Heme biosynthesis and Porphyrias Flashcards
What are Cytochrome P450 enzymes?
Heme is used by the liver to produce these proteins. They are used for liver detoxification, bilirubin metabolism (jaundice), synthesis of vitamin D.
What are porphyrins?
Oxidized versions of porphyrinogens. This oxidation makes them conjugated which allows them to absorb light. Release of the absorbed energy produces reactive oxygen species that damage tissues.
Step One of Heme Biosynthesis?
Succinyl CoA and glycine
ALAS (ala synthase) makes delta-ALA
Which enzymes are inhibited by lead?
How would you treat lead poisoning?
What are some symptoms of lead poisoning?
How would you diagnose lead poisoning?
ALAD (ala dehydratase)
-also has a higher affinity so it gets inhibited first.
and Ferrochelatase.
Use lead chelators so lead will be excreted in urine.
Malaise, abdominal cramps, arthralgia, nausea, neuropathy.
Accumulation of ALA in urine, absence of iron so ZPP (zinc protoporphyrin is formed), basophilic stippling in smear
what is the cause of acute intermittent porphyria? Treatment?
inhibition of PBG deaminase leading to the buildup of ALA and PBG. Hyperactivity of ALAS leads to reduced PBG deaminase activity.
Treatment would be to inhibit ALAs so you could use heme which inhibits ALAS1. Carbon loading or using insulin
Why does heme synthesis stop when RBC mature?
RBC’s lose mitochondria and the first step occurs in mitochondria, so does incorporation of iron into heme.
What are two other names for PBG deaminase?
PBG is also being made into hydroxymethylbilane and uroporphyrinogen III so other names are Hydroxymethylbilane Synthase
Uroporphyrinogen I synthase
Talk about solubility?
ALA and PBG (porphyrin precursors) (PBG looks like a pyrolle) is water soluble.
Then it decreases with each step due to loss of carboxyl chains.
Where is vitamin B6 found?
vitamin B6 is a cofactor in the first committed step.
What are the 4 Ms that induce transcription of ALAS1 in the liver and how?
Medication (barbituates, alcohol, steroids)
Menstruation
Maladies
Malnutrition
The liver activity increases, increasing the number of p450 cytochrome enzymes which are heme containing themselves. Demand for heme goes on which stimulates transcription of ALAS1.
How is ALAS2 regulated.
ALAS2 is inhibited by low iron. The IRP (iron response protein) will bind to iron response element on the ALAS2 mRNA, degrading it or something.
What are the two symptoms of sideroblastic anemia?
one: ring sideroblasts appear in the bone marrow (they have excessive accumulation of iron in the mitochondria - this would impair heme synthesis as urod is inhibited)
two: the mature RBCs are smaller than normal (microcytic) and appear pale (hypochromic) because of less hemoglobin.
Can be heredited or induced by lead.
Most porphyrias are inherited in an autosomal dominant manner, name the two exceptions.
Porphyria Cutanea Tarda - can be aquired.
Congenital Erythropoietic Porphyria - is autosomal recessive.
Name the three porphyrias, their associated deficiencies, symptoms and treatment.
Starting with AIP
Acute intermittent porphyria - deficiency in PBG-deaminase (aka hydroxymethylbilane synthase, uroporphyrinogen I synthase), abdominal pain, no skin lesions, propensity for liver cancer, peripheral neuropathy, gastrointestinal disturbances. Urine will have a dark brown color, due to PBG in urine. Avoid the 4M’s, load on glucose, administer hemin/hematin.
PCT
PCT (most common) - definciency of Uroporphyrinogen DECARBOXYLASE (UROD), caused by alcohol, liver iron overload, HPB,C, or HIV infection.
Symptoms are high uroporphyrin levels (from the lab)
BULLAE-bumps on skin filled with clear fluid,
HYPERTRICHOSIS- abnormal skin growth on cheeks
Heliotrope: red purple coloration of skin.
SKIN LESIONS, photosensitivity.
Detection: way more urophorphyrins compared to coproporphyins in urine. or you can assay for enzyme activity of UROD.
Remove environmental exposures, use sunscreen, iron chelators, phlebotomy (bleeding, reduces iron stores and improves UROD activity)
