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Biochem 1 (WPH) > Heme - Offner > Flashcards

Heme - Offner Flashcards

1
Q

what does a pyrrole group look like

A

five-membered ring with one N and two double bonds

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2
Q 
pyrrole side chain abbreviations:
M
V
A
P
A 
M = methyl -CH3
V = vinyl -CH=CH2
A = acetyl -CH2-COO-
P = propionyl -CH2-CH2-COO-
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3
Q

structural formula of heme

A

cyclic tetrapyrrole with side chains
MV, MV, MP, PM
α-C is between the two MV groups

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4
Q

what is the simplest tetrapyrrole ring

A

porphyrin
all side groups are H
lots of double bonds (conjugated)

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5
Q

do porphyrins and/or porphyrinogens fluoresce under UV?

A

porphyrins (oxidized, conjugated)

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6
Q

how do porphryinogens compare to porphyrins?

A

more complex
different side-chains (not just H)
reduced (not conjugated with double bonds)
colorless (do not UV fluoresce)

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7
Q

how many steps in the heme biosynthesis pathway

A

8

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8
Q

what is your mnemonic for heme biosynthesis?

A

So Guys, A Proper Bili Uses Condoms, Protection Protection for Him

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9
Q

what are the 9 molecules in the path of heme biosynthesis?

A 
succinyl CoA + glycine
ALA
PBG
Urogen
Coprogen
Protogen
Proto
Heme
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10
Q

what does ALA stand for in heme synthesis

A

delta aminolevulinic acid

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11
Q

what does PBG stand for in heme synthesis

A

porphrobilinogen

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12
Q

what does bilane stand for in heme synthesis

A

hydroxymethyl bilane

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13
Q

what does urogen stand for in heme synthesis

A

uroporphyrinogen III

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14
Q

what does coprogen stand for in heme synthesis

A

coproporphyrinogen III

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15
Q

what does protogen stand for in heme synthesis

A

protoporphyrinogen IX

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16
Q

what does proto stand for in heme synthesis

A

protoporphyrin IX

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17
Q

what are the 8 enzymes involved in heme biosynthesis?

A 
ALA synthase
ALA dehydrase
PBG deaminase (urogen I synthase)
urogen III cosynthase
urogen III decarboxylase
coprogen III decarboxylase
protogen dehydrogenase (oxidase)
ferrocheletase
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18
Q

what are the products of the ALA synthase reaction

A

CO2
CoA-SH
ALA

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19
Q

what are the products of the ALA dehydrase reaction

A

2H20

PBG

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20
Q

what are the products of the PBG deaminase reaction?

A

4NH2

bilane

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21
Q

what are the products of the urogen III cosynthase reaction?

A

urogen III (cyclic)

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22
Q

what are the products of the urogen III decarboxylase reaction?

A

4CO2

coprogen III

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23
Q

what are the products of the coprogen III decarboxylase reaction?

A

2CO2

protogen IX

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24
Q

what are the products of the protogen dehydrogenase reaction?

A

6H+

proto

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25
Q

what are the products of the ferrocheletase reaction?

A

heme

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26
Q

when in heme biosynthesis is a linear tetrapyrrole formed?

A

bilane

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27
Q

when in heme biosynthesis is a cyclic tetrapyrrole first formed?

A

urogen III

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28
Q

what are the side-chains on bilane?

A

AP, AP, AP, AP

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29
Q

what are the side chains on urogen III?

A

AP, AP, AP, PA

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30
Q

what is the “type III problem” in heme biosynthesis

A

the problem of why only Urogen III: AP,AP,AP,PA is found in heme biosynthesis, and not for instance Urogen I: AP,AP,AP,AP
-solution - PBG deaminase forms only Urogen III isomer

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31
Q

what does succinyl CoA look like?

A

COOH-CH2-CH2-CO-S-CoA

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32
Q

what does ALA look like?

A

COOH-CH2-CH2-CO-CH2-NH2

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33
Q

how many ALA in a PBG?

A

2

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34
Q

what does PBG look like?

A

mono pryrrole with AP and a -CH-NH2 branch

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35
Q

how many PBG in bilane?

A

4

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36
Q

how many ALA in bilane?

A

8

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37
Q

what does bilane look like?

A

linear tetrapyrrole with AP, AP, AP, AP and a methanol on the end

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38
Q

when in heme biosynthesis are pyrrole rings made?

A

PBG

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39
Q

what does coprogen III look like?

A

cyclic tetrapryrrol with MP,MP,MP,PM

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40
Q

what happens in the transition from urogen III to coprogen III

A

loss of 4CO2
cyclic tetrapyrrol with AP,AP,AP,PA becomes
cyclic tetrapyrrol with MP,MP,MP,PM

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41
Q

where do the 4CO2 come from in the urogen III decarboxylase reaciton?

A

the A groups turn to M groups
AP,AP,AP,PA urogen
MP,MP,MP,PM coprogen

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42
Q

which is more hydrophobic, urogen III or coprogen III?

A

coprogen III

MP (1PM) groups instead of AP (1PA) groups

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43
Q

which is more hydrophilic, urogen III or coprogen III?

A

urogen III

AP (1PM) groups instead of MP (1PM) groups

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44
Q

what does protogen IX look like?

A

cyclic tetrapyrrole with MV,MV,MP,PM

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45
Q

what is the difference between coprogen III and protogen IX?

A

coprogen III is MP,MP,MP,PM

protogen IX is MV,MV,MP,PM

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46
Q

how does coprogen decarboxylase change coprogen III into protogen IX?

A

turns two propionyl groups into vinyl groups
MP,MP,MP,PM becomes
MV,MV,MP,PM

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47
Q

what is the difference between protogen IX and proto IX

A

-6H+
deprotonates α,β,γ,δ carbons
deprotonates pyrrole I & pyrrole III nitrogens
ring is now conjugated (red color)

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48
Q

what color is protogen IX?

A

no color (not conjugated)

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49
Q

what color is protoporphyrin IX?

A

red (conjugated)

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50
Q

what is the evolution of side-chains through heme biosynthesis?

A 
AP (PBG)
AP,AP,AP,AP (bilane)
AP,AP,AP,PM (urogen III)
MP,MP,MP,PM (coprogen III)
MV,MV,MP,PM (protogen IX)
MV,MV,MP,PM (proto IX)
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51
Q

how many ALA does it take to make one heme?

A

8

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52
Q

which heme biosynthesis intermediate is most hydrophobic?

A

proto IX

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53
Q

where in the cell does heme biosynthesis take place?

A

ALA transported out of mitochondrion

coprogen III transported back into mitochondrion

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54
Q

which heme biosynthesis intermediates is transported out of the mitochondria?

A

ALA

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55
Q

which heme biosynthesis intermediate is transported back into mitochondria?

A

coprogen III

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56
Q

how does heme regulate its own synthesis?

A
  • inhibit ALA synthase
  • inhibit ALA synthase transcription (when complexed with aporepressor protein)
  • inhibit ALA synthase translation
  • inhibit ALA synthase transport from cytoplasm to mitochondria
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57
Q

which is the rate limiting enzyme of the heme biosynthesis pathway?

A

ALA synthase

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58
Q

how soluble is heme in water?

A

poorly soluble

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59
Q

heme associates with apoproteins to form __

A

hemoproteins

60
Q

4 common hemoproteins

A

Hb, Mb, cytochromes, P-450

61
Q

where are cytochrome proteins found

A

inner mitochondrial membrane; endoplasmic reticulum

62
Q

where is heme found to be broken down?

A
  • senescent erythrocytes

- hepatic hemoproteins being turned over

63
Q

where does heme breakdown occur?

A

mononuclear phagocytic system MPS

  • spleen
  • Kuppfer cells of liver
  • tissue macrophages (small amount)
64
Q

where does cleavage of heme occur?

A

the α carbon

between MV MV pyrroles

65
Q

what enzyme catalyzes the cleavage of heme at the alpha carbon?

A

heme oxygenase

66
Q

what is the first step in heme catabolism?

A

heme
2O2 + NADPH + H+ + heme oxygenase
biliverdin
CO + Fe

67
Q

what is the structure of biliverdin?

A

linear tetrapyrrole with (II)MV,MP,PM,MV(I)
with lactam oxygens on either end
conjugated

68
Q

what is the color of biliverdin?

A

blue green

conjugated

69
Q

what is your mnemonic for heme catabolism?

A 
Ho!
BiliV
BiliR
BiliR Di
BiliR
U
Suck
70
Q

in heme catabolism, what is biliverdin converted into?

A

bilirubin

71
Q

what are the 7 intermediates in heme catabolism?

A 
heme
biliverdin
bilirubin
bilirubin diglucuronide
bilirubin
urobilinogen
stercobilin
72
Q

what enzyme converts biliverdin into bilirubin?

A

biliverdin reductase

73
Q

what is the difference between biliverdin and bilirubin?

A

the double bond at the old γ carbon has shifted left

74
Q

what are the colors of biliverdin and bilirubin?

A

blue-green

yellow-orange

75
Q

is bilirubin soluble?

A

no

76
Q

where do the heme oxygenase and biliverdin reductase reactions take place?

A

blood, MPS?
phagocytic cells in spleen
kuppfer cells in liver
some tissue macrophages

77
Q

how is bilirubin transported in blood?

A

complexed with albumin (otherwise heme is insoluble)

78
Q

in the process of heme catabolism, where is bilirubin transported to for further breakdown?

A

hepatocytes of liver

79
Q

what happens to bilirubin in the hepatocytes?

A 
undergoes conjugation
bilirubin +
2 UDP glucuronic acid +
bilirubin glucuronyl transferase -->
bilirubin diglucuronide
80
Q

what enzyme conjugates bilirubin into bilirubin diglucuronide?

A

bilirubin glucuronyl transferase

81
Q

what does bilirubin glucuronyl transferase do?

A

uses 2 UDP glucuronic acids to conjugates bilirubin into bilirubin diglucuronide

82
Q

in heme catabolism, what happens to bilirubin diglucuronide?

A

secreted from hepatocyte into bile

83
Q

what is the purpose of conjugating bilirubin in the liver?

A

make it soluble so it can be secreted into bile

84
Q

which heme catabolism intermediates are bile pigments?

A

biliverdin (green-blue)

bilirubin (yellow-orange)

85
Q

what is the difference between bilirubin and bilirubin diglucuronide?

A

2 sugars (diglucuronydyl) makes soluble

86
Q

where do heme catabolites go in bile?

A

from liver
to small intestine
to large intestine

87
Q

what happens to heme catabolites in the large intestine?

A 
intestinal bacteria (beta glucuronidase) convert
bilirubin diglucuronide
to bilirubin, reduce to
uroblinogen, further reduce to
stercobilin
88
Q

in what 3 locations does heme catabolism take place?

A
  • MPS (mononuclear phagocytic system)
  • hepatocytes
  • large intestine
89
Q

what intermediates and enzymes in the heme catabolism pathway take place in the MPS?

A

heme-biliV-biliR
heme oxygenase
biliverdin reductase

90
Q

what intermediates and enzymes in the heme catabolism pathway take place in the hepatocytes?

A

biliR-biliRDi

bilirubin glucuronyl transferase

91
Q

what intermediates and enzymes in the heme catabolism pathway take place in the large intestine?

A

biliRDi-biliR-urobolinogen-stercobilin
β glucuronidase
reducing bacterial enzymes
reducing bacterial enzymes

92
Q

what are the enzymes involved in heme catabolism?

A 
heme oxygenase (+O2+NADPH+H+)
biliV reductase (+NADPH)
biliR glucuronyl transferase (+2UDPgluc acid)
β glucuronidase
reducing bacterial enzymes
reducing bacterial enzymes
93
Q

in heme catalysis, what happens to bili R in the large intestine

A

reduced by bacteria to urobilinogen

94
Q

in heme catalysis, what happens to urobilinogen in the large intestine

A

reduced by bacteria to stercobilin
or
reabsorbed into blood to be urinated

95
Q

in heme catalysis, what happens to stercobilin

A

excreted in feces

96
Q

in heme catalysis, where does urobilin come into play

A

urobilinogen reabsorbed in large intestine is excreted in urine along with its oxidized form, urobilin (yellow pigment)

97
Q

what color is urobilin

A

yellow

98
Q

what is the difference between urobilinogen and stercobilin

A

stercobilin is reduced

99
Q

what is the difference between urobilinogen and urobilin

A

urobilin is oxidized

100
Q

how much urobilinogen is processed into stercobilin to be excreted in feces, and how much urobilinogen is reabsorbed to be urinated?

A

90% stercobilin feces

10% reabsorbed urine

101
Q

what circulatory system is responsible for reabsorbing a minor percentage of the urobilin in the large intestine?

A

enterohepatic system

102
Q

from left to right on biliverdin / bilirubin, what are the pyrrole ring numbers?

A

II, III, IV, I

103
Q

from left to right on biliverdin / bilirubin, what are the carbons?

A

β, γ, δ

no α, it was the site of cleavage

104
Q

from left to right on biliverdin / bilirubin, what are the pyrrole side chains?

A

MV, MP, PM, MV

105
Q

what does “hyperbilirubinemia” mean

A

high bilirubin levels in the blood

106
Q

what is the van den Berg reaction

A

attacking bilirubin at middle methelyne carbon, separating rings II & III from IV & I
-used to measure biliR levels in blood spectrophotometrically

107
Q

5 possible causes of hyperbilirubinemia

A
  • increased bilirubin produciton
  • decreased uptake into hepatocytes
  • impaired conjugation
  • defected secretion of conjugated biliR
  • biliary obstruction (cholestasis)
108
Q

what is found in the blood and urine in hemolytic jaundice

A

blood - more unconjugated biliR
urine - more urobilinogen
(increased heme catabolism & biliR production = hepatocytes cannot conjugate fast enough so biliR in blood, more biliR moving through hepatocytes and bile so more urobilinogen reabsorbed by enterohaptic circulation and in urine)

109
Q

what is juandice

A

yellow skin caused by high levels of bilirubin (in MPS, blood, etc)

110
Q

what is found in the blood and urine with a defect in biliR uptake into hepatocytes

A

blood - more unconjugated biliR

urine - less urobilinogen

111
Q

what is found in the blood and urine with a defect in biliR glucuronyl transferase?

A

blood - more unconjugated biliR
urine - no urobilinogen
if completely defective, death
(Crigler-Najar, Gilbert’s)

112
Q

what is Crigler-Najar Syndrome Type I

A

mutation in biliR glucuronyl transferase gene
cannot conjugate biliR
death

113
Q

what is Crigler-Najar Syndrome Type II

A

mutation in biliR glucuronyl transferase gene

bili R conjugation reduced

114
Q

what is Gilbert’s syndrome

A

mutation in promotor region of gene for biliR glucuronyl transferase
higher levels of unconjugated biliR in blood
-often asymptomatic

115
Q

why does neonatal jaundice commonly occur?

A
  • activity of biliR glucuronyl transferase does not reach full levels until 5-14 days after birth
  • buildup of unconjugated biliR
116
Q

what is the symptomatic risk of neonatal jaundice and how is it prevented?

A
  • buildup of unconjucated biliR can be neurotoxic (kernicterus)
  • treated with UV lights which convert biliR into non-toxic soluble compounds that can be excreted
117
Q

how is neonatal jaundice treated?

A

-UV lights which convert biliR into non-toxic soluble compounds that can be excreted

118
Q

in the context of heme catabolism, what is kernicterus?

A

neurotoxicity caused by build-up of unconjugated bilirubin from low biliR glucuronyl transferase activity in liver

119
Q

in the context of heme catabolism, when are increased levels of urobilinogen in urine found?

A

when heme catabolism / biliR production is abnormally high

120
Q

in the context of heme catabolism, when are increased levels of biliR diglucuronide found in urine?

A
  • with Dubin-Johnson Syndrome defect in hepatocyte excretion of biliRDiG
  • with biliary obstruction (cholestasis)
121
Q

what is cholestasis?

A

“slow bile”

due to biliary obstruction

122
Q

when are neither BRDG or urobilin found in urine?

A
  • with Crigler-Najar or Gilbert Syndrome defect in biliR conjugation by biliR diglucuronyl transferase
  • with defect in biliR uptake by hepatocytes
123
Q

what is a possible way of treating Crigler-Najar syndrome?

A

injecting hepatocytes with functional biliR diglucuronyl transferase enzymes

124
Q

what is Dubin-Johnson Syndrome?

A

defect in hepatocyte secretion of conjugated bilirubin

-high levels of BRDG in blood and dark urine

125
Q

what is the name for an inherited disorder of heme synthesis

A

porphyria

126
Q

what are porphyrias

A

disorders of heme synthesis (mutations in biosynthetic enzymes)

127
Q

are porphyrias most commonly homozygous or heterozygous?

A

heterozygous - expressing ~50% of functional enzyme

128
Q

what are the consequences of porphyrias?

A
  • failure to synthesize sufficient heme to downregulate ALA sythase
  • inetermediates accumulate and backup causing tissue damage
129
Q

what are the common symptoms of porphyrias

A
  • cutaneous lesions
  • neurologic dysfunction
  • liver disease
130
Q

cutaneous lesions, neurologic dysfunction, and liver disease together are suggestive of

A

porphyria

  • defect in heme biosythesis enzyme
  • failure to synthesize sufficient heme to downregulate ALA sythase
  • inetermediates accumulate and backup causing tissue damage
131
Q

what is the most common of the hepatic porphyrias?

A

PCT porphyria cutanea tarda

132
Q

PCT porphyria cutanea tarda

A
  • defect in urogen III carboxylase gene (20%) or spontaneous defect (80%)
  • cutaneous lesions, neurologic dysfunction, and liver disease are symptoms common of porphyrias, due to inability of heme production to downregulate ALA synthase and build up of heme intermediates
133
Q

is PCT porphyria cutanea tarda genetic or spontaneous?

A

20% genetic

80% spontaneous

134
Q
  • how does spontanous PCT porphyria cutanea tarda occur?

- how is it treated?

A
  • often Hepatitis C virus or hemochromatosis and their treatments cause hepatic iron overload and reactive oxygen species that can inhibit urogen III decarboxylase
  • treated with phlebotomy to reduce Fe concentrations
135
Q

what are the defects leading to unconjugated and conjugated hyperbilirubinemias?

A 
unconjugated
-hemolytic jaundice
-impaired biliR uptake
-Crigler-Najar & Gilbert's (bad BRGT)
conjugated
-Dubin-Johnson (bad BRDG excretion)
-biliary obstruction (cholestasis)
136
Q

what are the defects leading to unconjugated hyperbilirubinemias?

A

unconjugated

  • hemolytic jaundice
  • impaired biliR uptake
  • Crigler-Najar & Gilbert’s (bad BRGT)
137
Q

what are the defects leading to conjugated hyperbilirubinemias?

A

conjugated

  • Dubin-Johnson (bad BRDG excretion)
  • biliary obstruction (cholestasis)
138
Q 
acute intermittent porphyria AIP:
enzyme affected
intermediate builtup
acute or chronic
light sensitive?
A

PBG deaminase
PBG
acute
not light sensitive

139
Q 
porphyria cutanea tarda PCT:
enzyme affected
intermediate builtup
acute or chronic
light sensitive?
A

urogen III decarboxylase
urogen III
chronic
light sensitive

140
Q 
heredetary coproporphyria HC:
enzyme affected
intermediate builtup
acute or chronic
light sensitive?
A

coprogen III decarboxylase
coprogen III
acute
light sensitive

141
Q 
variegate porphyria VP:
enzyme affected
intermediate builtup
acute or chronic
light sensitive?
A

protogen III dehydrogenase
protogen III
acute
light sensitive

142
Q

which porphyria is not light sensitive?

A

AIP

PBG built up

143
Q

which porphyria is chronic?

A

PCT porphyria cutanea tarda

urogen III built up

144
Q

what are the 4 porphyrias you have to know, and what do you have to know about them?

A

AIP (PBG, not light sensitive)
PCT (urogen III, chronic)
HC (coprogen III)
VP (protogen IX)

145
Q

what are the primary sites of heme synthesis?

A
  • liver

- bone marrow

Biochem 1 (WPH) (15 decks)

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