Heme/Porphyrin Metabolism/Iron Homeostasis Flashcards
generally describe porphyrin/heme/hemoglobin synthesis
starts in mitochondria, goes to cytoplasm, then goes back into the mitochondria where protoporphyrin IX is incorporated with iron (Fe2+), making heme. alpha2 and beta2 chains are made in the ribosomes and are incorporated with heme, making hemoglobin
what is heme made of?
protoporphyrin IX and reduced Fe2+ (ferrous iron)
what is hemoglobin made of
alpha2 and beta2 globin chains, and heme
what is heme a prosthetic group for?
hemoglobin myoglobin cytochromes cyclooxygenase catalase cytochrome P450 containing enzymes
where is heme degraded?
spleen and liver
where is heme synthesis
de novo in all cells, bone marrow (erythroid progenitor cells) and liver
what is reduced form of iron
Fe2+
what is oxidized form of iron
Fe3+
what can protoporphyrin IX bind?
Fe2+ and F3+
what is hemin
protoporphyrin IX and oxidized iron Fe3+ (ferric), which cannot bind oxygen
how is heme synthesis regulated?
heme acts as a negative feedback regulator to inhibit the rate limiting step delta-aminolevulinic acid synthase (delta-ALAS)
how is iron incorporated into protoporphyrin IX?
ferrochelatase which requires ascorbic acid/vit C and cysteine as reducing agents
what is the regulated/committed step of heme biosynthesis
when succinyl Coa and glycine are condensed by ALA synthase/B6/PLP to make delta ALA.
what is the ALAS1 isoform?
delta ALA synthesis in non-erythroid cells (hepatocytes)
what is the ALAS2 isoform?
delta ALA synthesis in erythroid cells (bone marrow)
when is expression of ALAS1 increased?
in response to drugs and toxins
describe what occurs upon activation of ALA1
heme synthesized in hepatocytes is incorporated in cytochrome P450 enzymes, therefore there is increased cytochrome p450 production in detoxification reactions
describe activation of ALA2
heme made in erythroid cells is committed to hemoglobin synthesis
when is expression of ALA2 increased?
hypoxia and erythropoietin increases heme synthesis
what does what does ALAS2 mRNA contain?
iron responsive element in its 5’ untranslated region (UTR) and is responsive to intracellular availability of iron
why would a B6 deficiency result in microcytic, hypochromic anemia?
B6 is needed for delta ALAS to make delta ALA, a precursor for heme. if delta ALA cannot function, heme cannot be made. therefore, hemoglobin is made with not enough heme, making the RBC small, and less oxygen binding
what are acquired disorders of heme synthesis
iron deficiency anemia, lead poisoning, B6 deficiency
what causes microcytic hypochromic anemia?
thassemia, lead poisoning, Vitamin B6 deficiency, iron deficiency - aka problems synthesizing heme
what are congenital disorders of heme synthesis?
porphyrias (if any enzymes are wrong, no heme), (delta ALAS, ferrochelatase, uroporphyrin III cosynthase, etc)
pathophysiology of lead poisoning
lead (Pb2+) is a competitive inhibitor of Fe2+ but doesn’t actually get inserted into protoporphyrin IX. therefore, Zn2+ is incorporated into PPIX instead, making zinc protoporphyrin ZnPP. lead also inhibits delta ALA dehydratase and ferrochelatase
what is an important indicator of lead poisoning/iron deficiency?
Zn PP (zinc protoporphyrin), bc in the absence of iron or blockage of iron binding, takes the place of iron in protoporphyrin, BUT MOSTLY DELTA ALA IN THE URINE
what would you expect to see in lead poisoning?
- increase in zinc protoporphyrin 2. increase in delta ALA in urine d/t inhibition of delta ALAS - leading indicator of heavy metal poisoning 3. increase in protoporphyrin IX d/t inhibition of ferrochelatase 4. decreased heme synthesis 5. microcytic hypochromic anemia
what would you expect to see in B6 deficiency?
won’t see increase in delta-ALA, because delta ALA dehyratase is not inhibited, delta ALA synthase is inhibited, so delta ALA won’t be made. just decreased heme and microcytic hypochromic anemia.
what causes acute intermittent porphyria (AIP)?
dominantly inherited deficiency of uroporphyrin I synthase aka porphobilinogen deaminase aka hydroxymethylbilane synthase
prevalence of acute intermittent porphyrin
only 10% of individuals with genetic trait show clinical manifestations, and they are usually late onset.
clinical manifestations of AIP
- excruciating abdominal pain (esp. menstruating women)
- constipation
- muscle weakness
- CV abnormalities
- agitation, seizures, mental derangement (hallucinations, paranoia, insomnia, anxiety, disorientation)
- DARK URINE = PORPHYROBILINOGEN IN URINE
symptoms last few days - months.
what proteins would be accumulated with AIP?
- ALA
- porphobilinogen
IN BLOOD AND CSF
what occurs if a person with AIP is treated with sedatives?
this increases cytochrome p450 synthesis via delta ALAS, which depletes the pool of free unbound heme, causing delta ALAS to be unrepressed (active), making the buildup of porphobilinogen`
how would a person with AIP be treated?
withdrawal of offending drugs, infusion of hematin (a stable derivative of heme), which represses delta ALA synthase
ALSO carb rich diet bc it represses synthesis of ALA synthase
what is the most common porphyria
porphyria cutanea tarda
what causes porphyria cutanea tarda?
- deficiency in uroporphyrinogen decarboxylase
- alcoholism or liver damage
why is iron overload important in porphyria cutanea tarda?
uroporphyrinogen decarboxylase is sensitive to inhibition by iron salts.
symptoms of porphyria cutanea tarda
cutaneous photosensitivity - common in older men during summer - sunlight hits uroporphyrinogen III and becomes a free radical
what is the difference between acute intermittent porphyria and porphyria cutanea tarda?
AIP produces neurological and abdominal symptoms.
PCT only produces decreased heme and cutaneous sensitivity to light.
how is porphria cutanea tarda treate
avoid sunlight, abstinence of alcohol, phlebotomy to reduce iron overload
lifespan of RBC
120 days, then degraded by liver and spleen
where does most heme come from?
- RBC
- turnover of heme containing proteins - cytochrome p450 enzymes, catalase, myoglobin
what is heme broken down into?
bilirubin and Fe2+
what is the initial reaction of heme catabolism?
cleavage of porphyrin ring by heme oxygenase, producing bilverdin (yellow-green) and CO, and releases oxidized Fe2+
what breaks down biliverdin?
biliverdin is broken down into bilirubin by biliverdin reductase in the macrophages (red-orange)
how is bilirubin transferred to the liver?
binds to albumin