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Biochem > Lecture6-HEME BIOSYNTHESIS&DEGRADATION > Flashcards

Lecture6-HEME BIOSYNTHESIS&DEGRADATION Flashcards

1
Q

how much iron does a healthy adult male body contain?

A

3/4 grams

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2
Q

How is the iron balance maintained ?

A

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

1 mg is excreted

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3
Q

what are the ways that iron is excretion

A

urinary loss
desquamation of skin
desquamation of intestinal track
bile

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4
Q

What inhibiting uptakes of iron

A

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

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5
Q

What promotes uptake of iron

A

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

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6
Q

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

A

iron porphyrin complexes, hemoglobin, myoglobin and heme containing enzymes

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7
Q

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

A

heme, fe, cofactor

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8
Q

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

A

stored as ferritin and hemosiderin —>relative non-reactive

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9
Q

What are functional compounds of iron?

A

Hemoglobin
myoglobin
heme enzymes
non heme enzymes

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10
Q

what are storage complexes of iron?

A

ferritin
hemosiderin

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11
Q

what is ferritin

A

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

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12
Q

what is on the inside of ferritin

A

iron oxide hydroxide complex (that stores iron)

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13
Q

Where is ferritin found?

A

liver and kidney

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14
Q

how many polypeptides chains are in ferritin ?

A

24

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15
Q

Explain the dietary iron uptake (Not done)

A

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

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16
Q

1 molecule of transferrin can hold how many molecules of iron

A

2 (1 for each subunit of transferrrin)

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17
Q

True or false, all cells except erythrocytes have transferrin receptor

A

True this is because erythrocytes acquire iron through diet.

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18
Q

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

A

transferrine

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19
Q

Explain the binding and release of trasnferrrin

A
  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.
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20
Q

What is Apo-TF?

A

transferrin without iron

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21
Q

What does DMT1 do?

A

transports iron across membranes

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22
Q

In an acidifies endosome what occurs?

A

iron is releases and everything is recycled

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23
Q

What is the driving force for the movement of iron?

A

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

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24
Q

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

A

True

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25
Q

What is Hemochromatosis?

A

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

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26
Q

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

A

True

27
Q

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

A

True

28
Q

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

A

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

29
Q

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

A

bone marrow and liver

30
Q

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

A
  1. Formation of pyrrole
  2. assembly of tetrapyrrole
  3. modification of side chains
  4. oxidation and insertion of ferrous iron (Fe2+)
31
Q

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

A

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

32
Q

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

A

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

33
Q

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

A

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

34
Q

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

A

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

35
Q

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

A

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

36
Q

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

A

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

37
Q

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

A

Uro III to Copro’gen III
enzyme: uroporphyinogen III decarboxylase

The A side chains are decarboxylated and methyl groups take over

38
Q

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

A

Copro’gen III to Proto’gen IX
enzyme: coproporphyrinogen III oxidase

Vinyl groups take over the “p” side chains

39
Q

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

A

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

40
Q

What are the two isozymes of ALAS?

A

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

erythroid-specific gene—erythroid isozyme: ALAS2

41
Q

ALAS2 can be regulated at

don’t need to know specifics

A

transcriptional
translational
mitochondrial import
activity

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

42
Q

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

A

True

43
Q

What is Porphyrias?

A

mutations in DNA that lead to abnormalities of heme synthesis enzymes

44
Q

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

A

Accumulation of ALA of PGB: causes neuropsychiatric symptoms

Accumulation of porphyrinogens in skin in tissues: light sensitivity

45
Q

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

A

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

46
Q

What is the function of heme degradation?

A

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

47
Q

What is the first step of heme degradation?

A

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

48
Q

Is bilirubin soluble or insoluble

A

insoluble

49
Q

Because biliurubin is insoluble what occurs?

A

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

50
Q

How does bilirubin get conjuagted in the liver?

A
51
Q

What is hyperbilirubenemia and its physical characteristic?

A

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

52
Q

What is Gilbert’s syndrome?

A

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

53
Q

What is Crigler-Najjar Syndrome?

A

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.

54
Q

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

A

transferrin, transferrin receptor and ferritin.

55
Q

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

A

the bone marrow and liver.

56
Q

Heme biosynthesis occurs in

A

mitochondria and cytosol.

57
Q

In mammals, the heme biosynthetic pathway comprises eight enzymes;

A

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

58
Q

Intermediates of the heme biosynthetic pathway reactions include:

A

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

59
Q

_______catalyzes the rate-limiting step of heme biosynthesis.

A

5-Aminolevulinate synthase (ALAS)

60
Q

______ 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.

A

Porphyrias

61
Q

Heme molecule contains

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

A

d

62
Q

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

A

d

63
Q

All of the following are products of the reaction involving heme and heme oxygenase
EXCEPT:

A. Biliverdin
B. Bilirubin
C. Fe3+
D. CO

A

b

Biochem (17 decks)

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