L52 porphyrins

Question 1

structure and importance to humans

Answer 1

cyclic compounds with 4 Pyrole rings
-8 side chains, 2/pyrrole

methenyl bridges (oxidized) (colored) =

methylene bridges(reduced) (colorless) (OGEN)

only TYPE II with asymmetry on D ring are important to humans

HEME: protoporphyrin IX with Ferrous iron Fe2
-STRONG AFFINITY FOR METAL IONS ESP IRON

Question 2

synthesis of heme, where

Answer 2

85% erythropoeises bone marrow
10% liver
5% all else

mito: 1, 6-8
cytoplasm 2-5

alsways acrive but upregulated when higher demand for heme…in liver with drug/alcohol metabolism

in BM with blood loss

Question 3

Biosynthesis of Porp (draw out)

Answer 3

GLYCINE + SUCCINYL COA

include: ala synthase (RL)-reg VitB6
- ALAS1:hepatic, inhibited by free heme and hemin (Fe)
- ALAS2 erythroid tissue: stim by free intracellular iron

dALA Dehydrase (SENS TO LEAD POIS)

• 2molecules ALA
• Porphobolinogen

Tetrapyrrole int
-FOUR PBG COMBINE TO MAKE
Urophorphyrinogen III
-using hydroxymethybiliane synthase
-and uroporphobolinogen III synthaswe
then decarboxylation to make
Coproporphyrinogen III
-ENTERS MITO
-two oxidases make PROTOPORPHORIN IX

4. Formation of Meme
   spontaneously combine wiht iron

Question 4

regulation ALA1 synthase

Answer 4

liver via cytochrome p450

• feedback expression by small cytoplasmic pool, bwhen body does not have increased demand on heme, levels of free heme and hemin increase, which decreases ALAS1 concentration
• hemin inhibits trascription of ALAS1
• heme inhibits translation of mRNA ALAS1
• and translocation of ALAS1 into mito

activationL increased demad (durga/alcohol 3-5/day)

Question 5

Regulation ALAS2

Answer 5

bone marrow, hemoglobin

intracellular iron increases, irons binds to IRP iron regulating protein, resulting is dissocation of IRP from IRE iron responsive element
-ala translation proceeds

intracellular iron decreases IRP binds to IRE, tranlslation nihibited, decrease in iron, decrease in heme, decrene sin hemoglobin synth

Question 6

HRI Kinase and EIF2

Answer 6

heme present Hb synthesis

heme absent
-heme does not block regulatory protien

slide 37

Question 7

review basics of porphorias

Answer 7

where, why, how

Question 8

Acute intermittent porphorya

Answer 8

hydroxymythylbilane synthase defect
ALA and DBG accumulation

no photosensitivity
abdominal pains/and neuro-psychosis

chilically latent AIP-regulatory heme pool sufficiently high to repress ALAS1 expression

clinically manifest AIP: precipitating factors, (drugs/alcohol)deplete heme pool, increasing ALA S1 expression
-ala and PBG accumulate

Question 9

Porphorya cutanea tarda

Answer 9

most commin withlate onset
acquired-alcohol or iron overload and/or partial defect of uroporphyrinogen decarboxylase
-accumulation of uroporphyrinogen III leads to spontaneous formation of uroporphyrinogen I and coproporphynogen I, all three undergo spontaneous oxygenation to photosensitive mols, which acc in urine

urin is red, and skin eryptions

avaoid precipitating factors, alcohol, meds with hep metabolism,
-intravenous injection of hemin or hematin (ALAS1 inhibitors)

porphyrins can absorb light bc of electorn confic. once stimulated, can return to stable stat with
-emmiting light (flourescence) (brown teetch that folouresce in UV
-trasfer that E to Oxygen making SUPEROXIDE RADICALS
-damage membrane lipids, photodynamic reaction
(blisters, scaring, thickens, sclerotic, fear of sunlight)

Question 10

Erythropoietic Porphyrias

Answer 10

cong eryth porph and eryth protoporphoria- char by skin rashes, photosentivity, and blisters in early children. NO NEUROLOGICAL

treat with phlebotomy
-even when serum levels or iron are not increased.

500ml of blood takedn weekly or biweekly
-decrease ALAs2 mrna and cuts down on excessive production of toxic intermediates.

patients with cutaneous porph should avoid sunlight and take Bcarotene which scavence oxygen free rads.