heme synthesis and regulation Flashcards
illustrate of porphyrin structure
- 4 pyrrole rings linked by methenyl bridges (-CH)
- form complex with metal ion ( Fe or Mg )
- conjugate with protein to form hemoprotein
- side chains of heme present in Hb (proto) : 2P propionyl , 2V vinyl & 4M methyl
illustrate the difference between heme and hemin
- heme : ferrous iron (Fe +2 ) + protoporphyrin IX
- hemin : “ hematin , oxidized heme “ ferric iron (Fe +3 ) + protoporphyrin
def of porphyrinogen
reduced ( hydrogenated ) porphyrin contain methylene (-CH2) not methenyl (-CH)
list types of hemeprotein and their function
- Hb : transpor O2
- myoglobin : storage O2 in muscle
- cytochrome P450 : hydroxylation of xenobiotic as drugs
- cytochrome C : in electron transport chain “ respiratory chain “
- catalase : degradation of H2o2
- cytoplasmic guanyl cyclase : formation of cGMP
- tryptophan pyrrolase : oxidation of tryptophan
list the site of biosynthesis of heme
-all tissue ( except RBCs, no mitochondria) especially :
bone marrow ( erythrocytic )
liver ( non erythrocytic)
list the site of biosynthesis of heme
-all tissue ( except RBCs, no mitochondria) especially :
bone marrow ( erythrocytic )
liver ( non erythrocytic)
the reactions are ……….
irreversible
to produce one heme we need ….. & ……
8 glycine (AA)
8 succinyl CoA ( from TCA cycle )
heme biosynthesis begins and ends in ……
but 3 intermediate reactions occur in ……
mitochondria
cytoplasm
illustrate step of heme synthesis
- in mitochondria :
1. formation of δ ALA (by ala synthase)
need pyridoxal phosphate “coenzyme of vit B6 “ - in cytoplasm :
2. add 2δ ALA to form porphobilinogen
“ PBG” by ALA dehydratase “ PBG synthase “ release 2H2o
( inhibited by lead which replace zinc)
3. condensation of 4 PBG to form first porphyrinogen
4. modification of side chain ( uro - copro -proto ) - in mitochondria:
5. oxidation of the ring ( porphyrinogen to porphyrin )
6. insertion of iron ( by ferro chelatase
( inhibited by lead )
rate limiting enzyme is ……..
ALA synthase
- there is 2 ALA synthase isomers :
ALAS1 in all tissue
ALAS2 in erythroid specific
what’s the importance of heme convert to hemin ( hematin ) ( Fe +2 toFe+3 ) ?
- act as repressor at gene level “ not allosteric “
- inhibit ALAS1 only transcription , dec stability of mRNA , and dec its import into mitochondria
inc activity of ALAS1 only in ……..
( how ?)
-liver ( derepression )
- by substance metabolized by cytochrome P450 ( steroids , barbiturates and insecticides )
in ……… ALAS2 is controlled by availability of intracellular …….
bone marrow
iron
………. increase activity of ALAS2 in erythropoietic tissues due to release of erythropoietin
hypoxia
what’s the nature of lesion :
porphyrias ( the vampire disease )
-rare group of genetic disorders of heme synthesis .
- result in the accumulation and inc excretion of porphyrins or porphyrin precursors
list symptoms of the vampire dissease ( why called that )
- sensitive to sun light that can easily result in burns and abrasions
- they prefer darkness
- they suffer from acute attacks of abdominal pains and vomiting
- their urine purplish red color ( wrongly believe that it results from drinking blood )
- inc hair growth + repeated damage = skin tightens and shrinks
- canine teeth to be more prominent and suggistive of fangs
list types of anemia
- ala synthase 2 deficiency ( X linked sideroblastic anemia “ XLSA”
- B6 deficiency ( ringed sideroblastic )
- lead poisoning ( ringed sideroblastic)
- sideroblasts are atypical nucleated erythrocytes with granules of iron accumulated in perinuclear mitochondria
list enzyme affected in them
- ALA synthase 2 deficiency = ALAS2
- B6 deficiency= ALA synthase
- lead poisoning = ALA dehydrates & ferrochelatase
what happen to iron in them ?
increase in all of them
list cause of each one
- ALA synthase 2 deficiency = ALAS2 deficiency ( hereditary or congenital hypochromic anemia )
- B6 deficiency= isoniazide drug for TB ( inhibit vit B6 )
- lead poisoning = lead paints , batteries
