Heme Synthesis and Degradation, and the Porphyrias Flashcards
Hemoproteins
Need essential heme cofactor to function
Cytochrome P450
Important hemoprotein involved in ET and metabolism
Heme types
A - chain
B - kind in hemoglobin
C - attached to protein
Heme synthesis starting mateirals
Succinyl-CoA and Glycine
Heme synthesis locations
Starts in mito, moves to cyto, back into mito
1st 3 steps of heme synthesis
ALA-synthase takes glycine and succinyl-CoA to 5-aminolevulinic acid
ALA-dehydratase takes 5-animolevulinic acid to porphobilinogen
PBG-deaminase takes porphobilinogen to hydroxymethylbilane
Final 5 steps of heme synthessi
UPG 3 synthase takes hydroxymethylbilane to urophorphyrinogen 3
UPG 3 decarboxylase takes uroporphyrinogen 3 to coproporphyrinogen 3
CPG oxidase takes coproporphyrinogen 3 to protoporphyrinogen 9
PPG-oxidase takes protoporphyrinogen 9 to protoporphyrin 9
Ferrochelatase uses iron to take protoporphyrin 9 to heme B
Sites of heme synthesis
Almost all cells
85% in erythroid
14 in hepatocytes
In hepatocytes,
Heme is required for insertion into cytochromes
ALA-synthase regulation
Hemin (3+ Fe) inhibits along with glucose
Barbituations stimulate
In erythroid cells, heme syntehsis controlled by
Heme differentiation…if not enough iron, then ferrochelatase step cannot work
Heme must last for 120 days
Porphyrias
Def in heme synthesis
Lead poisoning
Inhibits ALA dehydratase and ferrochelatase
Acute intermittent porphyria major symptoms and products
Neurovisceral
Urinary ALA and PBG
Porphyria cutanea symtpoms and products
Photosnesitivty
Urinary 7-carboxylate porphyrin, fecal isocoproporphyrin
Acute intermittent porphyria mutation, tx, symptoms,
PBG deaminase mutation
Ab pain, port wine urine, polyneuropathy, psych issues
Exacerbatedb y alcohol and some drugs
Use glucose/hemin to tx
Prophyria cutane tarda mutation and symptoms and tx
Most sporadic (some auto dom) Def in UPG 3 decarboxylase
Blistering and photosensitivity
Reduce exposure to sun, alcohol, anti-malarial drugs…remove iron from system
Barbituates and porphyrias
NEVER prescribe because activates ALA_synthase
Heme degradation steps
HMOX - Takes heme to biliverdin 9 (uses NADP and O2)
biliverdin reductase - takes biliverdin 9 to biliubin 9…uses NADPH
Biliverdin and bilirubin colors
Verdin - blue green
Rubin - red yellow
Change from biliverdin to bilirubin responsible for bruise
Bilirubin modified by
UGT1A in heptaocytes to increase solubility and aid in excretion
Bilirubin transport
In macrophage…breakdown to bilirubin
Transport to hepatocyte…conjugate and moved to intestine
In intestine, converted to urobilinogen…some of this converted to stercobilin…some moves to kidney
In kidney, convered to urobilin and excrete
Hyperbilirubinemia
Jaundice
Yellow coloring of skin and eyes
Neonatal jaundice
Due to immature UGT enzymes plus high turnover rate of RBC s to replace HbF with HbA
Apparent after 24 houts…resolved after 1-2 weeks
Phototherapy isomerizes bilirubin to more soluble form
