Heme Biochem Flashcards
what are the key features of hemoglobin and heme
Hemoglobin has 4 globular sub units that are each bound to an iron containing a heme
heme has a heterocyclic porphyrin ring with an iron present in center
key features of a porphyrin ring:
- have 4 5-membered rings containing nitrogen connected by single carbon bridges
- iron present in ferrous state (Fe2+)
- oxidation to ferric state inactivates hemoglobin
where does biosynthesis of Heme occur?
occurs in liver and erythroid cells of bone marrow
what are the 3 phases of biosynthesis of Heme
Phase 1: in mitochondria, synthesis of delta-aminolevulinic acid (ALA) from glycine and succinyl coenzyme A
Phase II: In cystol, condensation of two delta-ALAs to form porphobilinogen (PB), condensation of four PBs to assemble the tetrapyrrole ring system of coproporphyrinogen III
Phase III: in mitochondria, two oxidation reactions of coproporphyrinogen III to install the side chain vinyl groups in protoporphyrinogen IX and generate the fully conjugated ring system of protoporphyrin IX insertion of Fe2+ by ferrochelatase
what happens if their is a defect in any phase of the making of heme?
a defect in one or more stages of heme synthesis causes porphyrias
important enzymes in each of the three phases of heme production
Phase 1: ALA synthase (need vitamin B6)
-generation of ALA
Phase II: ALA dehydrase
-Generation of Coproporphyrinogen III
Phase III: ferrochelatase
-generation of protoporphyrin and introduction of iron to form heme
what is required by ALA synthase to make ALA?
B6 (pyroxidal phosphate)
what happens in lead poisoning
Lead can inactivate 2 important enzymes in the heme synthesis
Ala dehydratase (contains Zn) Ferrochelatase (contains Fe)
leads to both ALA and Protoporphyrin IX accumulation
causes anemia (microcytic and hypochromic)
impacts ATP synthesis and energy metabolism
how does production of Heme affect the heme biosynthesis pathway
Heme acts as a negative feeback inhibiting ALA synthase
what are Porphyrias?
inhereted metabolic disorders
-defect in heme synthesis
Acute Hepatic: neurological symptoms
Erythropoietic: affect skin, photosensitivity
Acute intermittent porphyria
PBG demainase (in liver)
Autosomal dominant
deficiency leads to excessive production of ALA and PBG
-Periodic attacks of abdominal pain and neurological dysfunction
Hepatic
Congenital erythropoietic porphyria
Uroporphyrinogen III synthase (in erythrocytes)
autosomal recessive
accumulation of uroporphyrinogen I and its red-colored, air oxidation product uroporphyrin I
Photosensitivity, red color in urine and teeth
hemolytic anemia
Erythropoietic
Porphyria cutanea tarda (PCT)
Uroporphyrinogen decarboxylase
autosomal dominant
accumulation of uroporphyrinogen III converting to uroporphyrinogen I and its uroporphyrin oxidation products
most common in US
photosensitivity resulting in vesicles and bullae on skin of exposed area, wine red colored urine
Hepatoerythropoietic
Variegate porphyria
Protoporphyrinogen IX oxidase
autosomal dominant
Photosensitivity and neurologic symptoms and developmental delay in children
Hepatic
also called Celebrity porphyrias
-KIng george III had it
how is heme degraded and what is it broken down too
handled by the reticulo-endothelial system
-degrades hemoglobin to globin and heme
globin broken down to amino acids
heme processed for degradation
what is difference between heme and bilirubin
heme is the porphyrin ring
bilirubin is a cut in the corner and flattened out making a tetrapyrrole rings and has no Iron
step by step of heme degradation
Heme oxygenase removes the bridge between pyrrole rings
- requires oxygen
- carbon monoxide released
Iron oxidized from ferrous to ferric
Biliverdin synthesized
Biliverden reduced to bilirubin by enzyme biliverdin reductase
-requires NADPH
Conjugation of Bilirubin
Bilirubin is released in BLood stream and is very hydrophobic
-Free/uncongugated/indirect BR is insoluable so will bind to albumin
will then get picked up by liver and get conjugated with glucuronic acid making it soluble (conjugated/direct BR)
- glocose converted toe UDP-glucose then converted to UDP-glucuronic acid
- UDP glucuronyl transferase will put the gluconic acid on to BR to mono and then diglucuronide
- UDP glucuronyl transferase is the rate limiting step
where does the bilirubin-diglucuronide go after being made in liver
goes straight into the gall bladder then will go into small intestine where it gets converted to bilirubin via microbial reduction
then in large intestine it will turn to Uroblinogen where it will go into the kidney and be converted to urobilin (color of urine)
also will stay in large intestine and go to colon where it turns to stercobilin and that is what makes the feces brown
what is jaundice
aka Hyperbilirubinemia
Elevated levels or BR in blood stream
-Imbalance between production and excertion of bilirubin
Pre-hepatic Jaundice
Increased production of unconjugated BR
- excess hemolysis (hemolytic anemia)
- glucose 6-PO4 dehydrogenase deficiency
- internal hemorrhage
- Problems with incompatibility of maternal-fetal blood groups
- Capacity of liver to uptake exceeded
elevated levels of unconjugated/indirect BR -normal conjugated BR normal ALT -normal ASL -Urobilinogen present in urine
Intra-Hepatic Jaundice
Impaired hepatic uptake, conjugation, or secretion of conjugated BR
- generalized liver dysfunction
- liver cirrhosis
- viral hepatitis
- Criggler-najjar syndrome
- gilbert syndrome
variable increases in unconjugated and conjugated BR depending if pre and post
increased ALT and AST
Urobilinogen levels are normal
Post hepatic Jaundice
AKA cholestatic jaundice or cholestasis (decreased bile flow)
Problems with BR excretion
- cholangiocarcinoma
- gall stones
- obstruction of biliary drainage
- infiltrative liver disease
- drugs (anabolic hormones, chlorpromazine, phenytoin)
- lesions
elevated Blood levels of conjugated BR
- normal AST and ALT
- Elevated alkaline phosphatase (ALP)
- conjugated BR is present in urine (dark)
- no urobilinogen in urine
- no stercobilin in feces
Neonatal jaundice
many newborns develop jaundice due to elevation of uconjugated bilirubin
-called physiological jaundice
Immature hepatic metabolic pathways unable to conjugate and excrete bilirubin
deficiency of UDP-GT enzyme
breakdown of fetal hemoglobin as it is replaced with adult hemoglobin
accumulation of excess BR in blood
premature birth aggravates this situation
Phototherapy
used to treat jaundiced newborns
when exposed to blue florescent light, BR undergoes photo-conversion to form more soluble isoforms
or intramuscular injection of tin-mesoporphyrin which is a strong inhibitor of heme oxygenase to prevent heme breakdown to form bilirubin
