Heme Biosynthesis Flashcards
what is heme
a heterocyclic porphyrin ring with 4 pyrols (pyrols are a 5 membered ring)
what state is iron in in heme
Ferrous state
Fe2+
Iron in heme exists in ferrous state. what would happen if we oxidized it to ferric state
Hb inactivates
Heme is located in
myoglobin
Hb
cytochromes
Where is heme made?
- Liver
2. Erythroid cells of the bone marrow
What are the 3 stages of heme synthesis and where does this occur?
Phase 1- mitochondria
Phase 2- cytosol
Phase 3- mitochondria
If we have a defect in one stage of heme synthesis, this can cause ________
porphyrias
Step 1 of heme biosynthesis
ALA is made in the mT.
- Glycine + succinyl coA–> aminolevulinic acid (ALA)
via ALA synthase
*Needs a vitamin b6 cofactor
aminolevulinic synthase
What co-factor does it need?
vitamin b6
What happens when there is a deficiency in vitamin b6?
If there is a deficiency in vit. B6
- Decreased heme synthesis
- RBCs are pale
- Increase in Fe stores
CAN CAUSE ANEMIA!
What are the two isoforms of ALASynthase
ALAS I and ALAS II
ALAS I–> ubiquitous
ALAS II–> only in erythroid in bone marrow.
What is special about ALAS II
Has a Fe response element in mRNA.
When Fe is present, it increases transcription and translation
What inhibits ALAS?
heme and hemin
What happens once we make ALA
Once we make ALA,
it will leave the MT and go into the cytosol so that we can begin phase 2
Phase 2 (general)
Occurs in the cytosol
Make porphyrin ring
4 steps
Phase 2
Step 3
ALA + ALA= PBG
via ALA dehydratase
Phase 2
Step 4
FOURRRRR PBG–> hydroxymethylbilane
via PBG deaminase
Phase 2
Step 5
hydroxymethylbilane –> UPR III
via UPR III co-synthase
Phase 2
Step 6
UPR III–> CPR III
via UPR decarboxylase
What produce now has all 4 porphryin rings?
CPR III
PBG
porphobillinogen
UPR III
uroporphyrinogen III
CPR III
coproporphyrinogen III
which has all 4 rings
CPR
coproporphyrinogen III
Which has 1 porphyrin ring?
PBG
Step 3
Occurs in the MT again
Create protoporphyrin IX and introduce iron to make heme
Step 7
CPR III moves into the mT
Phase 3
Step 8
CPR III–> protophoryinogen IX
via CPR oxidase
Phase 3
Step 9
protophoryinogen IX–> protoporphoryin IX
Via protophoryingoen oxidase
Phase 3
Step 10
Protoporphyrin IX + Fe2+–> HEME
via ferrochelatase
Lead poisoning will impact
- ALA dehydratase
2. Ferrochelatase
Lead poisoning leads to a build up of
- ALA
2. Protophorphyrin IX
Consequences of lead poisoning
- Production of heme is lowered, causing anemia
2 NRG production is impacted because cytochromes are not made
Porphyrias
INHERITED metabolic disorders caused by defects in heme synthesis
Types of porphyrias
- acute hepatic –> causes neurological sx
2. erythopoietic –> fucks with skin and photosensitivity
if its a hepatic porphyria, you will have what types of problems?
neurological
Acute intermittent porphyria
Genetics:
Type of porphyria
Enzyme affected:
Effects:
Acute intermittent porphyria
Genetics: Autosomal dominant
Type of porphyria: Hepatic
Enzyme affected: PBG Deaminase (in the liver)
Effects: Excess ALA and PBG, neurological deficit
Congenital Eythropoietic Porphyria
Genetics:
Type of porphyria
Enzyme affected:
Effects:
Genetics: Autosomal recessive
Type of porphyria: Erythropoietic
Enzyme affected: UPR III Synthase (in blood cells)
Effects: Increase in [UPR I] and its oxidation product [uroporphyrin I] (which produces red color in teeth/urine and skin photosensitivity)
PCT (porphyria cutanea tarda)
Genetics:
Type of porphyria
Enzyme affected:
Effects:
Genetics: Autosomal dominant
Type of porphyria: Hepatoeythropoietic
Enzyme affected: UPR decarboxylase
Effects: increase in UPR III, wine red urine color
Variegate porphyria (CELEBRITY PORPHYRIA)
Genetics:
Type of porphyria
Enzyme affected:
Effects:
Genetics: Autosomal Dominant
Type of porphyria: Hepatic
Enzyme affected: protoporphyrinogen IX oxidase
Effect: neurological sx
Which porphyria is celebrity?
variegate
What is the most common porphyria in the US?
PCT
porphyria cutanea tarda
Congenital Erthrypoietic porphyria
ezyme affected
UPR III synthase
Congenital Erthrypoietic porphyria
Results
Build up of
Uroporphyrinogen I and its oxidation product
uroporphyrin I.
Red urin, red fluorescence and skin photosentivity
UDP glucouronic acid is the same thing as
UDP-glucourinate
in the small intestine,
bilirubin diglucourinate is converted to
urobilinogen
urobilinogen can then
Go to the kidney and be converted to urobilin (excreted as pee
Go to the large intestine –> stercobilin (red/brown)–> POOP
Jaundice is also called
hyper[biliruben][emia]
Jaundice
Jaundice occurs when we have high levels of bilirubin in the blood. we have an imbalane between production and excrecretion
Unconjugated/indirect bilirubin is located
ALL before the liver
Conjugated/direct bilirubin is located
in and after the liver
Normal blood levels of unconjugated/indirect bilirubin
0.2-0.9
Normal blood levels of conjugated/direct bilirubin
0.1-0.3
What should we have more of in our blood
A. Unconjugated/indirect bilirubin
B. Conugated/direct bilirubin
Unconjugated/direct billirubin blood levels should be 0.2-0.9 mg/dL
Jaundice is diagnosed based on
conjugation
Thus, we have three types of jaundice
- pre-haptic
- haptic
- post-haptic
Prehepatic jaundice
increase levels of unconjugated BR
Normal levels of conjugated BR
in prehepatic jaundice, where do all of the problems exist/
BEFORE THE LIVER!!!
Intrahepatic jaundice
can be caused by
Problems with :
- hepatic uptake of bilirubin (maybe a problem with the transporter that takes it up)
- Conjugations (perhaps with problem with the enzyme in the conjugation)
- secretion of the conjugated BR (maybe not being secreted into the gallbladder).
Intrahepatic jaundice can be caused by
generalized hepatic dsyfunction such as
- Liver cirrhosis
- Criggler-Najjar syndrome
- Gilbert syndrome
In intra-hepatic, how are levels of unconjugated/conjuguated?
They vary. it depeond on if the problem occured pre-conjugation or post-conjugation
In intra-hepatic jaundice, what type of serum ASL and AST would we expect to see?
Liver enzymes would be high!
In in-hepatic jaundice, how is everything in the GI?
Good.
Only problem is in the liver
Post-hepatic jaundice will occur when?
When we have problem excreting our billirubin.
thus, we have decreased bile flow.
Post-hepatic jaundice
______ blood levels of conjugated BR
high
Post-hepatic jaundice
_________ serum AST and ALT levels
normal
Post-hepatic jaundice
________ blood levels of unconjugated BR
slightly higher
Describe the urine of people with post-hepatic jaundice
High amounts of conjugated BR in the urine,
so it will be dark.
In people with Post-hepatic jaundice, is there urobilinogen in the pee?
No. We cannot break down out conjugated BR
In people with post-hepatic jaundice, is there stercobilin in the feces?
No. We cannot break down our conjugated BR so their stool will be pool.
People wilth Post-hepatic jaundice will have
_______ stool
_______ urine
PALE stool
DARK urine
What is neonatal jaundice
Neonatal jaundice is also called physiological jaundice.
neonatal jaundice occurs when newborns have high levels of unconjugated/indirect/free BR in their blood cause they do not have mature enough hepatic pathways to conjugate and excrete their bilirubin. They have a deficiency in UDP- gluconyl transferase
so they have intra-hepatic
Neonatal jaundice is also called
physiological jaundice
In neonatal jaundice, there is a deficiency of _______
UDP-gluconyl transferase
What is the tx for neonatal jaundice?
Phototherapy using a blue fluorescent light. This allows BR to undergo photo conversion to create more soluble isomers.
Crigler-Najjar syndrome and Gilbert syndrome are what types of jaundice?
Intra-hepatic.
They are both due to problems with UDP-gluconyl transferase enzyme (which permits the conjugation of bilirubin.
Neonatal jaundice is due to
deficient UDP-gluconyl transferase enzyme
Which is worse: Crigler Najjar syndrom or Gilbert?
Criggler Najjar is worse because it is the COMPLETE absence of the UDP-GT enzyme
Crigler Najjar syndrome
Intra-hepatic jaundice
Type 1 (BAD)–> because - caused by the complete absence of the UDP-GT enzyme.
Thus, severe hyperbilirubinemia.
BR will accumulate in the brains of babies and cause kernicturus (encephalopathy and brain damage)
Kernicturus
Kernicturus is encephalopathy often caused by high amount of BR in the brain of babies. Kernicturus is often seen in Crigler Najjar syndrome
Criggler-Najjar Syndrom Type II
a less worse (benign) form of Criggler Najjar.
The UDP-GT enzyme has a mutation but has 10% function. So its all good.
Gilbert Syndrom
Intrahepatic jaundice
relatively common
2-10%
Results from a reduced activity of UDG-GT (has about 25% of its function)
Hepatitis
Hepatitis is inflammation of the liver that leads to liver dysfunction.
People with Hep have increased levels of conjugated AND unconjugated BR in the blood
Thus, BR will accumulate in skin and eyes and cause a yellow discoloration
Urine is dark tea colored
how do we get hepatitis
inflammation of the liver that leads to liver disorder
What are our levels of BR in hepaptis
High levels of CONJUGATED and UNCONJUGATED!!!!!
What is is the sequential breakdown of Hb
Hb heme (red) biliverdin (green) Bilirubin (orange) Iron (hemosiderin) (red/brown)
Color of iron/hemosiderin
red brown
color of billirubin
ORANGE!!!!
