Heme Metabolism Flashcards
heme structure
cyclic/porphyrin
central iron ion
common heme containing proteins
hemoglobin
myoglobin
cytochromes
enzymes- catalase, peroxidase
involved in electron transport or redox rxns
common places for synthesis
bone marrow - RBCs
liver- cytochromes
step 1
synthesis pathway
condensation
glycine + succinyl-CoA = 5-ALA
en: 5-ALA synthase w/ vitamin B6
RATE LIMITING
succinyl coA from TCA cycle, @ mitochrondria
step 2
synthesis pathway
condensation
2 5-ALA’s > porphobilinogen (PB)
en: ALA dehydratase
inhibited by lead
cytosol
step 3
synthesis pathway
4 porphobilinogen (PB) > hydroxymethylbilane
en: PB deaminase
hydroxylme is linear so not photosensitive
step 4
synthesis pathway
hydroxymethylbilane > uroporphyrinogen III
en: uroporphyrinogen III synthase
now first cyclic compound so photosensitive
step 5
synthesis pathway
decarboxylation
uroporphyrinogen III > coproporphyrinogen III
en: uroporphyrinogen (UP III) decarboxylase
enters mitochondria
step 6
synthesis pathway
oxidation
coproporphyrinogen III > protoporphyrinogen IX
protoporphyrinogen IX unstable so readily oxidizes to protoporphyrin IX
step 7
synthesis pathway
protoporphyrin IX > heme
en: ferrochelatase
requires Fe2+
inhibited by lead
regulation
- feedback inhibition from heme
- lead poisoning
- vitamin B6 deficiency
- iron deficiency
alcohol impact
stimulates hepatic heme synthesis via MEOS
cytochrome P450 synthesis consumes heme = no heme to inhibit ALA synthase
step 1
lead poisoning
inhibits ALA dehydratase (2) AND ferrochelatase (6)
accumulate: ALA and protoporphyrin IX @ urine AND serum iron/ferritin
anemia, nausea, neuropathy
ferritin is storage form of Fe2+
B6 deficiency
co-factor for ALA synthase (1)
low ALA and protoporphyrin
inc serum iron and ferritin
impact healthy RBCs
sideroblastic anemia
iron deficiency
impact heme synthesis
microcytic hypochromic anemia pale and small RBC
low serum iron/ferritin
inc protoporphyrin NORMAL ALA
acute intermittent porphyria
biochem features
porphobilinogen (PB) deaminase (3)
acc: ALA and porphobilinogen (PB)
acute intermittent porphyria
clinical features
acute episodes abdom pain
neuropathic - paranoia, anxiety, paralysis
latent before puberty
exacerbated by steroids, contraceptives, fasting, and alc
*dark red color urine
more common in women
porphyria cutanea tarda
biochem features
uroporphyrinogen decarboxylase (4) mutation
acc: porphyrins (esp uroporphyrin) @ urine
generate ROS bc porphyrins absorb UV light
under UV urine looks pink fluorescent
bilirubin
formation
catabolism of heme
majority from breakdown of hemoglobin in RBC
heme degradation
- heme oxygenase cleaves heme ring = biliverdin
- biliverdin reductase converts it to bilirubin INDIRECT/UNCONJUGATED so water insoluble
- bilirubin-UGT converts to CONJUGATED/DIRECT so soluble
1. requires oxygen
2. requires NADPH
excretion bilirubin
- old RBC destroyed = hemoglobin released in spleen
- heme converted to unconjugated bilirubin
- binds albumin in circulation
- complex travels to liver
- gets conjugated w/ glucuronic acid
- secreted by hepatocytes into biliary canaliculi > thru bile duct into gut
- gut bacteria convert to urobilinogen
- spontaneous oxidized to stercobilin >excreted in feces
- reabsorbed urobilinogen oxidized to urobilin >excreted by kidney
stercobilin gives brown color to feces
is bilirubin detectable in urine normally
NOPE
jaundice
plasma bilirubin high = hyperbilirubinemia
yellow/orange appearance of skin and white eyes
yelow/red color of urine
acc of unconj in brain (kernicterus) = death
jaundice
disease conditions causes
hemolytic crisis/prehepatic
hepatic damage/hepatocellular
bile duct occlusion/posthepatic/cholestatic
hemolytic crisis
inc destruction of RBC inc serum bilirubin
-albumin capacity reached
-liver unable to conjugate excess so enters skin and other tissues
cannot be excreted by kidney
hemolytic crisis
indications
acc unconjugated serum
feces and urine normal
low hemoglobin
causes of prehepatic
G6PDH deficiency = oxidative damage in RBC
sickle cell
Rh factor disease
hepatic damage
aka hepatocellular
damaged liver cannot conjugate
hepatic damage
indications
acc unconjugated bilirubin in plasma and tissues
pale feces and urine
high serum ALT and AST
kernicterus
hepatic damage causes
infections (Hep A, B, C)
liver cirrhosis
alc/drugs
genetics-UGT enzyme deficiency
Crigler Najjar, Gilbert ex of genetic
bile duct occlusion/posthepatic
obstruction of biliary duct from
-gallstones
-pancreatic cancer
-biliary cirrhosis
so liver can’t excrete conjugated
bile duct occlusion
indicatiosn
conjugated bili excreted by kidney w/ urine
dark orange urine
pale feces bc no bilirubin or urobilin
alkaline phosphatase in serum
