function of heme?
1. oxygen carrier proteins like hemoglobin, myoglobin
2. e- tranfer enzymes like mito cytochromes and cytochrome B5 of microsomes
3. cytochrome P450 drug toxification enzymes
5. prostaglandin synthase
6. tryptophan dixoygenase
and other enzymes
where's heme synthesized
mostly in the livery and erythropoetic tissues like marrow
however all tissues produce heme
where does heme synthesis occur
both mito and cyto
structure of heme
ring structure, "protoporphyrin IX"
4 pyrrole rings linked by methene bridges
iron in the middle of the ring
what is heme synthesized from
succinyl CoA + glycine
succinyl CoA is from valine, methionine, isoleucine, threonine via methylmalonyl mutase-B12 rxn
how does heme itself control the synthesis pathway
1. it inhibits translation of ALA mRNA, activity of ALA synthase, and transfer of ALAS into the mito
2. inhibit ferrochetolase
what inhibits ferrochetolase
heme, product inhibitor
2nd step of heme synthesis?
2 moles of ALA leave mito -> Cyto; there, via ALA dehydratase condense to form Porphobilinogen, PBG, a pyrrole ring structure
what is the first step of heme synthesis, where does it occur
in the mito
succinyl CoA from the TCA cycle or from Valine, Isoleucine, Leucine, or Threonine is present
succinyl CoA + glycine -> delta aminolevulinate, ALA via delta aminolevulinic synthase, ALA synthase w/ cofactor PLP-B6
H+ + CO2 + CoA are released in this rxn
rate limiting step
HEME end-product inhibits it
overall heme synthesis pathway?
1. in mito, succinyl CoA + glycine -> ALA via ALA synthase, w/ PLP-B6 cofactor; H+ -> CO2 and CoA released
2. ALA -> Cyto
2 moles ALA condense via ALA dehydratase -> 4 PBG
3. 4 PBG via Porphobilogen Deaminase + Uroporphyrinogen Synthase -> Uroporphorinogen III
4. Uroporphorinogen III -> Coproporphorinogen III via Uroporphyrinogen decarboxylase
5. Coproporphorinogen III -> Protoporphyrinogen IX via coproporphyrinogen oxidase
5. Protoporphyrinogen IX -> Mito
6. In mito, Protoporphyrinogen IX -> Protoporphyrin IX via Protoporphyrinogen oxidase
7. Protoporphyrin IX -> HEME via Ferrochetolase which inserts Ferrous (2+) iron into protoporphyrin, producing Heme IX
which enzymes of the heme synthesis pathway are sensitive to lead?
1. ALA dehydratase which makes ALA -> PBG
2. Ferrochetolase which makes Protoporphyrin IX -> Heme
why is lead poisoning toxic
it inhibits ALA dehydratase and ferrochelatase so inhibits heme synthesis
this causes ALA accumulation -> destroys RBCs -> anemia
what is the paint chip issue
old paint had lead as base
children may ingest lead paint chips, and this is toxic
difference between heme made in erythropoetic tissue and heme made in liver?
erythropoetic tissue's heme -> hemoglobin
liver's heme -> cytochromes, esp Cytochrome P450 enzymes
how is Fe toxic
Fe increases ROS
We ingest most Fe; if loose in blood may be destructive to RBC and WBC b/c catalyzes O2 Radical formation
how is Fe stored in tissues
in ferritin, a complex of Fe 3+ and apoferritin
function of ferritin
powerful antioxidant - it binds Fe, makes Fe stable, doesn't catalyze O2 radical reactions (i.e. Fenton rxn, Haber-Weiss rxn)
in what state is iron absorbed?
in what state is it carried through the body?
absorbed: Ferrous (Fe2+) state
carried: Ferric (3+) state by apotransferrin
how is iron usually found in body
bound to proteins, b/c free Iron is toxic
what does amount of ferritin in the blood indicate
amount of iron in storage b/c little ferritin is usually present in the blood, but its amount increases as iron stores increase
thus ferritin amount in blood is most sensitive indicator of amount of iron in body's stores
what is hemosiderin
a ferritin complexed w/ additional iron that cannot be readily mobilized
it's how excess iron absorbed from the diet is stored
what happens if there's a deficiency in a heme biosynthesis pathway enzyme?
accumulation of the porphyrin substrates
causes symptoms and diseases called porphyrias
what are important symptoms caused by porphyrias
skin damage, photosensitivity, neurological probelms, GI tract irritation, nausea
why do the symptoms of porphyrias occur?
b/c porphyrins accumulate in the skin, intestinal t rack, brain
many have = bonds, and are easily oxidized by singlet O2
treatment for porphyrias?
lifetime of a RBC?
1/2 life of CYT?
what causes heme breakdown?
hemoglobin or CYTP450 enzymes or other enzymes
how is heme broken down to bilirubin?
1. heme cleaved by heme oxygenase, a CYP450, to biliverdin
requires O2, NADPH
CO is released
this is mixed funciton oxidase
2. biliverdin is reduced by viliverdin reductase to bilirubin
NADPH is the reductant
3. uncojugated/indirect bilirubin + albumin -> liver
3. in liver, bilirubin is conjugated to glucuronic acid by UDP-Glucuronoyltransferase
produces conjugated/direct bilirubin
4. conjugated bilirubin -> gut, or -> kidney
how is bilirubin transported from nonhepatic tissues -> liver
binds to albumin, moves as non-conjugated/indirect bilirubin-albumin complex
goes to liver conjugated to albumin
once in liver, undergoes conjugation
what happens to bilirubin once in the liver
conjuating enzymes put a glucose residue as UDP-glucuronate on to the bilirubin; make bilirubin diglucuronide
that -> direct conjugated bilirubin -> bile, -> feces, -> excreted
biliverdin reductase fxn?
biliverdin -> bilirubin
function of heme degredation?
recycle hemoglobin of RBCs which have reached end of their lifespan
globin is recycled to amino acids, Fe2+ is recycled, and heme is excreted as bilirubin
what gives feces its brown color
breakdown product of bilirubin diglucunoride
what gives urine its yellow color
some urobilinogen, an intestinal intermediate, is reabsorbed into blood and excreted as urobilin into urine
uroblinogen gives urine the yellow color
cause of jaundice?
accumulation of bilirubin, -> yellowish coloration, bilirubin toxicity, esp to developing brain
what metabolically underlies cause of jaundice?
due to hemolysis and RBC breakdown, so bile ducts get blocked
decreased conjugation enzyes - usually these develop after the first few days of life; newborns thus are very sensitive to having bilirubin accumulate b/c may not have conjugating enzymes
how to treat jaundiced newborn?
put them under blue light radiation which reacts w/ these e- and fragments the bilirubin to small fragments
why are aa considered precursors of heme?
4 aa become succinyl CoA - Met, Isol, Thre, Val - and Succinyl CoA + glycine is the first step of heme synthesis pathway
why does lead cause anemia?
it inhibits the ALA hydratase and Ferrochelatase steps of heme synthesis
this causes accumulation of ALA
ALA accumulation is toxic -> destroys RBC -> anemia
additionally, insufficient heme + RBC -> insufficient oxygen-carrying-capacity in blood
how is heme synthesis regulated
by Heme itself, which end-product inhibits Ferrochetolase
and ALA Synthase, as well as the translation of ALA mRNA, activity of ALA synthase, and transfer of ALAs into the mito.
"typical" symptoms associated w/ porphyrias?
GI tract irritation
reaction catalyzed by heme oxygenase?
heme oxygenase is a CYP450 that catabolizes heme to biliverdin through a mixed function oxidase reaction that uses O2 + NADPH + H+ -> NADP+ + Fe3+ + CO
what is oncjugated bilirbin and what function does conjuation provide?
Conjugated bilirubin is bilirubin in the liver that has been conjugated to glucuronic acid by UDP-glucuonoyltransferase; this conjugated, direct bilirubin is soluble, and can be excreted to the bile. This is as opposed to unconjugated bilirubin, which is not soluble in water.