Heme Biosynthesis (Flipped Classroom) Flashcards
Highest rate of heme biosynthesis?
Bone marrow erythroid cells (85%)
- constant turnover of erythroid cells
- mature RBCs lack mitochondria, heme synthesis stops when RBCs mature
- also produced in liver
Heme produced in liver mainly for
Synthesis of CYP450 class of enzymes
Function of enzymes:
1) phase I liver detoxification
2) detoxify xenobiotic stuff/chemicals/etc to H2O,O2
3) bilirubin metabolism (product of heme breakdown!)
4) synthesis of: cholesterol, bile/bile acids, vitamin D
Porphyrin precursors
1) ALA (Aminolevulinic acid)
2) PBG (Porphobilinogen)
~molecules before we make the first pyrrole molecule~
Porphyrins
- H2O soluble
- excreted & measured in urine
- biologically inactive
- OXIDIZED (conjugation system, allows molecules to absorb visible light)–>release of energy products ->ROS that damage tissues
- COLORED
- these accumulate in urine and we can measure them to distinguish between different types of porphyrias (spectrophometric & fluorescent properties)
Porphyrinogens
-4 pyrrole molecules
—–>condensed in reduced form, colorless
-biologically ACTIVE
-large
-aqueous solubility depends on # of carboxylic acid side chains
Ex: least soluble: 2C, protoporhyrin excreted in feces
Uro-
Urine
Copro-
Feces
-much less water soluble and is excreted in feces as well as in urine
Sterco-
-feces
Committed and regulated step of heme biosynthesis
1) location?
2) enzyme/cofactors required?
Succinyl CoA+ glycine –> d-ALA
1) mitochondria
2) ALAS (d-aminolevulinic acid synthase), pyridoxal phosphate (inhibited by Fe)
ALAS1
Housekeeping & liver
ALAS2
Erythroid specific
When is 1st pyrrole molecule made in heme biosynthesis?
- location?
- Enzyme?
- inhibited by?
- H20 soluble?
D-ALA—> PBG
-cytoplasm
Enzyme: d-ALA dehydrase (ALAD) aka PBG synthase
- contains zinc
- inhibited by Pb
- H20 soluble, excreted in urine (for following, H20 solubility decreases bc of decaboxy steps; excreted in bile)
Mitochondrial enzymes in heme biosynthesis
ALAS, coproporphyrinogen oxidase, protoporhyrinogen oxidase, ferrochelatase
Ferrochelatase is inhibited by
Pb
Allosteric feedback inhibition of. ALAS by
Heme
–>inhibition of newly synthesized ALAS protein transport from cytosol to mitochondria
Insulin, glucose, carbohydrate loading
Drugs: hemin, he matin (pharmacological analogs of heme, oxidized analogs of Fe3+)
Induction of transcription of ALAS1 by:
4M’s
1) medication (barbs, alcohol, steroids, sulfa antibiotics); these are metabolized by CYP450 enzymes
2) menstruation (any bleeding)
3) malnutrition (starvation, dieting)
4) maladies (stress, trips, exams, infection)
* **somehow these decrease HEME so that is why ALAS1 transcription is induced!!!
Less heme –> promote its synthesis
What induces ALAS-1 transcription?
Peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1A)
—> insulin, glucose, heme inhibits it!
PGC-1a is a coactivator of nuclear receptors & transcription factors
Regulation of ALAS2 in _____ cells
Regulation of ALAS2 in erythroid cells
There is a repression of translation by low iron content
- translational repression of ALAS2 by IRE in 5’ UTR
- dec Fe promotes binding of IRP to IRE –> ALAS2 mRNA translation is inhibited
- inc FE promoted unimpressed translation; nothing bound to IRE, ALAS2 mRNA translation good to GO
- ->ensures ALAS2 made only when sufficient iron available for heme synthesis
2 common features of sideroblastic anemia
1) ring sideroblastic in bone marrow (due to excessive accumulation of iron in mitochondria)
2) impaired heme biosynthesis
What do mature RBCs look like in sideroblastic anemia?
1) microcytic (smaller than normal)
2) hypo chromic (pale due to shortage of hemoglobin)
Congenital X-Linked Sideroblastic Anemia
- hereditary
- erythroid specific
- ALAS2 mutation
- —->reduced production of heme and excessive accumulation of iron in cells
Mitochondrial Cytopathy (sideroblastic anemia)
- hereditary
- abnormality in mitochondrial DNA (mtDNA)
Myelodysplasia
- acquired sideroblastic anemia
- mtDNA point mutations
Drugs that result in acquired sideroblastic anemia
- isoniazid (for tuberculosis)
- —–> decrease active form of pyridoxal phosphate
-Ethanol
Toxins & nutritional stuff that can cause an acquired sideroblastic anemia
Toxin: lead (inhibited ALAD, aka PBG synthase)
Nutritional: pyridoxine deficiency (required for ALAS)
What 2 key enzymes does LEAD inhibit of heme synthesis
1) ALAD (d-ALA –> PBG)
2) Ferrochelatase (Protoporphyrin IX —> Heme)
**** ferrochelatase is less sensitive than ALAD to the effects of lead
Treatment of lead poisoning
-lead chelators
—>Bind lead & lead is excreted in urine
Chelators:
1) desferrioxamine mesylate
2) sodium calcium edetate
3) penicilliamine
Mechanism of lead poisoning
Inhibits ALAD and ferrochelatase
—> accumulation of ALA
Deficiency in Acute intermittent Porphyria
PBG-Deaminase aka hydroxymethylbilance synthase of uroporphyrinogen I synthase
Deficiency in Porphyria Cutanea Tarda
Uroporphyrinogen decarboxylase
Deficiency in Erhythropoietic Protoporphyria
Ferrochelatase
Substrate accumulation in AIP
PBG
Solubility increase –> greater neurological symptoms
Substrate accumulation in PCT
Uroporphyrinogen
Photo sensitivity increase
-blister formation, hypertrichosis for skin with highest sun exposure
Substrate accumulation in Erhythropoietic Protoporphyria
Protoporphyrin IX
Extreme cutaneous photo sensitivity burning stinking pain w sunlightq
Treatment of AIP
He matin/hemin, glucose
Want to inhibit ALAS
Treatment of PCT
Phlebotomy, Chelation
Want to reduce Fe2+ stores, reduce UROD inhibition
Treatment for EPP
Sun avoidance
What inducers heme synthesis
P450 drugs, Alcohol, etc.
4Ms
