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Heme 2 > Hemoglobin formation > Flashcards

Hemoglobin formation Flashcards

1
Q

What are the functions of heme?

A

Transport of oxygen (hemoglobin, myoglobin)
Electron transport (respiratory cytochromes)
Oxidation-reduction reactions (cytochrome P450 enzymes)

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2
Q

What are the sites of heme synthesis?

A

Major sites of synthesis:
bone marrow–> hemoglobin (6-7g hemoglobin are synthesized
each day to replace heme loss through normal turnover of RBC)
** liver** –>cytochrome P450 enzymes (drug detoxificaton)

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3
Q

heme is required for other important cellular
proteins and is synthesized in virtually all cells, except
_________ which lack mitochondria.

A

mature erythrocytes

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4
Q

________are cyclic tetrapyrroles capable of chelating to
various metals to form essential prosthetic groups for
various biological molecules.

A

Porphyrins

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5
Q

_____is predominantly a planar molecule composed of a
porphyrin derrivative + a single ferrous ion (Fe2+ = reduced
form of iron)

A

Heme

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6
Q

Heme consists of a ferrous (Fe2+) chelate of ________ which is rapidly
autooxidized to ______

A

protoporphyrin IX

ferriprotoporphyrin IX

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7
Q

“hemin”; contains ferric Fe3+ iron
The substituent groups provide important
sites for binding of porphyrins to their
respective apoproteins.

A

ferriprotoporphyrin IX

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8
Q

7 major steps in heme synthesis:

1st & last 3 steps
occur in the
______.
Intermediate steps
occur in_____

A

mitochondrion

cytosol

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9
Q

All carbon & nitrogen
atoms of porphyrin
molecules are provided
by

A

succinyl CoA
and glycine.

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10
Q

_______ catalyzes the committed
step of heme biosynthesis: the condensation of glycine
(nonessential amino acid) and succinyl-CoA (intermediate of the
TCA cycle), with decarboxylation, to yield 5-aminolevulinate
(ALA)

A

5-aminolevulinate synthase (ALAS)

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11
Q

5-aminolevulinate synthase (ALAS) catalyzes the committed
step of heme biosynthesis:

the condensation of glycine
and succinyl-CoA with decarboxylation, to yield :

A

5-aminolevulinate

(ALA)

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12
Q

ALAS is localized to the ________ but is encoded by a
nuclear gene family; therefore, the nascent protein must be imported into the
mitochondrion.

A

inner mitochondrial membrane

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13
Q

ALAS is a __________ dependent enzyme. Condensation with
succinyl-CoA takes place while the amino group of glycine is in Schiff base
linkage to the PLP aldehyde. CoA and the glycine carboxyl are lost following
the condensation.

A

pyridoxal phosphate (PLP)

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14
Q
A
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15
Q

There are 2 forms of ALAS:

ALAS1 is in the

ALAS2 is in the

A

1 is liver

2 is reticulocytes

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16
Q

Heme biosynthesis in erythroid cells is _________ by feedback repression of ALAS2 by heme.

A

NOT regulated

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17
Q

How do erythrocytes ensure that heme and globin are synthesize in the correct ratio?

A 
in reticulocytes (immature RBCs), **heme stimulates synthesis** of globin and ensures that heme & globin are synthesized in the correct ratio for
assembly into hemoglobin. (ALAS2 enZ)
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18
Q

Drugs that cause a marked
elevation in ALAS1 activity, such as
_____, do not affect ALAS2

A

phenobarbital

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19
Q

In ALAS1 in liver; Feedback inhibition by_____
or_____ regulates heme biosynthesis in the liver:

A

heme

hemin

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20
Q

Heme (hemin) exerts multiple regulatory effects on hepatic hemebiosynthesis by
inhibiting ALAS1 synthesis at what three levels?

A

both transcriptional and
translational levels, as well
as its mitochondrial import.

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21
Q

~100 different drugs or metabolites can increase
ALAS1 activity… HOW?

A

Many drugs are metabolized
by cytochrome P450s in the
liver; many drugs increase the
synthesis of cytochrome P450
enzymes, thereby increasing
the demand for heme.

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22
Q

_______ is a cytosolic
enzyme catalyzing the condensation of two
molecules of ALA to form one molecule of
porphobilinogen (PBG)à the first pathway
intermediate that includes a pyrrole ring.

A

ALA dehydratase (ALAD)

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23
Q

ALA dehydratase (ALAD) is a cytosolic
enzyme catalyzing the condensation of two
_____ to form one molecule of
_______–> the first pathway
intermediate that includes a pyrrole ring.

A

molecules of ALA

porphobilinogen (PBG)

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24
Q

ALAD The enzyme requires _____ which is
complexed to an active site cysteine.

A

Zn2+

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25
Q
A
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26
Q

Lead and other heavy metals can displace
the Zn2+ and eliminate catalytic activity.
Thus, lead poisoning (increase ALA in urine)
can lead to :

A

clinical manifestations that mimic
acute porphyrias

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27
Q

Inhibition of ALA dehydratase (aka, porphobilinogen synthase) by
lead (Pb2+) results in __________, as impaired heme
synthesis leads to _______of transcription of the ALAS gene.

A

elevated blood ALA

de-repression

28
Q

High_____ is thought to cause some of the neurological effects of
lead poisoning, although Pb2+ may directly affect the nervous
system.

A

ALA

29
Q

ALA is toxic to the brain, perhaps due to:

A 
• Similar ALA & neurotransmitter GABA
(γ-aminobutyric acid) structures.
• ALA autoxidation generates reactive
oxygen species (ROS).
30
Q

________ catalyzes the head-to-tail condensation of 4 porphobilinogen molecules to form a linear________ (hydroxymethylbilane). Each condensation results in the liberation of one ammonium ion.

A

Porphobilinogen deaminase (PBGD)

tetrapyrrole

31
Q

The tetrapyrrole can spontaneously cyclize to form
uroporphyrinogen I (nonenzymatic) which contains a symmetric
arrangement of side chains and IS NOT in the normal pathway for
heme biosynthesis. However, PBGD is tightly associated with a
second enzyme ________

A

uroporphyrinogen III cosynthase (UROS)

32
Q

______has no enzymatic activity alone but serves to direct the
stereochemistry of the condensation reaction to yield the
uroporphyrinogen III isomer which IS on the pathway for heme
biosynthesis

A

UROS

33
Q

__________ catalyzes the decarboxylation of acetate side chains to methyl groups on uroporphyrinogens III to yield the respective coprophorphyrinogen III products

A

Uroporphyrinogen decarboxylase (UROD)

34
Q

Uroporphyrinogen decarboxylase (UROD) catalyzes the decarboxylation of acetate side chains to methyl groups on uroporphyrinogens III to yield the respective

A

coprophorphyrinogen III products

35
Q

Coproporphyrinogen III is transported into the intermembrane space where it is converted to protoporphyrinogen IX by

A

coproporphyrinogen III oxidase (CPO)

36
Q

CPO is located __________ of the mitochondrion,
implying that its product or protoporphyrin IX must cross the inner mitochondrial membrane because heme is formed within
the inner membrane.

A

in the intermembrane space

37
Q

Another mitochondiral oxidase,
_________
converts protoporphyrinogen IX to
protoporphyrin IX.

A

protoporphyrinogen IX oxidase (PPO)

38
Q

converts protoporphyrinogen IX to
protoporphyrin IX

A

protoporphyrinogen IX oxidase (PPO)

39
Q

Insertion of Fe2+ into _________ to generate HEME occurs spontaneously but at a slow rate. This rate is enhanced by_______.

A

protoporphyrin IX

ferrochelatase

40
Q

This enzyme is inhibited by lead (lead poisoning; increase protoporphyrin in urine) and is alsoinhibited during iron deficiency (anemia).

A

ferrochelatase.

41
Q

In the absence of Fe2+, ferrochetalase can insert Zn2+ into the protoporphyrin ring to yield

A

a brilliantly fluorescent complex

42
Q

=
defect in
heme
biosynthesis

A

Porphyrias

43
Q

Porphyrias are a group of inherited genetic or acquired (disorders resulting from deficiency in specific enzymes of the porphyrin/heme biosynthetic pathway.

Which is more common, inherited or acquired?

A

Inherited, rarely acquired

44
Q

How are porphyrias classified?

A

Porphyrias are classified as either hepatic or erythroid,
reflecting the principal sites of heme biosynthesis and depending on the site of expression of the enzyme defect (different isoforms).

45
Q

All porphyrias, with the exception of ________ which is autosomal recessive, are inherited as_______

A

congenital erythropoietic porphyria

autosomal dominant disorders.

46
Q

Porphyrias are rare or common?

Affect how many in US?

A

Rare

200,000

47
Q

most common porphyria, ________, is 1 in 10,000

the most common acute porphyria, ________, is about 1 in 20,000

most common erythropoietic porphyria,
_________, is estimated at 1 in 50,000 to 75,000.

A

porphyria cutanea tarda (PCT)

acute intermittent porphyria (AlP)

erythropoietic protoporphyria (EPP)

48
Q

___is the most common porphyria in
childhood, and the one associated with the longest delays in diagnosis.

A

EPP

49
Q

________ is extremely rare with prevalence estimates of 1 in 1,000,000 or less.

A

Congenital erythropoietic porphyria (CEP)

50
Q

Accumulation of intermediates_______ from the enzyme defect (measure in urine, blood, feces) results in the clinical symptoms associated with thevarious porphyrias

A

upstream

51
Q

Defects_____ in the biosynthetic pathway (accumulation of ALA,
prophobilinogen) result in neurologic dysfunction.

A

early

52
Q

Accumulaiton of _______are seen in early defects to porphyrin path

A

ALA, prophobilinogen

53
Q

Defects _____in the pathway (accumulation of cyclic tetrapyrroles, but not prophobilinogen) result in sunlight-induced cutaneous lesions: in the presence of molecular oxygen, UV irradiation of cyclic tetrapyrroles generates reactive oxygen species that can produce cellular damage

A

later

54
Q

Porphyia can be acute or chornic, in acute: Periodic acute attacks; symptoms include

A

abdominal pain,
neurologic deficits, psychiatric symptoms, and reddish-colored urine.

55
Q

4 examples of acute porphyria

A

Doss porphyria (ALA dehydratase deficiency)
Acute intermittent porphyria
Hereditary coproporyphyria
Variegate porphyria

56
Q

New recognized causes of acute porphyria attacks:

A 
Nutritional changes (e.g., hypoglycemia) , smoking, certain drugs (such as barbiturates and sulfonamide antibiotics)
and steroid hormones, especially progesterone

Some women develop attacksduring the second half of the menstrual cycle, when progesterone levels are high

57
Q

3 chronic porphyria diseases

A

Congenital erythropoietic porphyria (Guntherʼsdisease)
Erythropoietic porphyria/protoporphyria
Porphyria cutanea tarda

58
Q

Dermatologic diseases that may or may not include the liver and nervous system.

A

Chronic porphyria

59
Q

Congenital erythropoietic porphyria (Guntherʼs
disease)
Erythropoietic porphyria/protoporphyria
Porphyria cutanea tarda

A

chronic porphyrias

60
Q

1st Example that Porphyria Syndromes can be Acquired

A

Acquired Porphyria Cutanea Tarda (PCT)

61
Q

how did people get the aquired porphyria cutanea tarda?

A

ate wheat that was covered in fungicide HCB

62
Q

____ and ____ are very sensitive to inhibtion by Lead

A

Ferrochelatase adn ALA dehydratase

63
Q

In lead poisoning ____ and ____ accumulate in urine

A

Protoporphyin and ALA

64
Q

is relatively rare except in South Africa where it is estimated that the incidence is 3/1,000.
~10,000 persons areaffected, all descended
from a single Dutchsettler who immigratedin 1680.

A

Variegate porphyria

65
Q

Acute disease caused by deficieny in protoporphyrinogen oxidase resulting in protoporphyrinogen IX and other intermerdiates priro to block to accumulate in urine

Pts are photosensitive

A

Varigate Porphyria

66
Q
A

Heme 2 (14 decks)

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