Heme Flashcards
Heme users
All cells that use oxygen need heme, tissue specific reg and synth, any complete block of heme is death
Loc of heme synth
Most made in RBCs so heme made where RBCs made
Fetal =yolk to liver
Neonate = spleen
Adult = bone marrow
Draw heme synth pathway
Paper
Heme synth step 1
Succinyl CoA and glycine to delta-ALA (x2)
enzyme = delta-ALA synthase
rqrs PLP
Heme synth step 2
2 delta-ALA to porphobilinogen rxn x4 to 4 porphs enz = delta-ALA dehydratase rqrs Zn (plubism can inhib Zn)
Heme synth step 3
4 porphobilinogens to hydroxymethylbilane
Enz = porphobilinogen deaminase
Heme synth step 4
hydroxymethylbilane cyclizes to uroporphyrinogen 3
Enz = Uroporphyrinogen 3 cosynthase
Heme synth step 5
Uroporphyrinogen 3 to Coproporphyrinogen 3
Enz = Uroporphyrinogen decarboxylase
Heme synth step 6
Coproporphyrinogen 3 oxidized to Protoporphyrinogen 9
Enz = coproporphrinogen Oxidase
Heme synth step 7
Protoporphyrinogen 9 oxidized to protoporphyrin 9
Enz= portoporphyrinogen Oxidase
Heme synth step 8
Iron (Fe2) and protoporphyrin 9 combine to heme
Enz = ferrochelatase
Plubism inhibs iron
Heme Synth Reg
Erythropoietic Tissue (BM) - controled by iron availability, makes heme at full capacity
Non-erythro tissue (liver) ALA synthase regulated allosterically by heme (neg feedback) and by hemin/hematin (hemin is heme with iron-3 which inhibs ALA synthase, promotes excretion to porphyrin precursors and heme degrade)
Heme degrade step 1
Degraded to biliverdin, CO and Iron-3
Enz = Heme oxygenase
Rqrs Oxygen and NADPH
In macrophages
Heme degrade step 2
Biliverdin to Bilirubin
Enz = Biliverdin reductase
Rqrs NADPH, also in macro
*Both bili’s are inhib of lipid peroxidation
Heme degrade step 3
Bilirubin to blood (albumin) to liver
conjugates with 2 glucoronates (from UDP-glucouronate from glucose) to bilirubin diglucoronide
Enz =bilirubin glucoronyl transferase
Conjugates bilirubin to bile
Heme degrade step 4
Once with bile it goes to SI where bact convert to urobilinogen
Goes to urine as urobilin (yellow) or stays in gut to oxidize to sterobilin (brown poo)
Porphyrias gen
Usually autodominant (except congenital Eryth Porphyria = AR), most common = Porphyria Cutanea Tarda
Always decreases heme synth
Any step after porphobilinogen is photophobic
Acute Intermittent Porphyria
no photosensitivity
Mutation in porphobilinogen deaminase (hydroxymethylbilane synthase)
Leads to prevention of polymer asembly
Congenital Erythropoietic Porphyria
AR
Mutation in Uroporphyrinogen 3 cosynthase leading to accumulation of hydroxymethylbilane
Phototoxic and photosensitive since hydroxymethybilane is a conjugated molecule which can form radicals
Treatment of Porphyrias
Admin heme/hematin, avoid direct sunlight, Ingest beta carotene (Vit A)
Dubin Johnson Syndrome
Mutations in bilirubin glucoronyl transferase, AR
Black liver and hyperbiliruinemia
Jaundice
Overproduction of bilirubin or hepatic failure
Hemolytic Jaundice
Massive amount of RBC lysis (malaria/sickle) exceeds liver capacities to degrade bilirubin
Neonatal jaundice
decreased bilirubin glucornyl transferase leads to build up of unconj bilirubin and mimics hepatic failure
Treat with UV and Vit B2 (riboflavin)
