Heme Synthesis Flashcards
heme has a heterocyclic _____ with ____ present in the center
porphyrin ring with iron present in the center
porphyrin rings have 4 _____ containing _____ connected by ____
5-membered rings (pyrrole rings) containing nitrogen connected by single carbon bridges
iron is present in what state while bound to Hb
ferrous (Fe2+)
what does the oxidation to the ferric state of oxygen do
inactivates hemoglobin
where does the biosynthesis of heme primarily occur
liver and erythroid cells of bone marrow
- in the mitochondria
what occurs in phase 1 of heme biosynthesis and where does it occur
synthesis of ALA from glycine + succinyl CoA
- in the mitochondria
what occurs in phase 2 of heme biosynthesis and where does it occur
2 ALA –> PBG
4 PBG –> hydroxymethylbilane –> UPP III –>
CPPP III
- in the cytosol
what occurs in phase 3 of heme biosynthesis and where does it occur
two oxidation reactions: CPPP III --> PPP IX PPP IX --> PP IX insertion of Fe2+: --> heme - in the mitochondria
why does deficiency in B6 cause anemia
B6 is needed in phase 1 of heme synthesis as a cofactor for ALA synthase glycine + succinyl CoA into ALA
ALA synthase 1 vs ALA synthase 2
ALAS1: ubiquitous
ALAS2: only in erythroid cells of bone marrow, has an iron response element in mRNA
ALA synthase
enzyme that converts succinyl CoA + glycine –> ALA
how does the concentration of iron affect ALA synthase
presence of iron increases its translation and transcription
what is ALA synthase inhibited by
heme and hemin
enzyme that catalyzes ALA –> PBG
ALA dehydratase
enzyme that catalyzes PBG –> HMB
PBG deaminase
enzyme that catalyzes PP IX –> heme
ferrochelatase
how does lead poisoning occur
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
why do lead poisoning symptoms occur
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)
porphyrias
- what are they
- cause by what
- acute hepatic porphyrias are characterized by
- erythropoietic porphyrias are characterized by
inherited metabolic disorders
- caused by defects in heme synthesis
- acute hepatic: neurological symptoms
- erythropoietic: skin, photosensitivity
acute intermittent porphyria
- enzyme defect
- type of porphyria
- reaction inhibited
defect in PBG deaminase in liver
- hepatic porphyria
(PBG –> hydroxymethylbilane)
congenital erythropoietic porphyria
- enzyme defect
- causes buildup of
- type of porphyria
- reaction inhibited
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
porphyria cutanea tarda
- enzyme defect
- type or porphyria
- reaction inhibited
defect in UPP decarboxylase
- hepatoerythropoietic porphyria
(UPP III –> CPPP III)
variegate porphyria
defect in PPP oxidase
(hepatic porphyria)
(PPP IX –> PP IX)
symptoms of variegate porphyria
- being a celebrity
- abd pain, delirium, hallucinations, convulsions
ex: king george III, queen anne, vincent van gogh
what handles heme degradation
reticulo-endothelial system
what happens to globin and heme during degradation
globin –> broken down into amino acids
heme –> removed for degradation
Heme oxygenase
removes the bridge between pyrrole rings of heme during degradation
heme –> biliverdin
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
Biliverdin reductase
breaks the double bond in biliverdin and adds hydrogen ions to form bilirubin molecule
free/unconjugated/indirect bilirubin is soluble or insoluble
conjugated/direct bilirubin is soluble or insoluble
unconjugated: insoluble
conjugated: soluble
what binds to bilirubin once its made to transport it
- and where is it transported
albumin
to the liver
how is conjugated bilirubin formed
hepatocyte microsomes conjugate BR with glucoronic acid making it soluble
UDP-glucose dehydrogenase (UDP-GD)
converts UDP-glucose into UDP-glucoronic acid in the start of conjugation of bilirubin
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
urobilin
causes yellow color of urine
- urobilinogen is reabsorbed and processed by kidneys
stercobilin
causes brown color of feces
- urobilinogen undergoes further microbial reduction to stercobilin
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
hyperbilirubinemia
jaundice; elevated levels of BR in the blood stream
normal blood levels of unconjugated BR
0.2 - 0.9 mg/dL
normal blood levels of conjugated BR
0.1 - 0.3 mg/dL
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
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
intra-hepatic jaundice
impaired hepatic uptake/conjugation/secretion of conjugated BR
- generalized hepatic dysfunction
- liver cirrhosis, viral hepatitis
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
post-hepatic jaundice
caused by problems with BR excretion possible causes: - obstruction to biliary drainage - cholangiocarcinoma - gall stones - infiltrative liver disease - lesions - drugs
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)
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
neonatal jaundice can be aggracated by
premature birth
how can neonatal jaundice cause encephalopathy (kernicturus)
bilirubin diffuses into basal ganglia
phototherapy for jaundice
newborn is exposed to blue fluorescent light and bilirubin undergoes photoconversion to form more soluble isomers
how does intramuscular injection of tin-mesoporphyrin treat jaundice
inhibits heme oxygenase which prevents the formation of bilirubin
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
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
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
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
red bruise - what breakdown level for Hb
heme
green bruise indicates what breakdown level for Hb
biliverdin
orange bruise - what breakdown level of Hb
bilirubin
reddish/brown bruise- what breakdown level of Hb
homosiderin
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)
