Heme synethesis and review of hemoglobin

Question 1

Iron deficiency

Answer 1

Iron deficiency is the most common nutrient deficiency in the world (many young women)
Iron is an essential trace element, toxic in excess, after bith dietary iron is the sole source of iron, adult body iron 3-4 grams)
Iron is conserved in the body (recycled with only a few mgs lost daily from the sloughing of intestinal cells or menstrual flow

Question 2

Main organs and cell types involved in the regulation of systemic iron homeostasis

Answer 2

Most of the body iron (1-2 g) is found in hemoglobin (heme) of the RBC

Bone marrow (heme syntheis)

Question 3

Functions of Heme

Answer 3

Heme containing proteins: Oxygen transporters: hemoglobin and myoglobin

Electron transporters: respiratory cytochromes

Oxidation reduction reactions: cytochrom p450 enxymes, catalase, NO synthase

Question 4

Sites of heme synthesis

Answer 4

Bone marrow (erythroblasts/reticulocytes)
accounts for 80% of total heme synthesis, hemoglobin (6-7 g of hemoglobin are synthesized every day to replace heme loss thru cell turnover of RBC

Liver (hepatocytes), accounts for 20% of total heme synthesis–> cytochrome p450 enzymes (drug detox)

heme is also required for other cellular proties nad is synthesized in all cells except mature erythrocytes (no mitochondria)

Question 5

porphyrins

Answer 5

cyclic proteins (tetrapyroles) that chelate to various metals to form essential prosthetic groups for various biological molecules, emit intense red light when excited by light

Heme is a porphyrous derrivative and a single ferrous (Fe2) reduced iron. predominantly planar molecule

Heme- ferroprotoporphyrin 9
heme is the ferrous (Fe2) chelate of protoporphyrin 9

side chains that thant help the binding

Ferroprotoporphoryn 9 (heme) is rapidly autooxidized to ferrIprotoporphoryn 9 : hemIn, and contains ferric (fe3) iron

Question 6

7 major steps of heme biosynthesis

Answer 6

1st and last 3 occur in mitochondria

intermediate steps occur in the cytosol

Question 7

Step 1: heme syntthesis

Answer 7

happens in the mito (inner membrane)
Step 1: ALAS (5 amino levulinate synthase) catalyzes the committed step of heme biosynthesis (glycine + succinyl coA)–> 5 aminolevulinate ALA. Needs pyrodoxyl phosphate as a coenzyme ALAS1 in liver, ALAS2 in erythroid/reticulocyte

ALAS1 (liver form) regulated by hemin feedback inhibition
ALAS2 (erythrid form) not regulated by heme feedback, but entriely dependent on iron availabily and translation in mitochondira via IREs

Question 8

Step 2 heme synthesis

Answer 8

Cytosole
ALA dehydratase (ALAD)
2 ALA –> 1 porphobilinogen (PB) makes a pyrrole ring

needs Zn, but if you get lead poisponing, it will take place of Zn

Question 9

lead poisoning

Answer 9

inhalation, intestine, skin
occupational kids drinking from lead pipes
blocks the socond step–> increased ALA in urin

accumulates in blood, soft tissue and bone, 30 day t.5, neuro issues (similar to GABA)

Give cheltation therapy

Step 2 and the last step

Question 10

Step 3 heme synthesis

Answer 10

Cytosol
Porphobilinogin deaminase (PBGD) takes 4 porphorobilinogens --> linear tetrapyrrole (hydroxymethylbilane) liberates 4 ammoniims

The tetrapyrrole can cyclize spontaneously–> uroporphorynogen 1

Question 11

Step 4

Answer 11

UROD- changes acetate groups to methyl gourps

Question 12

Step 5

Answer 12

CPO makes vinyl side chains in mito

Question 13

Step 6

Answer 13

PPO–> protoporphryn 9

Question 14

Step 7

Answer 14

ferrochelatase adds the iron now youve made heme

inhibited by lead

Question 15

Porphyrias

Answer 15

defects in any of the steps in heme synthesis, enzyme dificeincys

hepatic or erythroid

Autosomal dominant (congenital erythropoietic ecsception)

Question 16

Porphyrias, accumulation of intermediates upstream from the enzyme defect –> clinical symptoms

Answer 16

defects in the early steps–> neuro dysfunction
Defects in later–> sunlight induced cutaneous lesions (accumulation of cyclics, wearwolves)

acute- periodic acute attacs-
chronic derm

Question 17

Panhematin treatment

Answer 17

heme feedback inhibiotn
inhibits ALAS1
reduction of accumulation of ALA and neuro symptoms

Question 18

hemoglobin

Answer 18

tetramer needs heme (ferrous form) met hemoglobin is the ferric form and does not bind oxygen

Myoglobin is hyperbolic
Hemoglobin is simoidal
Cooperativity (low affinity is the T stae, high affinity is the R state)

Question 19

molecules that reduce the ability of Hb hold on to oxygen

Answer 19

23 DPG, CO2, H+

Oxygen is a positive homotropic allosteric effector

Question 20

Thalassemia

Answer 20

cant make part of the adult hemoglobin (a2B2)

B-thalassemia - B0 cant make any B, B+ (low B), apoptosis of just alpha