Lecture6-HEME BIOSYNTHESIS&DEGRADATION

Question 1

how much iron does a healthy adult male body contain?

Answer 1

3/4 grams

Question 2

How is the iron balance maintained ?

Answer 2

1 mg of iron is taken up from eating about 12-16mg per day

1 mg is excreted

Question 3

what are the ways that iron is excretion

Answer 3

urinary loss
desquamation of skin
desquamation of intestinal track
bile

Question 4

What inhibiting uptakes of iron

Answer 4

presence of phosphates, tennis and oxalates that forms insoluble complexes with Fe3+

Question 5

What promotes uptake of iron

Answer 5

Presence of fructose, ascorbate and citrates tend to form soluble complexes

Question 6

where is the major portion of iron? (70%)

Answer 6

iron porphyrin complexes, hemoglobin, myoglobin and heme containing enzymes

Question 7

There are many non-___ enzymes which either contain __ or require it as a _____

Answer 7

heme, fe, cofactor

Question 8

After the major portion of iron is used, where is the remaining iron in the body?

Answer 8

stored as ferritin and hemosiderin —>relative non-reactive

Question 9

What are functional compounds of iron?

Answer 9

Hemoglobin
myoglobin
heme enzymes
non heme enzymes

Question 10

what are storage complexes of iron?

Answer 10

ferritin
hemosiderin

Question 11

what is ferritin

Answer 11

efficient iron-storage protein found primarily in the liver and kidney

Question 12

what is on the inside of ferritin

Answer 12

iron oxide hydroxide complex (that stores iron)

Question 13

Where is ferritin found?

Answer 13

liver and kidney

Question 14

how many polypeptides chains are in ferritin ?

Answer 14

24

Question 15

Explain the dietary iron uptake (Not done)

Answer 15

Iron transport across the cells lining the gut (enterocytes)

Ferric iron (3+) is reduced and transported across the apical surface by DMT1

Once inside call iron can either be stored in ferritin or transported across the basolateral membrane by ferroportin1

Once iron is exported from Ferroportin into the blood,iron needs to be in oxidzed ferric state and it can be transported by transferrin

Question 16

1 molecule of transferrin can hold how many molecules of iron

Answer 16

2 (1 for each subunit of transferrrin)

Question 17

True or false, all cells except erythrocytes have transferrin receptor

Answer 17

True this is because erythrocytes acquire iron through diet.

Question 18

Which molecule is responsible for making sure that every cell gets iron?

Answer 18

transferrine

Question 19

Explain the binding and release of trasnferrrin

Answer 19

1. Specific binding of diferric transferrin to the transferrin receptor
   Results in the formation of an endocytic vesicle
2. The vesicle becomes protonated and in this acidic environment
   iron is detached from transferrin
3. The apotransferrin released has a high affinity for the transferrin receptor at the acidic pH within the endocytic vesicle and thus escapes digestion
4. The vesicle is then externalized . On exposure to physiological pH (7), the apotransferrin loses its affinity for the transferrin receptor and is released into the plasma.

Question 20

What is Apo-TF?

Answer 20

transferrin without iron

Question 21

What does DMT1 do?

Answer 21

transports iron across membranes

Question 22

In an acidifies endosome what occurs?

Answer 22

iron is releases and everything is recycled

Question 23

What is the driving force for the movement of iron?

Answer 23

Erythroid marrow (bone marrrow) because its the major site of the of the production of heme, which is needed to make hemoglobin

Question 24

True or False, most of iron in our body is recycled

Answer 24

True

Question 25

What is Hemochromatosis?

Answer 25

is a condition in which the body takes up and stores more iron than it needs. Excess iron in bodily tissues such as the liver, heart, pancreas, even the joints

Question 26

True or false Most of the body’s iron is recruited for synthesis of heme towards hemoglobin production

Answer 26

True

Question 27

True or false About 70 percent of the body's iron is found in red blood cells (RBCs).

Answer 27

True

Question 28

What is the structure of heme and is it a stable or unstable compound?

Answer 28

planar molecule, with 1 Fe2+ and a tetrapyrrole ring, protoporphyrin IX. Heme is a very stable compound due to its resonance features.

Question 29

Although heme is produced in virtually all mammalian tissues, most of heme biosynthesis occurs in the _____ and _______

Answer 29

bone marrow and liver

Question 30

What is the general (major) overview of heme biosynthesis?

Answer 30

1. Formation of pyrrole 2. assembly of tetrapyrrole 3. modification of side chains 4. oxidation and insertion of ferrous iron (Fe2+)

Question 31

The heme biosynthesis pathway occurs in two different compartments what are they and which steps occur in these compartments?

Answer 31

Cytosol: Intermediate 4 steps Mitochondira: 1st step and last 3 steps

Question 32

What is the first step of heme biosynthesis? Need to know enzyme

Answer 32

RATE LIMITING STEP Succinyl CoA(from TCA) + Glycine----- ALA (enzyme: ALAS with co-factor PLP)

Question 33

What co-factor is needed for step 1 of hemebiosynthesis to occur?

Answer 33

PLP because it s cofactor for ALAS, without it rxn can't occur.

Question 34

What is the second step of heme biosynthesis? (Gloria said we don't need to know enzyme, but can know)

Answer 34

2ALA to PBG enzyme: pophobilinogen synthase Here there is 8 ALA because you need two ALA to make 1 pyrrole ring, and we need to make 4 (tetrapyrrole) so we need 8 ACA total

Question 35

What is the 3rd step of heme biosynthesis? (Gloria said we don't need to know enzyme, but can know)

Answer 35

4PBG to HMB(HMB is lenar tetrapyrrole) enzyme: pophobilinogen deaminase Here we are putting the rings in a line, so we make a linear tetrapyrrole

Question 36

What is the 4rd step of heme biosynthesis? (Gloria did not mention if we need to know enzyme)

Answer 36

HMB to Uro III enzyme: uroporphyinogen III synthase The enzyme is cyclizing the linear tetrapyrrole. So it's put into a circle but it flips, so you have 2Ps and 2As next to each other. If they did not flip, diseases can occur

Question 37

What is the 5th step of heme biosynthesis? (Gloria did not mention if we need to know enzyme)

Answer 37

Uro III to Copro'gen III enzyme: uroporphyinogen III decarboxylase The A side chains are decarboxylated and methyl groups take over

Question 38

What is the 6th step of heme biosynthesis? (Gloria did not mention if we need to know enzyme)

Answer 38

Copro'gen III to Proto'gen IX enzyme: coproporphyrinogen III oxidase Vinyl groups take over the "p" side chains

Question 39

What is the 7 and 8th step of heme biosynthesis? (Gloria said we need to know enzyme from PPIX to heme)

Answer 39

Proto'gen III to PPIX to Heme enzyme: Proto to PPIX- protoporphyrinogen IX oxidase PPIX to Heme: ferrochelatase Step 7: here double bonds change positions for resonance and Step8: iron is added to heme

Question 40

What are the two isozymes of ALAS?

Answer 40

House-keeping gene---house keeping isozyme: ALAS1 (this is present in every single cell including erthyoid cells) erythroid-specific gene---erythroid isozyme: ALAS2

Question 41

ALAS2 can be regulated at don't need to know specifics

Answer 41

transcriptional translational mitochondrial import activity Specifics: Excess heme: inhibits transcription, mitochondrial import and activity less iron: inhibits translation

Question 42

True or false: The regulatory mechanisms of ALAS1 and ALAS2 are different but they are similar in the sense that they are always at multiple levels ranging from transcription all the way to proteins

Answer 42

True

Question 43

What is Porphyrias?

Answer 43

mutations in DNA that lead to abnormalities of heme synthesis enzymes

Question 44

These abormalaties can lead to accumulation of what two things? and what symptom do they cause?

Answer 44

Accumulation of ALA of PGB: causes neuropsychiatric symptoms Accumulation of porphyrinogens in skin in tissues: light sensitivity

Question 45

Why does accumulation of porphyrinogens in skin in tissues cause light sensitivity?

Answer 45

Because of spontaneous oxidation of porphyringoens to porphyrins so we are exciting resonance forms, ROS is performed, this leads to cell death, and blisters form on hands

Question 46

What is the function of heme degradation?

Answer 46

Every 120 days we degrade heme so that iron can be recycled and BILIRUBIN is excreted

Question 47

What is the first step of heme degradation?

Answer 47

Heme to Biliverdin (also CO, Fe3+, H2O) enzyme: heme oxygenase and we also need O2 and NADPH Biloverdin to Bilirubin enzyme: biliverdin reductase and we need NADPH

Question 48

Is bilirubin soluble or insoluble

Answer 48

insoluble

Question 49

Because biliurubin is insoluble what occurs?

Answer 49

it can't get to the liver so it binds to albumin and carries it to the liver (hepatocytes) and then it becomes conjugated in the liver

Question 50

How does bilirubin get conjuagted in the liver?

Question 51

What is hyperbilirubenemia and its physical characteristic?

Answer 51

a serum (bilirubin) more than 4 mg/dl Physical characteristic: jaundice (yellowing of eyes/skin)

Question 52

What is Gilbert's syndrome?

Answer 52

Mild-chronic unconjugated bilirubin. Deficient enzyme: UDP-glucuronyl transferase (remains insoluble, built up in system, yellow color in skin) TX: none b/c harmless

Question 53

What is Crigler-Najjar Syndrome?

Answer 53

Type 1:(very severe): serum (bilirubin)>20mg/dl absence of UDP-glucuronyl transferase Type 2: serum (bilirubin)< 20mg/dl decr efficiency of UDP-glucuronyl transferase.

Question 54

The transport and storage of iron is carried out by three proteins:

Answer 54

transferrin, transferrin receptor and ferritin.

Question 55

Heme is synthesized in most cells of the body, but predominantly in the

Answer 55

the bone marrow and liver.

Question 56

Heme biosynthesis occurs in

Answer 56

mitochondria and cytosol.

Question 57

In mammals, the heme biosynthetic pathway comprises eight enzymes;

Answer 57

glycine and succinyl-CoA are the substrates of the first enzyme of the pathway (5-aminolevulinate synthase). 8 Succinyl-CoA + 8 Gly + Fe2+ → Heme

Question 58

Intermediates of the heme biosynthetic pathway reactions include:

Answer 58

5-aminolevulinate; porphobilinogen; hydroxymethylbilane; uroporphyrinogen III; coproporphyrinogen III; protoporphyrinogen IX; protoporphyrin IX.

Question 59

_______catalyzes the rate-limiting step of heme biosynthesis.

Answer 59

5-Aminolevulinate synthase (ALAS)

Question 60

______ are a group of disorders associated with mutations in the genes encoding the enzymes of the heme biosynthetic pathway. With exception of the gain-of-function mutations in ALAS2, the mutations associated with the other seven enzymes heme biosynthetic pathway are all loss-of-function and thus cause decreased enzymatic activities.

Answer 60

Porphyrias

Question 61

Heme molecule contains A. One pyrrole ring B. Two pyrrole rings C. Three pyrrole rings D. Four pyrrole rings E. Five pyrrole rings

Answer 61

d

Question 62

In jaundice that accompanies neonatal isoimmune hemolysis the metabolite most likely to be elevated in serum is: A. β-glucuronidase B. Bilirubin diglucuronide C. Biliverdin D. Unconjugated bilirubin E. Urobilinogen

Answer 62

d

Question 63

All of the following are products of the reaction involving heme and heme oxygenase EXCEPT: A. Biliverdin B. Bilirubin C. Fe3+ D. CO

Answer 63

b