Hemoglobin formation Flashcards by Meghan May

What are the functions of heme?

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

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What are the sites of heme synthesis?

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

mature erythrocytes

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

Porphyrins

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

Heme

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

protoporphyrin IX

ferriprotoporphyrin IX

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

ferriprotoporphyrin IX

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7 major steps in heme synthesis:

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

mitochondrion

cytosol

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All carbon & nitrogen
atoms of porphyrin
molecules are provided
by

succinyl CoA
and glycine.

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_______ 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)

5-aminolevulinate synthase (ALAS)

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

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

5-aminolevulinate

(ALA)

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

inner mitochondrial membrane

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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.

pyridoxal phosphate (PLP)

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There are 2 forms of ALAS:

ALAS1 is in the

ALAS2 is in the

1 is liver

2 is reticulocytes

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

NOT regulated

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

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

phenobarbital

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

heme

hemin

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

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

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

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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_______ 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.

ALA dehydratase (ALAD)

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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.

molecules of ALA

porphobilinogen (PBG)

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

Zn2+

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

clinical manifestations that mimic acute porphyrias

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

elevated blood ALA de-repression

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

ALA

ALA is toxic to the brain, perhaps due to:

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

\_\_\_\_\_\_\_\_ 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.

Porphobilinogen deaminase (PBGD) tetrapyrrole

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 \_\_\_\_\_\_\_\_

uroporphyrinogen III cosynthase (UROS)

\_\_\_\_\_\_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 f**or heme biosynthesis**

UROS

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

Uroporphyrinogen decarboxylase (UROD)

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

coprophorphyrinogen III products

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

coproporphyrinogen III oxidase (CPO)

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.

in the intermembrane space

Another mitochondiral oxidase, \_\_\_\_\_\_\_\_\_ converts protoporphyrinogen IX to protoporphyrin IX.

protoporphyrinogen IX oxidase (PPO)

converts protoporphyrinogen IX to protoporphyrin IX

protoporphyrinogen IX oxidase (PPO)

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

protoporphyrin IX ferrochelatase

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

ferrochelatase.

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

a brilliantly fluorescent complex

= defect in heme biosynthesis

Porphyrias

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?

Inherited, rarely acquired

How are porphyrias classified?

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).

All porphyrias, with the exception of ________ which is autosomal recessive, are inherited as\_\_\_\_\_\_\_

congenital erythropoietic porphyria autosomal dominant disorders.

Porphyrias are rare or common? Affect how many in US?

Rare 200,000

**most common** porphyria, \_\_\_\_\_\_\_\_, is 1 in 10,000 the m**ost common acute porphyria**, \_\_\_\_\_\_\_\_, is about 1 in 20,000 **most common erythropoietic porphyria**, \_\_\_\_\_\_\_\_\_, is estimated at 1 in 50,000 to 75,000.

porphyria cutanea tarda (PCT) acute intermittent porphyria (AlP) erythropoietic protoporphyria (EPP)

\_\_\_is the most common porphyria in childhood, and the one associated with the longest delays in diagnosis.

EPP

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

Congenital erythropoietic porphyria (CEP)

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

upstream

Defects\_\_\_\_\_ in the biosynthetic pathway (accumulation of ALA, prophobilinogen) result in neurologic dysfunction.

early

Accumulaiton of \_\_\_\_\_\_\_are seen in early defects to porphyrin path

ALA, prophobilinogen

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

later

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

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

4 examples of acute porphyria

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

New recognized causes of acute porphyria attacks:

``` 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

3 chronic porphyria diseases

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

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

Chronic porphyria

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

chronic porphyrias

1st Example that Porphyria Syndromes can be Acquired

Acquired Porphyria Cutanea Tarda (PCT)

how did people get the aquired porphyria cutanea tarda?

ate wheat that was covered in fungicide HCB

\_\_\_\_ and ____ are very sensitive to inhibtion by Lead

Ferrochelatase adn ALA dehydratase

In lead poisoning ____ and ____ accumulate in urine

Protoporphyin and ALA

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.

Variegate porphyria

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

Varigate Porphyria