09 Hemoglobin and heme synthesis

Question 0

Heme composition and official name

Answer 0

Ferroprotopophyrin 9
4 crosslinked pyrrole molecules coordinated with Ferrous(2+) iron

Oxidized to Ferriprotoporphyrin 9 (Fe3+)

Question 1

Heme synthesis location

Answer 1

Mitochondria of almost all cells (RBCs have no mito)

6-7 grams synthesized per day to compensate for RBC turnover

Question 2

Locations of heme synthesis within the cell

Answer 2

1st step and last 3 steps occur in mitochondria, remaining 3 steps occur in cytosol

Question 3

ALAS

Answer 3

STEP 1

• 5-aminolevulinate synthase- COMITTED STEP
• Nuclear enzyme transported to inner mito membrane
• PLP dependent

Glycine +Succ-CoA = ALA

ALAS1=Liver(regulated expression[positive feedback from some drugs])
ALAS2=Erythroid (no regulation or feedback)

Question 4

ALAD

Answer 4

STEP 2

• ALA Dehydratase cause condensation of ALA to Porphobilinogen (pyrrole ring)
• Zn dependant (can be poisioned by lead)

Question 5

Lead poisioning

Answer 5

Poisons ALAD, and Ferrochelase
Buildup of ALA (similar to GABA)- causes neurotoxic affects
ALA synthase decreased
ALA auto-oxidation causes ROS

FE2+ cant be added to iron

Question 6

PBGD

Answer 6

STEP 3
Porphobillinogen deaminase- cytosolic Terrtrramerizes Porphobillinogen to form Hydroxymethylbilane

COUPLED WITH UROS
urporphyrinogen 3 cosynthase directs correct cyclization

Question 7

UROD

Answer 7

STEP 4
Uropophrynogen decarboxylase in cytosol replaces carboxyl groups with methyl groups and creates

Coproporphrynogen 3

Question 8

CPO

Answer 8

Coporphrynogen III oxidase in the inter-membrane space removes proprionic acid and replaces with vinyl groups to create PROTOPORPHYRINOGEN 9

Question 9

PPO

Answer 9

STEP 6

Mitochondrrial (protoporphrynogen 9 oxidase) moves double bonds to create PROTOPORPHYRN 9

Question 10

Ferrochelatase

Answer 10

STEP 7- Adds FE2+ into Protoporphyrin 9

CAN BE POISIONED BY LEAD

Question 11

OVERVIEW of heme synthesis steps

Answer 11

1) M: ALAs, SuccCoA+Glycine=ALA(PLP dependent)
2) C: ALAD, ALA+ALA=Porphopillinogen (Zn dependant [Pb poison])
3) C: PBGD + UROS, 4(PBG) = Hydroxymethylbilan -> Uroporphyrinogen 3
4) C: UROD, -4(COOH) + 4(CH3) = Coporphrynogen III
5) M: CPO, coporphrynogen III -4(propri) + 4(vinyl)= Protoporphyrinogen 9
6) M: PPO, Protoporphyrinogen 9 –> Protoporphyrin 9
7) M: Ferrochelase - +FE2+

Question 12

Porphyria

Answer 12

Hepatic vs erythroid problems with heme synthesis

Early–> Neurologic dysfunction 2/2 buildup of ALA

Late–> Light sensitivity- tetrapyrroles like Hydroxymethylbilane and Uroporphyrinogen create ROS when exposed to light

Question 13

Acute porphyrias

Answer 13

Doss porphyria (ALA dehydratase D)
Acute intermittent
Hereditary Coproporyphyria
Variegate porphyria

Question 14

Chronic Porphyria

Answer 14

Congenital erythropoietic porphyria
Protoporphyria/Erythropoietic porphyria
Porphyria cutanea tarda

Question 15

Carbonic anhydrase

Answer 15

CO2+H2O + H2CO3 –> HCO3- + H+

Question 16

MetHB

Answer 16

Methylated hemoglobin with Ferric iron (3+) that does not bind O2

Question 17

Myoglobin vs. Hemoglobin

Answer 17

Myoglobin: Monomer with a hyperbolic binding curve (holds O2 tighter)
Hemoglobin: Sigmoidal curve shifted to the right with ^ Temp, [CO2], [2,3BPG], [H+] (bohr effect)

Question 18

Relaxed vs. Tense

Answer 18

Tense form is low oxygen- less affinity

Relaxed state- is high affinity- Histidine is in line with FE

Question 19

2,3 BPG

Answer 19

Pretty much responsible for the sigmoidal curve of hemoglobin
stabalizes tense state

Question 20

Hemoglobin forms

Answer 20

95%HbA- (alpha2, Beta2)
3% HbA2- (alpha2,delta2)
3% HbF (alpha2, Gamma2)

Question 21

Sickle Cell disease

Answer 21

Beta E6V (glutamic acid substituted with nonpolar Valine) causes polymerization

Polymerization favored by: Deoxygenation, ^ Intracellular [Hb], low [HbF]