, which has lots of conjugated double bonds that allow them to fluoresce

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18
Q

how could you tell the difference between porphyrins and their precursors?

A

porphyrins are purple and fluorescent

PBG and other porphyrinogens are colorless and don’t fluoresce until they’re oxidized

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19
Q

ferrochelatase

A

enzyme responsible for 7th step of heme synthesis
catalyzes the introduction of iron (Fe2+) into protoporphyrin IX to make heme
lead inhibits
releases 2 H+

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20
Q

classes of disease associated with abnormal heme synthesis (4 - list)

A

1: acute porphyrias
2: non-acute porphyrias
3: lead poisoning
4: iron-deficiency anemia

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21
Q

what steps of heme synthesis are disrupted by lead?

A

the enzymes ALA dehydrase and ferrochalatase are inhibited by lead
the first condenses two molecules of ALA to make PBG
the second catalyzes the addition of iron to make the final heme

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22
Q

acute porphyrias

A

autosomal dominant disorders characterized by blockade of the early, rate-limiting steps of heme biosynthetic pathway
results in decreased production of heme (and hemin)
example = acute intermittent porphyria (AIP)

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23
Q

acute intermittent porphyria (AIP) (everything we’ve learned about it)

A

due to deficiency in hydroxymethylbilane synthase
clinical signs: intermittent attacks of abdominal pain and neuropsychiatric symptoms (that go away with bowel movements)
attack precipitated by ingestion of drugs and other compounds
compounds induce production of CYP enzymes => consumption of heme => increase in ALA synthase levels and accumulation of ALA and PBG - ALA committed step
lack of negative feed back makes things worse
ALA causes abdominal pain because of its massive accumulation in the liver
neuropsychiatric symptoms due to similarity between ALA and GABA => ALA antagonizes GABA receptors
diagnosis is made by detection of excess PBG in urine - when urine stands, it oxidizes and turns purple
treat with intravenous hemin and glucose
patients should avoid precipitating drugs
can identify affected family members by PCR

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24
Q

what deficiency causes acute intermittent porphyria?

what is the result of this deficiency (what will build up)?

A

deficiency of hydroxymethylbiane synthase enzyme, which condenses 4 molecules of PBG to make hydroxymethylbilane

this will result in the build up of PBG and ALA (the precursor for PBG)

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25
Q

what are the clinical symptoms of acute intermittent porphyria (AIP)?

A

abdominal pain

neuropsyciatric symptoms

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26
Q

what usually triggers an attack of acute intermittent porphyria (AIP)?
why does this trigger an attack?

A

attacks are usually triggered by ingestion of drugs and other symptoms
this is because these compounds induce the production of CYP enzymes => heme consumption => increases in ALA synthase activity => increases in ALA and PBG
the ALA and PBG builds up in liver
patients with AIP are advised to avoid precipitating drugs

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27
Q

what causes the abdominal pain that patients with acute intermittent porphyria (AIP) experience?

A

buildup of ALA in the liver

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28
Q

what causes the neuropsyciatric symptoms that patients with acute intermittent porphyria (AIP) experience?

A

ALA and the neurotrasmitter GABA have very similar structures
ALA antagonzies GABA receptors

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29
Q

how do you diagnose acute intermittent porphyria (AIP)?

A

detect excess PBG in urine
leave urine to stand so that it can oxidize
if the patient has AIP, the urine will turn purple (because when the PBG oxidizes it becomes porphyrin, which is purple)

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30
Q

how do you treat acute intermittent porphyria (AIP)?

A

with intravenous hemin and glucose - ala synthase also negatively regulated by glucose
(get rid of/avoid inducers - cytochrome P450 can’t work - so anything that needs those)
can consume blood - will alleviate symptoms

31
Q

how would you identify family members with acute intermittent porphyria (AIP)?

A

by PCR

32
Q

non-acute porphyrias (summary card - everything we’ve learned)

A

primary acquired diseases associated with liver damage
some are genetic
blockade of normal heme biosynthetic pathway occurs at specific steps beyond the formation of hydroxymethylbbilane
results in accumulation of of porphyrin derivatives in liver and skin => liver damage and rashes
heme production and ALA levels are normal so no neuropsychiatric symptoms
example = porphyria cutanea tarda (PCT)

33
Q

what is the defect that causes non-acute (chronic) porphyrias? why does this occur?

A

blockade of normal heme biosynthetic pathway at specific steps beyond the formation of hydroxymethylbilane
uroporphyrinogen can’t be converted to protoporhyrin IX
usually not genetic - due to liver damage

34
Q

what accumulates in non-acute porphyrias?

which tissues are affected, and what does the accumulation cause in these tissues?

A

abnormal uroporphyrinogen turns into uroporphyrins
these derivates accumulate in the liver and the skin
in the liver it causes liver damage
in the skin it causes photosensitive skin rashes
urine turns red

35
Q

what are heme and ALA levels in patients with non-acute porphyria?

A

both levels will be normal because both ALA synthase and hydroxymethylbilane synthase activities are increased through compensatory regulation mechanisms

36
Q

are there neurophysiological symptoms with non-acute porphyrias?

A

no. since ALA is normal, there will be no neurological effects

37
Q

porphyria cutanea tarda (PCT) (summary card)

A

most common porphyria
form of non-acute porphyria
due to reduced uroporphyrinogen decarboxylase activity => accumulation of uroporphyrins
treat with regular phlebotomy => helps remove excess porphyrin metabolites
patients should avoid alcohol, sunlight, other liver toxins

38
Q

what defect causes porphyria cutanea tarda (PCT)?

what accumulates as a result?

A

reduced uroporphyrinogen decarboxylase activity results in the buildup of uroporphyrins, which are abnormal metabolites

39
Q

how is porphyria cutanea tarda (PCT) treated?

A

with regular phlebotomy, which helps remove excess porphyrin metabolites

40
Q

what should patients with porphyria cutanea tarda (PCT) avoid?

A

alcohol
other liver toxins
excess sunlight

41
Q

what enzymes are inhibited in lead poisoning and what symptoms does this cause?

A

inhibits ALA dehydrase and ferrochelatase
clinical symptoms include all symptoms of AIP (due to inhibition of liver ALA dehydrase) plus anemia (due to inhibition of bone marrow heme synthesis)

42
Q

iron-deficiency anemia (summary card)

A

some of the heme-synthesis enzymes are erythroid specific isoforms and so are regulated by different signals than their liver counterparts
eg translation of erythroid ALA synthase mRNA is stimulated by iron
lack of iron results in decrease of erythroid heme synthesis => anemia
ALA synthase mRNA has iron response element (IRE) in transcript

43
Q

how does iron affect translation of enzymes involved in heme synthesis?

A

translation of some of the bone marrow enzymes is regulated by iron, especially erythroid ALA synthase
the transcript for ALA synthase contains and iron response element (IRE) sequence - makes it susceptible to regulation by iron - if iron not present, the mRNA is blocked from being translated

44
Q

how does lack of iron result in iron-deficiency anemia?

A

since regulation of ALA synthase mRNA is regulated by iron (through the IRE), lack of iron can prevent the protein from being transcribed, preventing synthesis of heme in bone marrow and causing anemia

45
Q

where does heme degradation occur?

A

primarily in the spleen and the liver

46
Q

steps of heme degradation:

A

1: heme oxidase catalyzes conversion of heme to biliverdin, using NADPH and O2
2: heme oxidase also catalyzes release of bound iron molecule when heme ring in broken
3: bilirubin reductase converts biliverdin to bilirubin
4: serum albumin carries the bilirubin through the bloodstream to the liver
5: bilirubin glucoronyltransferase (in liver) conjugates 2 molecules of glucuronic acid to bilirubin to make bilirubin diglucuronide
6: bilirubin diglucuronide is water soluble and is secreted in bile
7: bacteria in the intestine reduce bilirubin diglucuronide to make urobilinogen
8a: most of urobilinogen converted to stercobilin - brown compound that give feces color
8b: rest transported back to liver where converted to urobilin - yellow - excreted in urine

47
Q

heme oxygenase

A

enzyme that catalyzes the first two steps of heme degradation
uses NADPH and O2 to convert heme to biliverdin (green pigment) and iron molecule is removed when ring is broken - linearlizes
releases carbon monoxide

48
Q

biliverdin reductase

A

enzyme responsible for 3rd step in heme degradation
uses NADPH
reduces biliverdin to make bilirubin (fat-soluble, yellow-red pigment)
bound to albumin for transport

49
Q

bilirubin glucuronyltransferase

A

enzyme that catalyzes the 5th step in heme degradation
in liver
conjugates 2 molecules of glucuronic acid to bilirubin - makes bilirubin diglucuronide (conjugated bilirubin)
makes bilirubin water soluble so can now just move through the blood

50
Q

bilirubin diglucuroninde

A

water soluble compound made during the degradation of heme
made in liver and secreted in bile
made by bilirubin glucoronyltransferase from glucuronic acid and bilirubin
converted to urobilinogen in intestine by bacteria

51
Q

jaundice (summary card)

A

due to disorders that increase levels of bilirubin in the blood
results in yellow skin and sclerae
bilirubin can cross BBB - cause encephalopathy
measured with van den Bergh reaction
4 types of jaundice:
hemolytic
obstructive
hepatocellular
neonatal
if can accumulate to high enough level, can cross BBB and cause coma

52
Q

what are the symptoms of jaundice?

A

bilirubin builds up in the skin and sclerae, turns them yellow
can cross BBB and cause encephalopathy

53
Q

what assay is used to measure levels of bilirubin in the blood?

A

the van den bergh reaction

measures levels of both conjucated and unconjugated bilirubin in the blood

54
Q

types of jaundice (4 - list)

A

1: hemolytic
2: obstructive
3: hepatocellular
4: neonatal jaundice

55
Q

hemolytic jaundice

- cause?
- van den bergh assay results will show?
A

red cell lysis, e.g. in sickle cell anemia

increase in unconjugated bilirubin

56
Q

obstructive jaundice

- cause?
- van den Bergh test will show?
A

blockage of the bile ducts, e.g. by gallstones

increase in conjugated bilirubin

57
Q

hepatocellular jaundice

- cause?
- how to test and what will the results be?
A

due to liver damage e.g. by hepatitis

use liver tests - will see increase in AST and ALT

58
Q

neonatal jaundice

- causes?
- treatment?
A

due to relatively low levels of bilirubin glucuronyltransferase activity early in infancy - this enzyme isn’t expressed until birth/full term so if born early won’t be expressing the enzyme yet
treated by administration of blue fluorescent light to convert bilirubin to water-soluble molecules that can be excreted by the kidney

59
Q

steps of heme synthesis (molecules made)

A

1: succinyl CoA + glycine
2: ALA
3: PBG
4: hydroxymethylbilane
5: uroporphyrinogen
6: protoporhyrin IX
7: heme

60
Q

how would you diagnose lead poisoning?

A

basophillic strippling on blood smear

61
Q

how would you diagnose iron deficiency anemia?

A

blood smear shows pale, thin rimmed RBCs

62
Q

degradation of heme (molecules made and where)

A

1: heme - RBCs
2: biliverdin - macrophages, esp in spleen
3: bilirubin - macrophages, esp in spleen
4: conjugated bilirubin - liver
5: urobilinogen - intestine
6a: stercobilin - intestine
6b: urobilin - kidney

63
Q

how would you distinguish between producing too much bilirubin to not being able to get it into the intestine?

A

ask about color of urine and stool
liver function tests - for enzymes that only live in liver - look for damage to liver cells
van den bergh reaction

64
Q

van den bergh reaction

A

dissolve bilirubin in water and methanol
only conjugated bilirubin is dissolvable in water
dissolving in methanol will give total amount of bilirubin
can see how much is being conjugated

65
Q

why would we produce too much bilirubin?

A

high turnover of RBCs:
sickle cell anemia, phalycemia
causes hemolytic jaundice - high levels of unconjugated bilirubin

66
Q

why would we have too much conjugated bilirubin?

A

gall stone
obstruction jaundice
inability of bilirubin to get into intesting
pale stools

67
Q

how would you diagnose hepatocellular jaundice?

A

get rise in conjugated bilirubin and overall bilirubin - use van den bergh reaction
measure with liver enzyme tests - high levels of AST and ALT

68
Q

types of jaundice (summary card)

A 
1: hemolytic - eg sickle cell anemia
high levels of unconjugated bilirubin
2: obstructive jaundice - eg gallstones
high levels of conjugated bilirubin
3: hepatocellular jaundice - eg hepatits
high levels of both conjugated and unconjugated bilirubin
4: neonatal jaundice - premature infants
high levels of unconjugated bilirubin
69
Q

pyridoxal phosphate (PLP)

A

coenzyme required by ALA synthase to catalyze the first step of porphyrin synthesis

70
Q

sideroblastic anemia (lippincott)

A

loss of function mutation in one of the versions of ALA synthase (ALAS 2) which is located on the X-chromosome

71
Q

hemin (lippin)

A

decreases activity of ALAS1 by causing decrease in synthesis of the enzyme through inhibition of mRNA synthesis and use and by inhibiting mitochondrial import of the enzyme
when porphyrin production exceeds the availability of the apoproteins that require it => heme accumulation and is converted to hemin by oxidation of Fe2+ to Fe3++

72
Q

drugs on ALA synthase activity (lippin)

A

administration of any large number of drugs results in increased hepatic ALAS1 activity
drugs metabolized by microsomal cytochrome P450 monooxygenase system
in response, synthesis of cytochrome P450 proteins increases => enhanced consumption of heme => decrease in heme concentration in liver => increase in synthesis of ALAS1 and so increase in ALA synthesis

73
Q

porphobilinogen formation (lippin)

A

when two molecules of ALA are condensed by ALA dehydratase/porphobilinogen synthase
extremely sensitive to inhibition by heavy metals because enzyme contains Zn and heavy metals, like Pb, can replace the Zn and inhibit enzyme
results in elevation in ALA and anemia

biochem term 2 quiz 4 (7 decks)

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