Heme Synthesis and Breakdown Flashcards
porphyrin rings:
– Have Four 5-membered rings containing nitrogen connected by
single carbon bridges
– Iron present in ferrous state
– Oxidation to ferric states inactivates hemoglobin
(methemoglobin)
where does biosynthesis of heme occur?
in liver and erythroid cells of bone marrow
phase 1 of heme synthesis
- in Mito
- Gly and Succinyl Coa to ALA
what coenzyme does ALA synthase require?
B6 (pyridoxal phosphate)
what enzyme does Phase 1 of heme synthesis require?
ALA synthase
build up of heme causes feedback inhibition of what?
ALA synthase
what does lead inactivate in heme synthesis
ALA dehydratase and ferrochelatase
what does lead poisoning cause
build up of ALA and protoporphyrin IX
- ALA= neurotoxic
- causes anemia
- impacts energy production (cytochromes not synthesized)
Porphyrias
inherited metabolic disorders
-defects in heme synthesis
what are two types of porphyrias
Acute Hepatic – neurological symptoms
Erythropoietic – skin, photosensitivity
Acute intermittent porphyria
defective PBG deaminase (in liver)
-hepatic
Congenital erythropoietic porphyria
Uroporphyrinogen III synthase (in erythrocytes) -build up of uroporphyrinogen I and its oxidation product uroporphyrin I Produce a red color in urine, red fluorescence in teeth, destruction of rbc, and skin photosensitivity -type: erythropoietic
Porphyria cutanea tarda (PCT)
uroporphyrinogen decarboxylase
- type: hepatoerythropoietic
- most common in US
variegate prophyria (celebrity)
Protoporphyrinogen IX oxidase
-type: hepatic
(King George III)
what system degrades hemoglobin
reticulo-endothelial
system
what is globin broken down to?
amino acids
jaundice (hyperbilirubinemia)
- elevated levels of BR in blood stream
- imbalance between production and excretion of bilirubin
Pre-hepatic jaundice
Increased production of unconjugated BR
-elevated blood levels of unconjugated or indirect BR
Intra-hepatic jaundice
Impaired hepatic uptake, conjugation, or secretion of conjugated BR -Criggler-Najjar syndrome -Gilbert syndrome • Increase in serum ALT and AST • Urobilinogen levels in urine normal • Conjugated BR detected in urine
post hepatic jaundice (AKA Cholestatic jaundice or cholestasis (decreased bile
flow)
• Problems with BR excretion
• Elevated blood levels of conjugated BR
• Conjugated BR is present in urine (dark).
-pale stool
Neonatal Jaundice (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 (unable to keep up with bilirubin excretion)
what is used to treat jaundiced newborns?
Phototherapy
When exposed to blue fluorescent light, BR undergoes
photoconversion to form a more soluble isomers.
or
intramuscular injection of tin-
mesoporphyrin (strong inhibitor of heme oxygenase)
Crigler-Najjar Syndrome type 1
-complete absence of gene for UDP-GT
-Severe hyperbilirubinemia
-BR accumulates in brain of babies
• Causes encephalopathy (kernicturus) and brain damage
Criggler-Najjar Syndrome Type II
-benign form
-mutation in the UDP-GT gene
• Enzyme has less activity (10% activity)
