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9. Heme metabolism
BrownMed
31
Business
Undergraduate 4
10/09/2010

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Term
porphyrins
Definition
contain 4 pyrrole rings linked together to form a macrocyclic compound that binds iron at the center. = tetrapyrroles
Term
heme
Definition
iron protoporphyrin IX. most abundant tetrapyrrole in vertebrates
Term
heme synthesis step 1
Definition
glycine+succinylCoA>ALA (delta-aminolevulinic acid). catalyzed by ALA synthase which requires pyridoxal phosphate and is inhibited by heme. (committed and rate-limiting step of hepatic porphyrin synthesis, takes place in the mitochondria.)
Term
heme synthesis steps 2 on
Definition
2ALA> porphobilinogen (in cytosol, inhibited by lead). 4 porphobilinogens>hydroxymethylbilane, which is cyclized to produce uroporphyrinogen III. side chain modifications > protoporphyrin IX.
Term
when does heme become heme?
Definition
when iron joins with protoporphyrin IX via ferrochelatase. (blocked by lead)
Term
where is heme synthesized
Definition
bone marrow and liver
Term
regulation of heme synthesis / in bone marrow specifically
Definition
liver's cytochrome P450 monooxidase system consumes heme to detoxify things. drugs that are metabolized in this cycle use up heme. this upregulates ALA synthase. lead, heme inhibit process. / erythropoietin and the availability of iron.
Term
regulation of hemoglobin synthesis
Definition
2 alpha and 2 beta globin protein chains, each attached to a heme group that can bind oxygen or CO2. *It is crucial to maintain a balanced ratio of the globin protein chains of hemoglobin with heme: excess heme turns off ALA synthase and excess globin turns off globin protein synthesis (and these two also regulate each other= elf2/HCI)
Term
elF2
Definition
is a translation factor that initiates the translation of globin protein and is inactivated when phosphorylated by HCI (heme-controlled inhibitor), which is only active when heme is not available to suppress its function. therefore, low heme leads to the inactivation of globin synthesis.
Term
porphyrias
Definition
defects in heme synthesis, all autosomal dominant except congenital erythropoietic porphyria. when the accumulated intermediate is a tetrapyrrole, you get photosensitivity.
Term
porphyria cutanea tarda
Definition
most common of the porphyrias. chronic disease of liver and bone marrow. deficiency of uroporphyrinogen decarboxylase, accumulation of uroporphyrin. dark red urine and photosensitivity.
Term
acute intermittent porphyria
Definition
defect in porphobilinogen deaminase. ALA and porphobilinogen accumulate (no photosensitivy - only one!) = GI pain, neurologic/psychiatric symptoms, cardiovascular symptoms. episodes may be preceded by drugs that consume P450 heme, activating ALA synthesis. (do NOT give phenobarb and send home, it will make it worse.)
Term
erythropoietic protoporphyria
Definition
deficiency in ferrochelatase causes protoporphyrin to accumulate > photosensitivity
Term
congenital erythropoietic porphyria
Definition
defect in uroporphyrinogen III synthase = accumulation of uroporphyrinogen I and coproporphyrinogen I. photosensitivity.
Term
heme degradation
Definition
85% of cells programmed to die are at end of 120 day cycle. within splenic macrophage, heme and globin are separated. heme decyclized to biliverdin, which is reduced to bilirubin, which binds to albumin in the blood. hepatocytes conjugate bilirubin with 2molecules glucuronic acid (to improve solubility), releasing bilirubin glucuronide into bile. in intenstine, is metabolized by bacteria to urobilinogen.
Term
urobilinogen> (2)
Definition
stercobilin (brown feces) or urobilin (yellow urine)
Term
hemolytic jaundice
Definition
normal bilirubin = 300mg/day, capacity=3000mg/day, but any more lysis and you get jaundice. (ex. sickle cell anemia, g6pd deficiency, pyruvate kinase deficiency)
Term
hepatocellular jaundice
Definition
liver damage = more unconjugated bilirubin. stools are pale, urine is dark, patients experience anorexia and nausea. high serum levels of AST, ALT
Term
obstructive jaundice
Definition
cancer or gall stones in bile duct. abdominal pain and nausea, dark urine, pale stool.
Term
neonatal jaundice
Definition
first 4wks = can't conjugate bilirubin. if level rises above capacity for albumin to bind this poorly soluble compound in blood, toxic encephalopathy occurs. treat with blue fluorescent light, makes it soluble.
Term
catalase
Definition
uses heme
Term
other things heme makes
Definition
oxidases (H2O2), bile pigments, chlorophyll, coenzyme b12 not in humans
Term
ALA dehydratase
Definition
inhibited by lead; enzyme that binds 2ALA into porphobilinogen
Term
ALA synthase regulation
Definition
heme, glucose. inducted by phenobarb, alcohol, hypoxia.
Term
t/f ferrochelatase allows iron to bind with heme
Definition
false - iron and heme bind spontaneously, but ferrochelatase is a catalyst
Term
excess iron is toxic due to
Definition
free radical generation
Term
serum iron is complexed to / cellular...
Definition
transferrin / ferritin
Term
carnivores absorb ___ but humans don't as effectively
Definition
heme.
Term
erythropoietic porphyrias
Definition
cutaneous symptoms, appear in early childhood, some complicated by liver cirrhosis
Term
what color is urobilinogen?
Definition
colorless
Term
how are different porphyrins distinguished from one another?
Definition
by types and distribution of side groups
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