Heme Synthesis Flashcards
How are porphyrins produced? What are side chains they can possess?
Linking 4 pyyrole rings
3 types of side chains: methyl, vinyl, propionate
What is another name for heme?
Fe Protoporphyrin IX
What is heme produced in the liver mainly used for?
Synthesis of CYPp450 enzymes.
Why are CYP enzymes important?
Phase 1 Liver detox Detoxify xenobiotic (toxicit/chemical/alcohols/carcinogens->convert to h20 and 02) Bilirubin metabolism Syn. Vit D Cholesterol synthesis Syn. Of bile and bile acids
What are the precursors to porphyrin? Are these molecules active?
ALA and PBG
Biologically inactive and water soluble (excreted in urine)
What are porphyrinogens? What form are they found in?
Larger molecules whose aq. Solubility varies based on number of COOH side chains
Biologically active
Reduced form.
Uro
Copro
Sterco
Urine
Feces/Urine
Feces
What are porphyrins? Why are they oxidized?
Molecules detected and measured in clinical laboratories (oxidized form)
-> oxidation creates conjugation system that allows molecules absorb visible light.
Why do oxidized porphyrins manifest clinically?
Release of absorbed energy produces ROS that damage tissue.
Where does Heme biosynthesis take place in the cell?
Both Cytoplasm and mitochondria
What steps of Heme syn. Occur in mitochondria?
1st step:
Generation of d-ALA from Succinyl CoA and glycine (via ALAS)
Last 2:
Coproprophyrinogen III —->Proroporphyrinogen (via copro oxidasse) —-> Protoporphyrin IX (via protopor oxidase) —->Heme (via Ferrochelatase+Fe2+)
What steps of hemesyn. occur in cytosol?
ALA —-> PBG (via ALAD)
PBG —-> hydroxymethylbilane (via PBGD)
Hydroxymethy…—->uroporphyrinogen III (uroporIII cosynthetase_
What two tissues have the highest rate of heme biosynthesis?
Bone marrow erythroid cells (constitutional)
Liver (depends on function desired)
Why do mature RBCs stop syn. Heme?
Lack mitochondria. (Progressive loss thru autophagy)
What is the committed and regulated step of Heme syn?
Succinyl CoA + glycine —-> ALA (via ALAS)
ALA formed in mitochondria, transported to cytoplasm.
What is difference btwn ALAS1 and ALAS2
Housekeeping (liver) ALAS1
Erythroid-specific - ALAS2
What is another name for ALAD (the enzyme responsible for converting ALA to PGB?
Porphobilinogen synthetase.
Cytoplasmic.
Zinc containing enzyme, 1st precursor to pyrole synthesized
INHIBITED BY LEAD
What does PBGD synthesize?
Hydroxymethylbilane
(Combination of 4 PBG) into a linear tetrapole.
What are the 2 pathways that Hydroxymethylbilane proceed thru?
Spontaneous (@ high [ ]) -> URO I —> COPROI
Uroporphyrinogen III (via URO III syn) —-> Coprophyrinogen (via URO III decarb)
Where is ferrochelatase found? What is it’s function?
Mitochondiral enzyme.
Adds Fe2+ to protoporphyrin IX to form Heme
INHIBITED BY LEAD (not as important as ALAD inhibition)
What is water solubility of ALA & PGB?
Water soluble. Excreted in urine
Rank the solubility of Copro/Proto/and Uro porphyrins? Why is there solubility changing?
- Uro
- Copro
- Proto
Decarboxylation makes these porphyrins less and less soluble.
What is the most important step of heme syn?
ALA synthase (committed step)
Succinyl CoA + glycine —-> ALA
What ALAS is found in liver cells? Erythroids?
Liver: ALAS 1
Erythroids: ALAS2
How is ALAS regulated in liver?
ALAS-1
- Allosteric feedback INHIBITION by HEME/(HEMIN/HEMATIN-stable oxidized forms of heme_
- Inhibition of new ALAS protein transport from cytosol to mitochondria
- Repression of transcription of ALAS by heme, insulin, glucose (carb loading)
How can we induce transcription of ALAS1?
4M’S
1. Medication
(Barbituates, alcohol, steroids, SMX/TMP, erythromycin
- Menstruation (or any bleeding really)
- Malnutrition
- Maladies
What happen if we take a drug that uses CYP enzymes to break down the medication?
Induces CYP enzymes leading to increased demand for heme.
B/c of this increased demand the [heme] in the cell decreases which then turns on transcription of ALAS
How do we regulate ALAS in erythroid cells?
ALAS2
There is a repression of TRANSLATION of ALAS2 when [iron] cell via an iron response element.
Low iron, iron responsive element binds and prevents translation.
If there is low IRON content in your erythroid cell, will you produce ALAS2?
NO. Iron is a positive feedback modulator. Your cells are saying why bother producing heme now, we don’t have the iron for it.
What are the 2 common features of sideroblastic anemias? (@ erythroids)
- Ring sideroblasts in bone marrow (excessive iron accumulation)
- Mature RBCs appear with hypochromic, microcytic anemia. B/c shortage of Hgb
What is an example of a hereditary Sideroblastic anemia?
Congenital X-linked (erythroid specific) d/t ALAS-2 mutation.
Disrupts overall heme production. Leads to accumulation of iron.
(Also Mitochondrial cytopathy)
What are some types of acquired sideoblastic anemia?
- Drug Tx : ISONIAZID, ETHANOL
- Toxins: Lead (ALAD inhib)
- Nutritional: Pyridoxine deficiency
All lead to decreased heme formation which increases Fe deposits.
What 2 enzymes in the heme syn. Pathway does Lead inhibit? Which one is more sensitive to effects of lead?
- ALAD - more sensitive
- Ferrochelatase
- Pyrimidine 5’-nucleotidase (not as important)
How do we treat lead poisoning?
Lead chelators:
- Desferrioxamine mesylate
- Sodium Calcium edetate
- Penicillamine
what are S/Sxs of Pb poisoning?
*important one, look for gingival and long bone lead line.
How do we Dx Lead poisoning?***
- Accumulation of ALA in urine (b.c. ALAD inhibition)
- Zinc protoporphyrin in blood* (zn substitutes with iron)
- Basophilic stippling in peripheral smear***
What is a porpyrias?
Pathology stemming from defects in heme biosynthesis. Most are autosomal dominant genetic diseases.
What are some of porphyrias that we talk about in class?
- AIP (Acute intermittent porphyria -PBGD inhib)
- Porphyria Cutanea Tarda (PCT - UROD inhib)
Has genetic and non-genetic factors - Erythropoietic protoporphyria (EP - Ferrochelatase defic?)
How do acute vs non-acute porphyrias differ?
Acute: accum. Of ALA + PBG +/- decrease of heme
Presents with Neuropsych s/sxs
Non-acute: accum. Of porphyrinogens in skin and tissues —>spontaneous oxidation or porphyrinogens to porphyrins—>photosensitivity
What enzyme is inhib in AIP? How common is it?
Acute Intermittent Porphyria. 2nd most common.
Partial deficiency in PGBD
1-10/100,000
Presents with neurosymptoms d/t accumulation of ALA/PGB
What are S/Sxs of AIP?
NO SKIN LESIONS
Only 10% develop diz, but all are at risk for liver diz
Peripheral neuropathy
W>M
How do the 4M’s interplay with AIP?
4Ms increase transcription of ALAS b/c heme is being used.
This increases ALA/PGB precursors that cannot be broken down fast enough
Qualify the color of PGB in urine
PGB oxidized to porphobilin –> dark brown ‘port-wine reddish color’
How do we Tx AIP?
- Avoid precipitating factors (4M’s)
- Glucose loading
- Heme Tx (end the feedback loop)
What porphyria results from deficiency of the UROD enzyme? How common is it?
Most common
Porphyria Cutanea Tarda (PCT)
Typically autosomal dominant w/ onset in 4th/5th decade
How is UROD influenced environmentally?
- Alcohol
- Hepatic Iron overload
- Exposure to sunlight
- HBV/HCV/HIV
- Hydrochlorobenzene
What are S/Sxs of PCT?
Exposed areas: Blisters (bullae), hair (hypertrichosis), milia,
DARK PINK FLUORESCING URINE
Uro: Coprophyrins 3-5:1
What is pathology for skin lesions in PCT patients?
Spontaneous oxidation of porphyrinogens to porphryins in the skin
How do we Tx PCT?
Remove enviromental UROD inhib (Alcohol/tobacco/ERT)
Sunscreen
Chelation with desferrioxamin
Phlebotomy (decreases iron stores)
*remember iron is a positive feedback modulator. If we have lots of iron, we will have lots of heme syn.
What is enzyme is deficient in Erythropoietic protoporphyria? (EPP)
Ferrochelatase
Autosomal Dominant
Onset in early childhood, severe cutaneous sensitivity
